11th COGNITIVE DAY Proceedings 12th MAY 2023, LJUBLJANA, SLOVENIA 11th COGNITIVE DAY Proceedings Published by: Centre for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana Edited by: Milica Gregorič Kramberger Proceedings was published at 11th Cognitive Day meeting on 12th May 2023. Cognitive Day is an annual scientific meeting with international participation organized by Centre for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana. Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani COBISS.SI-ID 152977155 ISBN 978-961-7080-06-3 (PDF) Contents 22 Cognitive impairment in patients with cerebrovascular disease: A white paper from the links between stroke ESO Dementia Committee 4 List of authors/ lecturers Ana VERDELHO, MD, PhD 5 Preface 29 Cerebrovascular disease in patients with 6 Program cognitive impairment: A white paper from the ESO dementia committee – A practical point of view with suggestions 7 The clinical assessment of prodromal for the management of cerebrovascular cognitive decline: the need for new tools? diseases in memory clinics Stefano F. CAPPA, MD, PhD Ana VERDELHO, MD, PhD 9 Designing the next-generation clinical care pathway for Alzheimer’s disease 34 Cognition in Multiple Sclerosis: Evaluation, Stefano F. CAPPA, MD, PhD Treatment, and Brain Networks Tom FUCHS, MD, PhD 15 Patient/site readiness for a potential new Alzheimer’s disease treatment paradigm 36 Statins in patients with Alzheimer's Eva ZUPANIČ, MD, PhD dementia – a friend or a foe? Milica Gregorič Kramberger, MD, PhD Bojana PETEK, MD 17 Functional brain networks in 39 Association of blood pressure variability neurodegenerative disorders with delirium in critically ill Tomaž Rus, MD, PhD Nika ZORKO GARBAJS, MD List of authors/ lecturers Stefano F. CAPPA, MD, PhD Professor of Neurology Head of Dementia Research Center IRCCS Mondino Foundation Director, IUSS Cognitive Neuroscience (ICoN) Center University School for Advanced Studies (IUSS-Pavia) Piazza della Vittoria 15, 27100 Pavia, Italy Eva ZUPANIČ, MD, PhD Consultant in neurology Neurology Clinic, University Medical Center, Ana Verdelho, MD, PhD Ljubljana, Slovenia Invited Professor of Neurology Department of Neurosciences University of Lisbon Tomaž RUS, MD, PhD Hospital de Santa Maria Consultant in neurology Av. Prof. Egas Moniz Neurology Clinic, University Medical Center, Lisbon Ljubljana, Slovenia Nika ZORKO GARBAJS, MD Maria ERIKSDOTTER, MD, PhD Consultant in neurology Dean Karolinska Institutet South Department of Vascular Neurology and Intensive Therapy, Professor, senior consultant in geriatrics University Medical Centre Ljubljana, Slovenia. Director SveDem Dept of Neurobiology, Care Sciences and Society Karolinska Institutet Bojana PETEK, MD Theme Inflammation and Aging, Clinical Institute of Genomic Medicine, University Medical Centre Karolinska university hospital, Huddinge, Sweden Ljubljana, Slovenia Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Eric WESTMAN, MD, PhD Society, Karolinska Institutet, Stockholm, Sweden Professor Head of Division and Acting/Vice Head of Department Karolinska Institutet Tom A. FUCHS, MD, PhD Department of Neurobiology, Care Sciences and Society (NVS) Research Associate, Anatomy and neurosciences Division of Clinical Geriatrics Amsterdam University Medical Center Neo floor 7 | SE 141 83 Huddinge Netherlands Preface Milica G. KRAMBERGER, MD, PhD Dear fellow colleagues, The Cognitive Day international meetings bring a significant contribution to a process of continuous education and to further it is with great pleasure that I present to you a selection of scientific improvement of clinical management of patients with cognitive articles and abstracts for the 11th Cognitive Day international impairments. A great pleasure for us is also the fact that we have meeting. longstanding support and the opportunity to host a number of internationally renowned experts from various fields (psychiatry, In the recent two years the scientific and general society are facing an geriatrics, neurology, psychology, neuroradiology) from several extremely important time with first emergance of positive results on countries. disease modifying treatment trials for Alzheimer’s disease (AD). AD is a neurodegenerative disease, and the aetiology behind 50-70% of all The primary purpose of this gathering is to provide an active cases of dementia. Due to an ageing population, dementia education to all those involved in the management of patients with prevalence is expected to nearly double over the coming three neurodegenerative diseases and to strengthen activities pursued by a decades, bringing enormous challenges for health and social care multi-disciplinary team targeting at patients with cognitive and systems. There is rapid development in the diagnosis and treatment movement impairments. By conducting expert gatherings and with of AD and other neurodegenerative disorders, across plasma-based this anthology we would like to inform the readers about the latest biomarkers , pharmacological treatments and non-pharmacological findings in the discussed topics. prevention strategies. New strategies for earlier and more accurate detection and diagnosis are emerging. The contents of this anthology which is also deemed higher education study material, should be an interesting read and helpful Patients seen in routine care with a suspected cognitive disorder to both medical students as well as trainee specialists and various often have comorbid illnesses, such as cardiovascular and specialists and other members of the multidisciplinary team who cerebrovascular disorders, type 2 diabetes, and psychiatric disorders. encounter such patients in their work. Comorbidities can have a decisive influence on neurodegenerative disease diagnostic investigations and the interpretation of their results, also impact the initiation of treatment. Sincere thanks to all participating lecturers and everyone involved! Program 08:30 - 09:00 Registration 11:30 Vascular cognitive impairment: an opportunity for prevention 09:00 Welcome and introduction Ana FIGUEIRA VERDELHO, Lisbon, Portugal Milica G. KRAMBERGER, Ljubljana, Slovenia 12:00 Cholinesterase inhibitors: effects on cognition, vascular 09:05 The clinical assessment of prodromal and renal function and mortality in Alzheimer patients cognitive decline: the need for new tools? Mia ERIKSDOTTER, Stockholm, Sweden Stefano CAPPA, Milan, Italy 12:30 - 12:40 Discussion 09:35 Patient/site readiness for a potential new Alzheimer’s disease treatment paradigm 12:40 - 13:40 Lunch Eva ŽUPANIČ, Ljubljana, Slovenia 13:40 Cognition in Multiple Sclerosis: Evaluation, Treatment, 10:05 - 10:10 Discussion and Brain Networks Tom FUCHS, Amsterdam, Netherlands 10:10 Unravelling the heterogeneity in neurodegenerative disorders with the help of neuroimaging, 14:10 Statins in patients with dementia-a friend or a foe? Eric WESTMAN, Stockholm, Sweden Bojana PETEK Ljubljana, Slovenia 10:40 Functional brain networks in neurodegenerative 14:40 Association of blood pressure variability with disorders delirium in critically ill Tomaž RUS, Ljubljana, Slovenia Nika ZORKO GARBAJS, Ljubljana, Slovenia 11:10 - 11:15 Discussion 15:10 - 15:20 Discussion 11:15 - 11:30 Coffee Break 15:20 Closing remarks The clinical assessment of prodromal Psychological Association Services, Inc. (APAS) have been doing important work in reviewing the evidence and providing practical cognitive decline: the need for new tools? support for the organization of teleneuropsychology activities (Bilder et al., 2020, Hammers et al., 2020). Stefano Cappa The solutions adopted have been found to be different. A first level is the administration of tests by telephone (a systematic review can be found in (Carlew et al., 2020). Available evidence indicates a fair applicability of this approach for cognitive screening measures, such as the MOCA (Wong et al., 2015), in surveying large populations given Alzheimer's disease is one of the greatest global health and social the simplicity of the access mode. However, the same approach care challenges of our time. Its prevention and efficient management appears not to be applicable for the systematic and extensive are urgent priorities in Western countries. Neuropsychological assessment of major areas of cognitive functioning. At a second level, assessment, included in current diagnostic criteria represents the it is possible to consider the administration of conventional tests in first step in the diagnostic pathway of patients with suspected videoconferencing mode. In this regard, two recent reviews of the Alzheimer's disease. The recent Italian inter-society consensus evidence (Brearly et al., 2017, Marra et al., 2020) concluded for recommendations (Boccardi et al., 2019) suggest the perform a substantial comparability of results between in-person (face-to-face) complete neuropsychological assessment in the T1 phase, which and administration via web telecommunication platform. The follows the clinical screening phase (T0). At this stage, the suspicion of limitations of this approach, which is widely used in this emergency a possible neurodegenerative disease is formulated by the specialist, phase, are related on the one hand to the availability of video thus opening the diagnostic pathway. This phase corresponds to the conferencing systems by the test subject, and on the other hand to "specialist phase" of the patient's journey defined by the RAND report the impossibility of performing tests that require motor responses or (Hlavka et al., 2019). Consensus recommendations include an perceptual processing of complex stimuli. For this reason, this assessment of the main cognitive domains, ideally with standardized approach privileges verbal tests, thus providing an incomplete tests with normative values for the Italian population. Beyond the overview of the subject's cognitive functioning. Not the least diagnostic phase, neuropsychological assessment plays a key role in limitation of this approach is the difficulty in standardizing the follow-up of the subject, both to assess the natural history and to administration procedures and collecting response times. allow the measurement of the effect of possible treatments The most advanced solution for teleneuropsychology is related to the (pharmacological and nonpharmacological). With this in mind, development of computerized neuropsychological batteries computerized approaches capable of evaluating patients with implemented in personal computers, laptops or tablets or suspected Alzheimer's disease with standardized, objective, and web-based. This area has undergone tremendous development in efficient methods on a large scale appear to be of great interest and recent decades, although the uptake in clinical practice remains topicality. relatively limited. The financial burden and reduced availability of The general concept of "teleneuropsychology" includes different technological devices in the elderly population has in fact limited their solutions to the problem of remote assessment. Although the use for many years. More recent advances in mobile-device Covid-19 pandemic has greatly amplified the demand for this type of technology, with reduced costs and wider dissemination in the service, different situations related to limitations in the availability of general population, including older individuals, have paved the way services or the characteristics of the population to be evaluated, for a 'desirable large-scale application of teleneuropsychology. In this especially in the case of patients with frail or comorbid conditions, regard, the aforementioned IOPC as early as 2012 felt the need to have stimulated research in this area. Particularly in the U.S., the provide guidelines with reference to quality standards and complex Inter Organizational Practice Committee (IOPC), involving the regulatory issues, with a number of recommendations that still hold American Academy of Clinical Neuropsychology/American Board of true today (Bauer et al., 2012). These include the need for scrutiny of Clinical Neuropsychology, the National Academy of Neuropsychology, the psychometric goodness of instruments, medical device status, Division 40 of the American Psychological Association, the American scope of application, technical characteristics of the platform, and Board of Professional Neuropsychology, and the American aspects of privacy, data security, and reporting. IOPCs' recommendations are essential in a field that sees, alongside some BAUER, R. M., IVERSON, G. L., CERNICH, A. N., BINDER, L. M., RUFF, R. M. & nonprofit platforms, such as the NIH Toolbox NAUGLE, R. I. 2012. Computerized neuropsychological assessment devices: (https://www.healthmeasures.net/explore-measurement-systems/nih joint position paper of the American Academy of Clinical Neuropsychology -toolbox), numerous commercial products, such as the Cantab (which and the National Academy of Neuropsychology. Archives of Clinical received FDA clearance as a medical device in 2017) Neuropsychology, 27, 362-373. (https://www.cambridgecognition.com/cantab/) or the Philips IntelliSpace Cognition BILDER, R. M., POSTAL, K. S., BARISA, M., AASE, D. M., CULLUM, C. M., (https://www.usa.philips.com/healthcare/solutions/neurology/digital- GILLASPY, S. R., HARDER, L., KANTER, G., LANCA, M. & LECHUGA, D. M. 2020. cognitive-assessment) (FDA Class II device). Computerized tests lend InterOrganizational practice committee recommendations/guidance for themselves optimally to remote assessment conditions. They can be teleneuropsychology (TeleNP) in response to the COVID-19 pandemic. The administered at home or in a dedicated setting, with assistance from Clinical Neuropsychologist, 1-21. an operator familiar with the procedure but who does not require specialized neuropsychological training. Data collection can be done BREARLY, T. W., SHURA, R. D., MARTINDALE, S. L., LAZOWSKI, R. A., LUXTON, in different ways depending on the platform used (tablet or PC: D. D., SHENAL, B. V. & ROWLAND, J. A. 2017. Neuropsychological test administration via app or via web). Data storage can be done on administration by videoconference: A systematic review and meta-analysis. cloud repositories using GDPR-compliant procedures; the software Neuropsychology Review, 27, 174-186. provides correction of scores based on normative data and generation of descriptive performance reports compared to the CARLEW, A. R., FATIMA, H., LIVINGSTONE, J. R., REESE, C., LACRITZ, L., control group. PENDERGRASS, C., BAILEY, K. C., PRESLEY, C., MOKHTARI, B. & CULLUM, C. M. 2020. Cognitive assessment via telephone: A scoping review of instruments. Archives of Clinical Neuropsychology. HAMMERS, D. B., STOLWYK, R., HARDER, L. & CULLUM, C. M. 2020. A survey of international clinical teleneuropsychology service provision prior to and in the context of COVID-19. The Clinical Neuropsychologist, 1-17. MARRA, D. E., HAMLET, K. M., BAUER, R. M. & BOWERS, D. 2020. Validity of teleneuropsychology for older adults in response to COVID-19: A systematic and critical review. The Clinical Neuropsychologist, 1-42. WONG, A., NYENHUIS, D., BLACK, S. E., LAW, L. S., LO, E. S., KWAN, P. W., AU, L., CHAN, A. Y., WONG, L. K. & NASREDDINE, Z. 2015. Montreal Cognitive Assessment 5-minute protocol is a brief, valid, reliable, and feasible cognitive screen for telephone administration. Stroke, 46, 1059-1064. Reproduced with permission NATURE AGING PERSPECTIVE Box 1 | The conceptual transformation of Alzheimer’s disease from a clinical–pathological and primarily symptom-based entity to a clinical–biological construct • • ‘T’ = tau pathology biomarker (CSF p-tau or tau PET) NINCDS-ADRDA137. • ‘N’ = neurodegeneration or neuronal injury (CSF total tau, • 18F-FDG-PET, or structural MRI) • Probable AD: Clinical entity; discordance between clini- • ATX(N): ‘X’ = additional novel pathophysiological cal diagnosis and AD-type neuropathology at postmortem markers9. showed approximately 30% mismatch138,139. • • progression24,140. by biomarkers alone and not clinical symptoms5. • AD: neuropathological or biomarker evidence of the • disease (that is, amyloid plaques and pathological tau • deposits). • Created a six-stage clinical scheme of the AD continuum5,147. • stages141. • IWG argued AD diagnosis should include positive biomark- • By 2016, the IWG expanded the natural history for AD - clinical phenotypes, whereas cognitively unimpaired individu- tomatic stages and atypical presentations24,142,143. als with positive biomarkers should be considered ‘at risk for • In 2010, the NIA-AA working groups formulated three progression to AD’4. research diagnostic criteria based on cognitive changes and • In 2018, the FDA staging system for AD was developed to facilitate treatment development in the early stages148. the dementia phase of AD, the symptomatic pre-dementia • Stage 1: normal cognition and biomarker evidence of AD. phase (MCI) of AD, and the asymptomatic, preclinical phase • Stage 2: cognitive symptoms detectable with very sensitive of AD144–146. assessments and biomarker evidence of AD. • In 2016, the AT(N) research framework was developed • Stage 3: easily demonstrable cognitive abnormalities; func- (Table 1)147. • ‘A’ = Aβ biomarker (amyloid PET or CSF Aβ42 or Aβ42/40 biomarker evidence of AD. ratio) • Stages 4–6: mild, moderate and severe dementia148. Clinical requirements • Amnestic variant • Amnestic syndrome of • Posterior cortical atrophy • Dementia (memory • Amnestic syndrome of a hippocampal type • Logopenic variant changes and another a hippocampal type • Posterior cortical variant cognitive impairment) • Primary progressive aphasia • Posterior cortical variant • Behavioral-frontal variant • Behavioral or dysexecutive • Behavioral-frontal variant • Logopenic variant frontal variant • Corticobasal syndrome • Semantic and nonfluent variants of primary • Amnestic syndrome of • MCI progressive aphasia a hippocampal type (amnestic or non-amnestic) • Dementia None None 1984 2007 2010 2011 2014 2016 2018 2021 NINCDS- IWG IWG NIA-AA IWG NIA-AA NIA-AA IWG ADRDA None • Pathophysiological • CSF Aβ and tau markers: CSF changes • Amyloid PET positive • Aβ marker (CSF or PET) (low CSF Aβ42, • Tau marker (CSF or PET) high phosphorylated tau or high total tau) or amyloid PET positive • CSF biomarkers • MRI atrophy • 18F-FDG PET PET • Aβ marker (CSF or PET) hypometabolism variant • Marker or degeneration (CSF tau, • Amyloid PET positive phosphorylated tau, Research Biological • AD autosomal dominant mutation 18F-FDG -PET and requirements T1-weighted MRI) Clinical and research Evolution of the diagnostic criteria for Alzheimer’s disease. This timeline highlights key milestones in the development and updates to the diagnostic criteria for AD, the biological and clinical requirements that accompany their use, and their applicability in research and clinical settings. ADRDA, Alzheimer’s Disease and Related Disorders Association (now the Alzheimer’s Association) Work Group. IWG, International Working Group; NIA-AA, US National Institute on Aging and Alzheimer’s Association; NINCDS, National Institute of Neurological and Communicative Disorders and Stroke. Cognitively unimpaired individuals are considered at risk for AD. Schematic is based on the information in ref. 4. NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 693 Reproduced with permission PERSPECTIVE NATURE AGING NATURE AGING PERSPECTIVE Table 1 | ATX(N) biomarkers and their contexts of use in Alzheimer’s disease 5,8,9,136 a PCP PCP and dementia specialist Identify other etiology and proceed to Dementia specialist appropriate non-AD care AT(N) Imaging CSF Blood FDA Class Negative A/amyloid Amyloid PET Aβ Positive 42, A β42/A β40 Aβ42/A β40 Diagnostic monitoring Gradual accumulation of Symptom detection Clinical assessment/ Biomarker Treatment Monitoring treatment T/tau Tau PET p-tau AD pathophysiology in the brain, differential diagnosis confirmation initiation response and 181, p-tau217 p-tau181, p-tau217 Prognostic monitoring and/or other medical conditions disease progression N/neurodegeneration MRI, FDG PET NfL, tau NfL, tau, GFAP Pharmacodynamic monitoring Healthy Prevention: ATX(N) examples SV2A PET, microglial PET, Synaptic analytes, Synaptic analytes, Pharmacodynamic monitoring aging • Exercise Select treatment options: • Anti-Aβ • Anti-tau astrocytosis PET inflammatory measures inflammatory measures • Social interaction • Diet • Other treatments targeting • Symptomatic treatment AD pathophysiology when appropriate The various biomarkers under the AT(N) system can be measured by neuroimaging or by detection in blood and CSF. ATX(N) demonstrates the dynamic and evolving nature of the AT(N) classification • Medication system where the X component represents additional biomarkers, for example, inflammatory biomarkers, that improve classification, based on the pathophysiology of disease. Tests available for • Family and medical clinical use now history • Regular clinical condition is often underdiagnosed and undertreated due to vari- the early symptoms of AD or mislabel these as normal aging23. With • Physical exam follow-up • Standard lab tests • CSF biomarker • PET imaging (Aβ, ous factors such as lack of awareness, stigma and limited health care these barriers in mind, we describe the next-generation clinical (Aβ tau) for treatment • Traditional 42, Aβ42/Aβ40, resources15. One key priority is to achieve access and equity of care care pathway for AD and its implementation in daily clinical prac- • Cognitive neuropsychological p-tau, t-tau, etc.) monitoring screening tests battery • PET imaging (Aβ, tau) • MRI for safety for the growing number of people living with the disease16. tice requiring innovation in health care system infrastructures and In this Perspective, we describe a blueprint for transitioning from workflow and bridging of the general public into a participatory the current clinical symptom-focused and inherently late-stage framework of medicine. Tests under development • Blood-based • Digital technologies • Blood-based • Digital technologies for clinical use in the biomarker biomarker • Blood-based management of AD to a biomarker-guided and digital y facilitated future • Digital technologies biomarker clinical care pathway that focuses on detection and intervention at Summary of key steps in future clinical care pathway for early stages of the disease. We will address critical hurdles to the Alzheimer’s disease. First-line diagnostic workup: primary care. The b Digital technology practical implementation of such a paradigm shift. We emphasize first step of the next-generation clinical care pathway for AD (Fig. 1) Strengths • Cognition that patient and care partner perspectives must be considered and involves a potentially affected individual or family members notic-Digital health data • User convenience • Sleep become central when developing and implementing a new clinical ing subtle changes in cognition and/or behavior and proactively • Accessibility and global reach • Mobility care pathway for AD. seeking medical and/or psychological consultation in a primary (e.g., smartphone-based) • Psychology • Continuous data generation • Vitality • Daily activities • Passive care setting. It may also be possible to detect changes during a rou- • Al-associated pattern recognition • Hearing Defining the next-generation clinical care pathway for tine visit. • Novel enriched clinician information • Vision Alzheimer’s disease • Digital cognitive assessment apps The first-line medical assessment consists of recording family • Individualized and patient-centric • Digital pen At present in a routine clinical setting, AD is often detected at the and medical history to assess for risk factors for AD (family his- • Lower burden • Active Clinical utility • Digital mobility/gait analysis mild-to-moderate dementia stage. Diagnosis is usually based on tory for neurodegenerative diseases, diabetes, history of traumatic • Screening and early detector clinical symptoms without biomarker confirmation, and pharma- brain injury, and so on) or other causes of reversible/irreversible • Remote assessment cological treatment options are largely limited to those addressing cognitive impairment (for example, cerebrovascular and cardio- • Remote monitoring • High burden • In-clinic • Improved patient engagemen • Demographic data • MRI • NP tests t the symptoms of AD dementia, such as cholinergic and glutama- cerebrovascular diseases, psychiatric disorders, metabolic/endocri-and treatment adherence • Clinical history • EEG PSG sleep data • Blood biomarkers • Traditional health • Genetic data tergic modulators approved two decades ago to mitigate cognitive nological diseases with neurological manifestations, cancer and its data • Caregiver support and behavioral/psychological symptoms. Non-pharmacological treatments, and potentially, neurological consequences of corona-treatments have shown promise in preventing cognitive decline; virus disease 2019)5,24–26. Assessments may be col ected digitally to for example, the Finnish Geriatric Intervention Study to Prevent facilitate both patient experience and clinician workflow. Fig. 1 | The next-generation clinical care pathway for Alzheimer’s disease. a, An overarching illustration. The next-generation clinical care pathway begins Cognitive Impairment and Disability (FINGER) demonstrated Physical examination (general and neurological) can iden- with healthy aging and participation in preventive lifestyle measures to slow or prevent accumulation of AD pathophysiology, with the goal of extending that a multidomain intervention aimed at reducing lifestyle-related tify signs of central and autonomous nervous system impairment healthspan across populations. Symptom detection, triggered by concerned individuals or family members, or detected during a routine wellness visit, may and vascular-related risk factors was effective at preventing cogni- that may suggest non-AD diagnoses (for example, early psychosis, involve cognitive testing and, in the future, blood-based biomarkers and digitally based assessments. This will be accompanied by clinical assessments tive decline among older individuals at risk for dementia17. This bradykinesia, postural reflexes, involuntary movements, severe involving standard laboratory tests and physical examination. Any recorded cognitive impairment will be confirmed with standardized biomarker tests. landmark study has led to the development of the World-Wide orthostatic hypotension and others)5,24. Digital assessments of bra-Individuals with confirmed disease will proceed to treatment initiation with relevant AD therapy followed by long-term monitoring, of which digital FINGERS network aiming to adapt, test and optimize the FINGER dykinesia, tremor and blood pressure may augment clinical evalu-technologies and blood-based biomarkers will play a key role in the future. b, Digital health technologies in future AD clinical care and the path toward model for risk reduction and prevention of cognitive decline across ations. First-line medical evaluation would continue to include a precision monitoring and detection platform. A precision monitoring and detection platform will require a transformation from the traditional data different countries and settings18. laboratory tests to identify other potential causes of reversible/ collection methods to the inclusion of digital technologies. This will include active engagement technologies that require individual interaction and Emerging treatments targeting AD-associated pathophysiology irreversible cognitive impairment, such as routine blood tests for engagement to passive engagement technologies that collect data in the background while the individuals keep to their daily routine. AI, artificial are directed at earlier stages of the disease and aim at maintaining vitamin B intelligence; EEG, electroencephalogram; NP, neuropsychiatric; PSG, polysomnography. 12 deficiency and hypothyroidism, electrolyte imbalance, cognition and function11. Early intervention may allow the affected severe anemia, hepatic and renal diseases, and, when appropriate, individual to function at the highest level longer. The availability screening tests for infectious diseases such as syphilis and human low-threshold digital assessment tools for measuring cognitive per- past stroke or hydrocephalus, to name a few36. Atrophy patterns of of such emerging treatments necessitates the identification of indi- immunodeficiency virus. formance wil be needed27,29,30. In addition, blood-based biomark- the brain can provide first signs for the presence of a neurodegen-viduals with early-stage AD in routine clinical settings beyond aca- Quick, easy-to-use and validated clinical assessment tools can ers of AD pathophysiology—currently under clinical validation erative disease35. demic and/or trial centers. Early detection of AD could empower be used to identify impairment in cognition, function and behav-and/or qualification—may also be used in the primary care setting The second-line diagnostic workup is characterized by in affected individuals and their care partners to make decisions about ior. Such tools already exist, including the Mini-Mental State in the future to better inform referral to AD specialists who would vivo demonstration of AD hal mark pathophysiological changes future treatment and care proactively, and to anticipate and adapt Examination (MMSE), Montreal Cognitive Assessment (MoCA) be in charge of the second-line diagnostic workup and therapeutic reflected by the amyloid/tau/neurodegeneration (AT(N)) classifica-to the cognitive and behavioral changes associated with disease or Mini Cognitive Assessment Instrument (Mini-Cog) for assess-decision-making29,31–34. tion system, that is, proteinopathies involving amyloid-β (Aβ) and progression19. ing cognition, the Instrumental Activities of Daily Living (IADL) or tau pathways, axonal damage and neuronal loss (Table 1)5. In the However, multiple hurdles to early detection and early interven- Functional Activities Questionnaire (FAQ) for assessing daily func-Second-line diagnostic workup and therapeutic decision-making: medium to long term, blood-based biomarkers may evolve from tion exist in routine clinical practice. Affected persons and family tion, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) Alzheimer’s disease specialist. In the AD specialist setting with a triage tools to confirmatory biomarkers comparable to the cur-may not understand the early signs of AD and how they differ from for assessing behavior27. However, primary care physicians (PCPs) neurologist, geriatrician or geriatric psychiatrist, a more compre- rent standard of amyloid positron emission tomography (PET) or normal aging, and may avoid seeking medical attention due to the often have substantial time constraints and may require training hensive clinical evaluation wil determine if the clinical presenta- cerebrospinal fluid (CSF) biomarkers. It is important to exclude any stigma associated with dementia diagnosis20. Currently across the and support to evaluate individuals with such methods. Moreover, tion is consistent with AD. Specialist assessment is particularly amnestic cognitive syndromes without Aβ and tau pathology such globe, the rate of undetected dementia is as high as ~60%21,22, with many of the standard instruments are impacted by linguistic, cul-important in complex cases with atypical presentation, early-onset as limbic-predominant age-related TDP-43 encephalopathy neuro-diagnosis of MCI being a rare exception rather than the norm. It is tural, educational and demographic factors, and referral to spe-or rapid progression35. Brain computerized tomography (CT) and pathological change (LATE-NC)37,38. Currently, this is only possible crucial for clinicians as wel as patients and families to recognize cialists for more in-depth neuropsychological evaluation may be magnetic resonance imaging (MRI) are recommended to identify by excluding AD specific pathology; in the future, positive biomark-the importance of early detection and diagnosis, and not overlook required for accurate diagnosis in certain situations28. In the future, structural explanations for cognitive impairment, such as neoplasm, ers for TDP-43 in the CSF may become available39. NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 694 NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 695 Reproduced with permission PERSPECTIVE NATURE AGING NATURE AGING PERSPECTIVE In situations where AD is excluded as the cause for cognitive Use of biomarkers in clinical care of Alzheimer’s disease Box 2 | Strengths and limitations of each biomarker modality impairment, the path for the individual would be redirected toward The incorporation of biomarkers represents a major innovation non-AD conditions. A diagnosis of AD would require discussions in the next-generation clinical care pathway for AD, supporting between the clinician and the individual/family for prognosis. The screening, diagnosis and disease staging as wel as predicting the Modality Strengths Limitations most critical prognostic outcomes to individuals and their care part- rate of progression, determining prognosis and assisting thera-PET • Localization of amyloid or tau • Limited access/high cost ners are related to cognitive decline, dependency and physical health40. peutic decision-making9. Established Aβ biomarkers such as those • Quantification of pathology load; qualitative reading program for • Each biomarker scanned for separately Therapeutic interventions wil consist of agents targeting measured by PET imaging or CSF analysis should be used to assess clinical practice • Exposure to radioactivity AD-associated pathophysiology, although at present patients must the presence of amyloid pathology and is mostly used today in spe- • Regulatory approval of Aβ PET tracers for in vivo detection of A β • Infrastructure requirements including cyclotrons to manufacture be aware that these treatments are unlikely to stop or reverse cog- cialized and tertiary care for diagnostic confirmation and thera- • Regulatory approval of tau PET tracer for in vivo detection of the tracer, scanners and software for quantitative analysis of the nitive decline. These therapies wil likely be given in combination peutic decision-making. Three radioligands for amyloid PET have tau pathology scans (in research setting) with existing symptomatic treatments (cholinesterase inhibitors been approved by the US FDA and European Medicines Agency CSF • More cost-effective than PET • No localization or memantine), and likely guided by the profile of biomarker and (EMA) for amyloid plaque imaging in cognitively impaired indi- • Multiple biomarkers from one draw • Invasive due to the need for lumbar puncture behavioral or functional changes11,41. Treatment continuation, ces- viduals being clinical y evaluated for AD and other causes of cog- • More accessible and scalable than PET • Pre-analytical factors (for example, how samples are collected sation or dose adjustment wil be determined based on clinical and nitive decline. These include 18F-florbetapir57, 18F-flutemetamol58 • Lumipulse G β-amyloid ratio (1-42/1-40) in vitro diagnostic test and stored) could affect results biological factors42,43. and 18F-florbetaben59. Amyloid PET was validated against the gold received FDA approval In the future when treatments for preclinical (presymptomatic) standard of neuropathology, has undergone extensive standardiza-Blood • More cost-effective than PET and CSF • No localization stages of AD become available, identifying such populations will tion and has been widely used in AD clinical trials34. The appropri- • More accessible and scalable than PET and CSF • Additional validation required to confirm accuracy become critical. At such time, a personalized, multidimensional ate use criteria for amyloid PET are available, providing guidance • Multiple biomarkers in one drop of blood • Not yet available for clinical use approach to the diagnosis of preclinical AD should be considered to clinicians on the types of patients and clinical circumstances in • Less invasive than CSF testing • Pre-analytical factors (for example, how samples are collected and for the best chance of diagnosis and progression prediction. This which amyloid PET should be used60,61. Interestingly, an applied • Easily repeated measurements over time stored) could affect results will likely include identifying genetic risk factors associated with study showed relevant clinical benefit of amyloid PET imaging even AD and abnormalities in fluid and neuroimaging AD biomarkers; for individuals who did not meet the appropriate use criteria62. The in particular, periodic screening with blood-based biomarkers of Imaging Dementia-Evidence For Amyloid Scanning (IDEAS) study specific and accessible biomarkers for detecting early AD-related diagnosis. These uncertainties may result in some clinicians steer-AD pathophysiology (Aβ42/40 and phosphorylated tau (p-tau) spe- provided evidence that amyloid PET positively impacts diagnostic pathophysiology78–84. In the near term, blood-based biomarkers ing their patients away from further biomarker testing88. Moreover, cies) in appropriate populations should be considered44. Such a accuracy and certainty as wel as patient management63. As such, reflecting core AD pathophysiology have the potential to serve as clinicians vary in their approach to informing a patient they have complex approach has several outstanding issues such as diagnos- amyloid PET is likely to be the first choice for clinical use in the con-screening and triage tools to identify those who should be tested early disease, with about one-half of clinicians preferring not to use tic accuracy, cost of diagnosis and treatment relative to benefit) yet text of anti-Aβ agents, especially in the United States and Europe. with more resource-demanding techniques such as PET imaging the term MCI88. Web-based tools are emerging to support clinicians without consensus on when a preclinical diagnosis of AD is indi- However, the limited availability of PET scanners, radioligand and/or CSF biomarker analysis. It will be important to define stan- and patients with decisions on diagnostic testing, interpretation of cated and how it should be performed22,45,46. Consensus process in manufacturing centers and nuclear medicine teams, as wel as the dard diagnostic pathways fol owing a positive blood biomarker test, individual y tailored biomarker test results, and the communication the future should involve clinical and biomarker experts, but also high cost and lack of reimbursement are al factors that constrain its including the development of an evidence base for predictive accu- of test results to individuals and their families89. Clinicians should patient advocacy groups and representatives of regulatory agencies global use in routine clinical practice34,64. racy within a primary care setting, provision of access to specialized receive appropriate education and practical training on the use of and payers. In addition to pharmacological interventions, multi-CSF biomarker analysis for Aβ42 has been developed and stan- care, and determination of thresholds of positivity that will guide new tools and assessments5,67,90. domain lifestyle interventions could prove beneficial over the long dardized using certified reference materials and methods65. The the use of new treatments targeting AD pathophysiology9,32,85. In the term in such populations, which may include modifications of diet, CSF Aβ Use of digital health technologies in clinical care pathway 42/40 ratio is highly concordant with amyloid PET, and evi- future, blood-based biomarkers may be developed for other con- exercise, sleep and social and cognitive stimulation47. dence suggests that Aβ abnormalities may be detected in CSF earlier texts of use such as to predict disease risk, track disease progression The rise of digital health technologies represents another major than by amyloid PET. Both the FDA and the EMA have encouraged and monitor treatment response9,32. opportunity to improve the AD clinical care pathway (Fig. 1). Such Communication with patients and their care partners. Patient and further study of CSF biomarkers in the context of clinical AD diag-Biomarkers reflecting other components of AD-related patho- technologies are particularly poised for early detection/case find-care partner perspectives must be considered when developing and nostics34,65. The appropriate use criteria for lumbar puncture and physiology, such as neuronal injury/neurodegeneration (CSF total ing and tracking longitudinal disease progression and/or treatment implementing the next-generation clinical care pathway for AD48–51. CSF testing during the diagnostic workup of AD have been estab-tau and neurofilament light chain (NfL), volumetric MRI), synaptic response. Their col ective involvement is essential to provide insight into pos- lished66, and further recommendations to optimize the safety profile dysfunction (CSF neurogranin, 18F-fluorodeoxyglucose (FDG)-PET The transition from traditional cognitive testing to nonintru- sible gaps in existing health services48–50. Qualitative studies have of lumbar puncture are available67. Recommendations and protocols and synaptic vesicle glycoprotein 2A (SV2A) PET) and inflamma- sive digital assessment offers several advantages. First, nonintrusive revealed the need for: (1) early diagnosis through a well-organized to standardize the pre-analytical aspects of CSF biomarker testing tion (CSF chitinase-3-like protein (YKL-40), glial fibrillary acidic testing offers ecological validity owing to the patient assessment in process, (2) a notably shorter pathway to accessing support services for AD are also established68,69. protein (GFAP) and soluble triggering receptor expressed on their normal environment and outside the hospital setting. Second, for their current needs and care goals, (3) easily accessible, adequate Besides Aβ, development of tau biomarkers has also advanced myeloid cel s 2 (TREM2), translocator protein (TSPO) PET and thanks to its convenience, digital assessments can be more frequent and clear information about cognitive testing, medications, disease markedly. Various tau PET radioligands could chart the spatial monoamine oxidase B (MAO-B) PET) are emerging, but are not yet as compared to traditional in-clinic assessments, thus al owing progression, finances and behavior, (4) effective disease manage- spreading of tau pathophysiology in vivo, which tightly correlates ready for clinical implementation (Table 1)34. documentation of, and control for, day-to-day variations in cogni- ment by highly knowledgeable and experienced clinicians, and (5) with cognitive and functional outcomes across AD clinical stages34,70. It is worth noting that a sizable portion of individuals with AD tive function. Third, assessment of everyday activities as a surrogate good communication skil s of clinicians48. Individuals at risk for AD Flortaucipir F18 was recently approved in the United States for exhibit comorbid pathologies such as vascular lesions or intracel- indicator of abstract cognitive functions increases the functional or with early AD and their families wil need substantial health liter- imaging tau pathology in individuals with cognitive impairment lular inclusions of TDP-43 (refs. 86,87). There is an urgent need for relevance of the patient assessment. And final y, zero-effort technol-acy to understand and apply the increasingly complex and nuanced who are being evaluated for AD, and several other investigational research to develop imaging and fluid biomarkers for common ogies provide access to patients outside standard cognitive testing, information such as risk prediction, early detection and prognosis tau tracers are being actively studied34,70. Among several contexts co-pathologies such as TDP-43, α-synuclein and other misfolded such as individuals with advanced stages of dementia, those with for decision-making on health-related issues. Overal health literacy of use of tau biomarkers71–73, monitoring downstream biological proteins. Further studies are needed to understand how comorbid reduced hearing, or those who are il iterate42. Digital cognitive test-can vary substantially, and effective and clear communication from effects on tau pathways fol owing anti-Aβ treatment and guiding pathologies contribute to the biological and clinical progression of ing also has the potential to overcome the socioeconomic and cul-clinicians with empathy and sensitivity to individual needs and future anti-Aβ and tau combination therapies represent two unique AD, and how to factor these in during the clinical management of tural biases embedded in some traditional neuropsychological tests. preferences is critical52. In the context of diagnosis and therapeu- opportunities34. patients. In addition, biomarker data on individuals aged 85 and In the near term, digital health technologies that require active tic workup, among a number of informative topics, clinicians must As PET imaging is expensive and of limited availability, and older (oldest old) are scarce; given that age is the greatest risk fac- input from the user to assess changes in cognition, function and effectively communicate the rationale for biomarker testing, the CSF sampling may be considered invasive, the rapidly advancing tor for late-onset AD and considering the pace of population aging quality of life are under development29,42,91. In the long term, the results and implications for treatment and to set appropriate expec- blood-based biomarkers for AD are particularly promising, given worldwide, more research is needed to map the biomarker land- rapid progress in sensor-based technologies, including mobile and tations, as treatments that target AD-associated pathophysiology the broad availability, scalability and cost-effectiveness of blood scape in this population13. Similarly, more biomarker research on wearable devices (smartphones and smart watches) may support are likely to slow clinical decline without noticeable improvement in tests global y (Box 2). Plasma Aβ42/40 shows great promise in accu-middle-age, at-risk populations is needed given the importance for increasingly early detection of subtle changes associated with AD symptoms53,54. Involving the patient and care partner to understand rately reflecting amyloid PET and CSF Aβ42/40 results74–76. A mass prevention efforts in such populations (Box 3). onset (for example, speech/language, oculomotor skills and move- what matters to them regarding health, cognitive, behavioral and spectrometry-based plasma Aβ42/40 test achieved an accuracy of 0.81 Although biomarkers form the cornerstone for the next-gener- ment) in a continuous, passive and unobtrusive manner (that is, functional status as a measure of treatment success and developing (area under the receiver operating characteristic (ROC) curve) in ation clinical care pathway for AD, their use is currently limited in digital biomarkers). This will enable risk assessment, screening a tool for this purpose is equal y important55,56. In addition, patient predicting brain amyloid status, and has recently received Clinical clinical practice. Clinicians may be reluctant to discuss biomarkers and disease prediction with little or no active engagement by the and care partner preference in how they would like to be informed Laboratory Improvement Amendments certification77. Besides Aβ, to avoid burdening their patients, perhaps in part because there are participants42,91–98. As an example, the Oregon Center for Aging & must be taken into consideration. plasma p-tau181, p-tau217 and p-tau231 are emerging as accurate, stil uncertainties regarding the clinical utility of a biomarker-based Technology (ORCATECH)/Col aborative Aging Research Using NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 696 NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 697 Reproduced with permission PERSPECTIVE NATURE AGING NATURE AGING PERSPECTIVE Box 3 | Glossary ensuring sufficient availability and accessibility to infusion centers genetics, comorbid cardiovascular disease or metabolic syndrome) and having the necessary infrastructure for monitoring treatment between races may play a role in the incidence and prevalence of Biomarker Mini-Mental State Examination (MMSE) safety and efficacy112,115,116. Other potential issues also include clini- AD, while cultural factors (for example, lack of access to medical Usual y refers to a group of broad medical characteristics that An 11-question measure widely used to test cognitive function cian capacity and capabilities; recent reports show a limited number care, trust issues between marginalized groups and the health care can be objectively measured as an indicator of the body’s normal among the older population; it includes a systematic and thorough of dementia specialists in the United States, Canada, Europe and system) may influence diagnosis and treatment121–123. Inherent biases biological processes, or as an indicator of pathogenic processes Japan, and clinicians may be reluctant to evaluate a patient for a may exist in cognitive screening tools that complicate the diagnosis and response to therapy. To qualify as a biomarker, a characteristic attention and calculation, recall, and language. Of a maximum decline in cognitive function if they don’t feel adequately trained of AD in less educated groups121 and there is an underrepresentation score of 30, 23 or lower is indicative of cognitive impairment. or believe that there are no therapeutic advantages to identifying a of marginalized groups in clinical research and clinical trials122,124,125. decline in cognitive function112,113. Improving diverse participation in clinical research and clinical Context of use Montreal Cognitive Assessment (MoCA) With these obstacles and challenges, there is a pressing need to trials is paramount to understanding how factors like race, ethnic-In relation to biomarkers, this usually refers to the description A rapid screening tool for mild cognitive dysfunction that determine the essential steps toward system preparedness for the ity, socioeconomic status, gender, sexual orientation, education and assesses cognitive domains including attention and concentration, next-generation AD clinical care pathway. Primary care is a critical culture interact with biological factors associated with AD122,125–129. biomarker is applied in drug development and clinical care. executive functions, memory, language, visuoconstructional skills, entry point into health care systems with a larger number of general The next-generation clinical care pathway wil need to address the conceptual thinking, calculations and orientation. Of a maximum providers compared with specialist services107,112. Better tools are issue of diversity as wel as social determinants of health to optimize Digital biomarker being developed to identify and triage patients in the primary care equity of care for all individuals with AD121–125. Clinically meaningful and objective physiological and behavioral considered a good screening tool for persons who score above the setting29. Digital health technologies, including digital cognitive data that can be measured using digital and sensor-based assessments, have the potential to detect early cognitive decline and Conclusions and perspectives technologies, including mobile and wearable devices such as monitor progression, while the emerging blood-based biomark- The conceptualization of AD as a clinical–biological construct smartphones and smart watches. Neuropsychiatric Inventory Questionnaire (NPI-Q) ers—fol owing analytical and clinical validation—could be used to and the emerging biomarker-guided pathway-based treatments An informant-based test for assessing behavior. It assesses enhance the likelihood of AD as the etiology of the observed cogni- targeting AD-associated pathophysiology highlight the impor-Digital health technologies neuropsychiatric symptoms including delusions, hal ucinations, tive decline31,32,42,97,117. To this end, a study showed that a brief cogni- tance and urgency of developing and implementing a global aggression, dysphoria/depression, anxiety, euphoria/elation, tive test in combination with a blood-based biomarker test of AD framework for the next-generation AD clinical care pathway. pathophysiology at the primary care level can substantial y improve Detecting the disease at its initial and early stages will be cru-related uses. motor behaviors, night-time behavioral disturbances and appetite/ triaging in primary care and lead to reduced waiting times for a cial, and primary care will have an important role in case finding. specialist visit during the diagnostic process31. Besides diagnostic Utilizing a ‘memory care enabled’ workforce including nurse prac-Functional Activities Questionnaire (FAQ) eating disturbances. evaluation, prognostic information including the risk of disease titioners, community health workers and geriatric care managers Patient journey progression is important to guide treatment decisions. For example, may reduce the burden and complete reliance on the PCPs as the A term usually used to refer to a patient’s experience throughout for cardiovascular diseases, the American Heart Association and gateway to diagnosis and care130. Diagnosis will include biomarker distinguishing feature of the FAQ is that, unlike the IADL, it the American College of Cardiology have issued predictive equa- assessments, which will also guide the initiation of treatment as measures more basic tasks such as eating and bathing. patient experiences within a health care ecosystem, including tions to guide treatment decisions based on projected risk of cardio- well as monitoring of treatment response, dose adjustments, and undergoing regular checkups and receiving treatment. Instrumental Activities of Daily Living (IADL) vascular events; similar tools for AD could give clinicians a holistic treatment continuation or cessation. Including patients and care view of a patient’s risk of progression118. To this end, the Interceptor partners early in the development process will ensure acceptance Polygenic risk score that allow an individual to live independently in a community Project in Italy is monitoring a group of patients with early-stage and accessibility of novel pathways and technology for those most A score related to the risk of developing a disease, estimated based and to improve quality of life. Domains assessed include cooking, cognitive decline to determine factors from the initial evaluation of affected. Although patient and public involvement has been ution the total number of changes or variations in an individual’s the patient that could predict progression119. lized in other medical specialties such as oncology and pediatrics, Telehealth wil be an essential component of the next-generation a pragmatic approach needs to be adapted and transformed for personalized disease risk prediction using genetic data. Mini Cognitive Assessment Instrument (Mini-Cog) pathway by providing coordinated care between a patient, care part- AD clinical care. Compared to other cognitive screening tools, this is a relatively Sensor technologies ners and clinicians (that is, nurse, PCP and specialist), and will allow The successful development and implementation of the next- quicker 3-min test to screen for cognitive impairment in older Sensor technologies require the use of sensors to detect physical, access to memory care and remote monitoring in individuals who generation AD clinical care pathway outlined above depends on chemical or biological properties of an individual and convert cannot leave home, or in those without adequate transportation or close interaction and cross-functional col aboration with stakehold-uses a three-item recall test for memory and a clock-drawing test. them into readable and meaningful information. living in a rural area120. More defined hub and spoke arrangements ers including regulators, pharmaceutical and biotechnology indus-linking PCPs to specialists through telehealth and related technolo- try, policymakers, and payors. While the current paper centered on gies may facilitate care by coordinated teams. the clinician and patient as wel as the care partner perspective, opti- Better care models and incentives are needed to increase a PCP’s mization of the clinical care pathway needs to be complemented by Technology (CART) platform utilizes ambient technologies and regions/countries wil not be able to meet the demand of patients involvement in AD care. For example, cognitive screening is a man- the health system and cost viewpoints. Both perspectives need to be wearables to longitudinal y monitor cognition, physical mobil- for diagnosis and treatment of AD107–110. In the United States, ~15 datory requirement of the driver’s license renewal process for older integrated in the near future once a clinical care pathway addressing ity, sleep and the level of social engagement in the homes of older million individuals with MCI would need to be evaluated by spe-people in Japan, while walk-in clinics are available for screening the most urgent needs of patients and family has been agreed on by adults99. Such data can be integrated and analyzed to find mean- cialists, undergo diagnostic testing and pursue treatment107. Current and consultation in memory centers in Korea110. The emergence health care system stakeholders. ingful behaviors that identify people at different stages of cognitive estimates show that the expected caseload of patients wil result in of telecare-enabled specialist support has helped to empower PCP The next-generation clinical care pathway for AD must address decline100. Digital health technologies will play a central role in an long average wait times for specialist visits (~50 months) with many sites in the United States107. In addition, accountability schemes the critical issues of diversity and inclusion to ensure health equity integrated care model (for example, the Integrated Care for Older patients developing AD dementia while on waiting lists107,111. The have emerged as incentives, such as use of age-adjusted dementia for the enormous and rapidly growing number of AD patients People (ICOPE) recommended by the World Health Organization) strained capacity of memory specialists will limit access to diagnosis diagnosis rates as a quality measure for general practitioners in the across the globe. A starting point is to ensure more inclusive par-that not only focuses on cognition but also addresses other func- and treatment107,111. United Kingdom112. ticipation in observational biomarker research and in clinical tri- tions that maintain brain research, such as mobility, psychology, There are additional obstacles to meet the demand of people Specialty care for AD wil need to evolve to accommodate a shift als so that therapeutic approaches wil be broadly applicable and vitality, hearing and vision101–103. with AD. Although some countries have dementia plans in place, from the current focus on diagnosis often at late stages of the dis- available. The new pathway needs to be adapted to local resources Important considerations for the use of digital technologies the emphasis is often on the management of patients with descrip-ease and counseling to more emphasis on diagnosing the disease and capabilities to maximize the health benefit for patients. From include privacy issues, specificity and sensitivity to AD versus other tive dementia syndromes and does not adequately address pro-at early stages and offering new treatments that target the under- there it will become clear that the next step is to devise the roadmap causes of cognitive impairment or dementia, user friendliness, reli- dromal symptomatic MCI, and etiology in general or early-stage lying pathophysiology. For example, memory clinics have been toward a transformation to precision neurology—a holistic and syn-ability, costs and access, among others42,104. Once in clinical practice, disease112–114. Coverage of services is also limited, especially for logistically located near general hospitals in the United Kingdom ergistic approach to AD care that encompasses genetic, biological the ultimate goal of digital health technologies is to facilitate patient routine use of confirmatory biomarker tests. For countries with the to provide one-stop, large-scale practices that can handle all aspects (that is, biomarker), clinical and environmental profiling of indi-self-management and maintain people living independently for as capacity to absorb increases in service demand, there may not be of care with biomarker testing, differential diagnosis and infusion vidual patients to guide the development of individualized treat-long as possible42,105,106. an incentive to scale up patient volume due to budgetary consid- therapy112. Agile learning health care systems will be required to ment schemes and ultimately, prevention and extension of brain erations112. Moreover, there will be challenges keeping pace with adjust continuously to new and emerging therapies for AD and healthspan131–135. Challenges and potential solutions: a holistic perspective the necessary infrastructure to accommodate recommended pro- related disorders. With biomarker-guided, pathway-based targeted therapies emerg- cedures, such as adding PET tracer manufacturing capacity and Ethnic, socioeconomic and racial disparities have been identified Received: 7 March 2022; Accepted: 7 July 2022; ing, modeling studies predict that health care systems in many installing PET scanners, increasing the volume of biomarker testing, in people with AD121–123. Differences in risk factors (for example, Published online: 19 August 2022 NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 698 NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 699 Reproduced with permission PERSPECTIVE NATURE AGING NATURE AGING PERSPECTIVE References 31. Mattke, S., Cho, S. K., Bittner, T., Hlávka, J. & Hanson, M. Blood-based 59. 85. 1. biomarkers for Alzheimer’s pathology and the diagnostic process for a information]. 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R.A. is a Biogen, Lil y, Longeveron, Novo Nordisk, TauRx P and Roche in the past 3 years. A.V. M. World Alzheimer Report 2016: improving healthcare for people living elderly brain: a community-based autopsy series. Acta Neuropathol. 126, scientific advisor to Signant Health and consultant to Biogen. S.M. serves on the board declares no competing interests related to the present paper and the contribution of with dementia: coverage, quality and costs now and in the future. 365–384 (2013). of directors of Senscio Systems and the scientific advisory board of AiCure Technologies, A.V. to this paper reflects entirely and only A.V.’s own academic expertise on the matter. (Alzheimer’s Disease International, 2016). 140. and Boston Millennia Partners, and has received consulting fees from AARP, Biogen, A.V. was an employee of Eisai (November 2019–June 2021). A.V. did not receive any 115. Sperling, R. A. et al. Amyloid-related imaging abnormalities (ARIA) in era of biomarkers. Lancet Neurol. 20, 222–234 (2021). Biotronik, Bristol-Myers Squibb, C2N, Eisai and Roche. Research programs of W.M.v.d.F. fees or honoraria since November 2019. Before November 2019, A.V. received lecture amyloid modifying therapeutic trials: recommendations from the 141. Dubois, B. et al. Research criteria for the diagnosis of Alzheimer’s disease: have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, honoraria from Roche, MagQu and Servier. H.W. has provided consultation to Eisai, Alzheimer’s Association Research Roundtable Workgroup. Alzheimers revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734–746 (2007). CardioVascular Onderzoek Nederland, Health~Hol and, Topsector Life Sciences Lundbeck, Roche and Signant Health pharmaceutical and assessment companies. H.W. Dement. 7, 367–385 (2011). 142. & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman owns the copyright of the individualized management system of neuropsychiatric 116. Liu, J. L., et al. Assessing the preparedness of the Canadian health care system lexicon. Lancet Neurol. 9, 1118–1127 (2010). stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Biogen MA, Boehringer symptoms (NPSIMS) and the smartphone-based application of brief cognitive infrastructure for an Alzheimer’s treatment (RAND Corporation, 2019). 143. Ingelheim, Life-MI, AVID, Roche BV, Fujifilm and Combinostics. W.F. holds the Pasman screening kit (shairenzhi). J.C. provided consultation to AB Science, Acadia, Alkahest, 117. and diagnostic criteria. Alzheimers Dement. 12, 292–323 (2016). chair. W.F. is a recipient of ABOARD, which is a public–private partnership receiving AlphaCognition, ALZPathFinder, Annovis, AriBio, Artery, Avanir, Biogen, Biosplice, 144. funding from ZonMW (73305095007) and Health~Hol and, Topsector Life Sciences Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, patterns. Front. Digit. Health 3, 751629 (2022). Alzheimer’s disease: recommendations from the National Institute on & Health (PPP allowance, LSHM20106). W.F. has performed contract research for GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, 118. Lloyd-Jones, D. M. et al. Use of risk assessment tools to guide decision-Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Biogen MA and Boehringer Ingelheim. W.F. has been an invited speaker at Boehringer LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PharmacotrophiX, making in the primary prevention of atherosclerotic cardiovascular disease: Alzheimer’s disease. Alzheimers Dement. 7, 270–279 (2011). Ingelheim, Biogen MA, Danone, Eisai, WebMD Neurology (Medscape) and Springer PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, a special report from the American Heart Association and American 145. Healthcare. W.F. is consultant to Oxford Health Policy Forum CIC, Roche and Biogen Unlearn AI, Vaxxinity, VigilNeuro pharmaceutical, assessment and investment College of Cardiology. Circulation 139, e1162–e1177 (2019). disease: recommendations from the National Institute on Aging-Alzheimer’s MA. W.F. participated in advisory boards of Biogen MA and Roche. All funding is paid companies. M.C., S.D.S., P.G. and R.K. are employees of Eisai. 119. Association workgroups on diagnostic guidelines for Alzheimer’s disease. to the institution of W.F. W.F. was associate editor of Alzheimer, Research & Therapy Alzheimers Dement. 7, 263–269 (2011). in 2020/2021. W.F. is associate editor at Brain. P.A. reports research agreements with Additional information a nationwide organizational model for early Alzheimer’s disease diagnosis. 146. Janssen, Lil y and Eisai, grants from NIA, the Alzheimer’s Association and FNIH and Correspondence should be addressed to Harald Hampel. J. Alzheimers Dis. 72, 373–388 (2019). disease: recommendations from the National Institute on Aging-Alzheimer’s consulting fees from Biogen, Roche, Merck, Abbvie, Immunobrain Checkpoint, Rainbow 120. National Institute on Aging. Telehealth: improving dementia care. Association workgroups on diagnostic guidelines for Alzheimer’s disease. Medical and Shionogi. L.A. has provided consultation to Eli Lil y, Biogen, Eisai, GE Peer review information Nature Aging thanks Niklas Mattsson-Carlgren and the other, https://www.nia.nih.gov/news/telehealth-improving-dementia-care (2020). Alzheimers Dement. 7, 280–292 (2011). Healthcare and Two Labs. L.G.A. receives research support from NIA U01 AG057195, anonymous, reviewer(s) for their contribution to the peer review of this work. 121. Chin, A. L., Negash, S. & Hamilton, R. Diversity and disparity in dementia: 147. NIA R01 AG057739, NIA P30 AG010133, Alzheimer Association LEADS GENETICS Reprints and permissions information is available at www.nature.com/reprints. Alzheimer Dis. Alzheimer disease biomarkers. Neurology 87, 539–547 (2016). 19-639372, Roche Diagnostics RD005665, AVID Pharmaceuticals and Life Molecular Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in Assoc. Disord. 25, 187–195 (2011). 148. Food & Drug Administration. Early Alzheimer’s Disease: Developing Drugs Imaging. L.G.A. received honoraria for participating in independent data safety published maps and institutional affiliations. 122. US Department of Health and Human Services. Racial and ethnic for Treatment: Guidance for Industry. https://www.fda.gov/media/110903/ monitoring boards and providing educational CME lectures and programs. L.G.A. Springer Nature or its licensor holds exclusive rights to this article under a publishing disparities in Alzheimer’s Disease: a literature review. https://aspe.hhs.gov/ download (2018). has stock in Cassava Sciences and Semiring. C.C. receives research grants from the agreement with the author(s) or other rightsholder(s); author self-archiving of the (2014). National Medical Research Council of Singapore. C.C. also receives research support accepted manuscript version of this article is solely governed by the terms of such 123. Vega, I. E., Cabrera, L. Y., Wygant, C. M., Velez-Ortiz, D. & Counts, S. E. Acknowledgements from Moleac, Roche, Eisai and Lundbeck; and has participated in advisory boards publishing agreement and applicable law. Alzheimer’s disease in the Latino community: intersection of genetics and for Cerecin and Eisai in the past 3 years. A.I. receives research grant from AMED R.A.’s grant support includes National Institutes of Health (NIH) grants (AG062109, social determinants of health. J. Alzheimers Dis. 58, 979–992 (2017). (Japanese Agency for Medical Research), JSPS (Japan Society for Promotion of Science), © Springer Nature America, Inc. 2022 AG068753, AG072654 and AG063635). Additional support was provided by the 124. McKindra, L. Dementia researchers issue urgent cal for more diversity in American Heart Association (20SFRN35360180 and 20SFRN35490098), the Alzheimer’s clinical trial participation. (University of Kansas Medical Center, 2021). Drug Discovery Foundation (201902-2017835) and Gates Ventures. W.M.v.d.F 125. Wilkins, C. H., Schindler, S. E. & Morris, J. C. Addressing health disparities received support from the Research of Alzheimer center Amsterdam, which is part of among minority populations: why clinical trial recruitment is not enough. the neurodegeneration research program of Amsterdam Neuroscience. The chair of JAMA Neurol. 77, 1063–1064 (2020). W.v.f.F is supported by the Pasman stichting. W.F. is a recipient of ABOARD, which 126. Anderson, J. G., Flatt, J. D., Jabson Tree, J. M., Gross, A. L. & Rose, K. M. is a public–private partnership receiving funding from ZonMW (73305095007) and Characteristics of sexual and gender minority caregivers of people with Health~Hol and, Topsector Life Sciences & Health (PPP al owance, LSHM20106). dementia. J. Aging Health 33, 838–851 (2021). More than 30 partners participate in ABOARD. H.W. receives research grant from 127. Ferretti, M. T. et al. Optimal Alzheimer’s disease detection and diagnosis the National Brain Project funded by the Ministry of Science and Technology, China under the sex and gender lens: a crucial step towards precision neurology. (2021ZD0201805). C.C. is supported by the National Medical Research Council of in World Alzheimer Report 2021: Journey through the diagnosis of dementia. Singapore (MOH-000707-00, NMRC/OFLCG/2019, NMRC/CIRG/1485/2018 and Alzheimer’s Disease International, 238–241 (2021). NMRC/CSA-SI/0007/2016). The Gérontopôle (chair B.V.) has received research grant 128. support from the European Commission as well as industries including Biogen, Green precision medicine. Nat. Rev. Neurol. 14, 457–469 (2018). Valley Pharmaceuticals, Novo Nordisk, Pfizer, Pierre-Fabre, Roche, Lily and Eisai. J.C. 129. Fredriksen-Goldsen, K. I., Jen, S., Bryan, A. E. B. & Goldsen, J. Cognitive is supported by NIGMS grant P20GM109025, NINDS grant U01NS093334, NIA grants impairment, Alzheimer’s disease and other dementias in the lives of lesbian, R01AG053798, P20AG068053 and R35AG71476 and the Alzheimer’s Disease Drug gay, bisexual and transgender (LGBT) older adults and their caregivers: Discovery Foundation. A.S. receives support from multiple NIH grants (P30 AG010133, needs and competencies. J. Appl Gerontol. 37, 545–569 (2018). P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 130. Galvin, J. E. et al. Early stages of Alzheimer’s disease: evolving the care team AG068193, T32 AG071444, U01 AG068057 and U01 AG072177). The authors thank D. for optimal patient management. Front. Neurol. 11, 592302 (2020). Henley for his contribution to the critical revision of the Perspective. Medical writing 131. Hampel, H., Lista, S. & Khachaturian, Z. S. Development of biomarkers to support was provided by L. O’Brien of CMC AFFINITY, McCann Health Medical chart all Alzheimer’s disease stages: the royal road to cutting the therapeutic Communications and was funded by Eisai. Gordian Knot. Alzheimers Dement. 8, 312–336 (2012). 132. Hampel, H. et al. PRECISION MEDICINE—the golden gate for detection, treatment and prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis. 3, Author contributions 243–259 (2016). H.H., A.V., S.D.S. and P.G. developed the initial concept and theoretical framework for 133. this Perspective. All authors contributed to researching the literature and data, discussing the content, and writing, reviewing and/or editing of the Perspective. an Alzheimer’s disease therapy: analysis of the blarcamesine (ANAVEX2-73) phase 2a clinical study. Alzheimer’s Dement. 6, e12013 (2020). Competing interests 134. Hampel, H., Vergal o, A., Perry, G., Lista, S. & Alzheimer Precision H.H. is an employee of Eisai and serves as senior associate editor for the Journal Alzheimer’s & Dementia and has not received any fees or honoraria since May 2019. J. Alzheimers Dis. 68, 1–24 (2019). H.H. is inventor of 11 patents and has received no royalties for: In Vitro Multiparameter 135. Altomare, D. et al. Brain Health Services: organization, structure, and Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative challenges for implementation. a user manual for Brain Health Services— Disorders patent no. 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis part 1 of 6. 13, 168 (2021). of Neurodegenerative Diseases patent no. 8298784; Neurodegenerative Markers 136. for Psychiatric Conditions publication no. 20120196300; In Vitro Multiparameter development. Adv. Exp. Med. Biol. 1118, 29–61 (2019). Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 702 NAT URE AGING | VOL 2 | AUGUST 2022 | 692–703 | www.nature.com/nataging 703 Patient/site readiness for a potential new demands from the general population for diagnosis and eventual treatment. Persons aged 65 years or older with MCI or mild AD Alzheimer’s disease treatment paradigm (MMSE–Mini Mental State Examination > 21 points or MoCA–Montreal Cognitive Assessment > 16 points) and Alzheimer’s disease positive biomarkers will be potential candidates for treatment. Alzheimer’s disease biomarkers include positive amyloid-PET imaging or cerebrospinal fluid (CSF) biomarkers, and since amyloid-PET imaging Eva Županič, Milica Gregorič Kramberger is currently not available in Slovenia, CSF biomarker analyses are used instead. At the present time, there are no reliable blood based biomarker that could substitute the lumbar puncture. In that scenario, blood-based biomarkers combined with cognitive testing could be performed in a primary level setting, which may serve as a gatekeeping mechanism. However, this would call for additional capacities of the primary level, which is, even at present, critically There were more than 34,000 people living with dementia in Slovenia understaffed. in 2018 and this number is predicted to double by 2050. (1) Dementias represent a global health challenge and also incur high Firstly, the site should have the diagnostic capacity to recognize economic costs. In Slovenia, all dementia costs (medical, formal and potential candidates for treatment. Secondly, the site should be able informal home help, nursing home placements costs) are estimated to prepare the infusions, safely monitor patients (with clinical at 377 million euros. (2) Reducing the dementia severity or even assessments and regular MRI scans) and deal with possible delaying the diagnosis would greatly reduce this burden; e.g. an complications, thus requiring enough room, personnel, and other intervention that would delay the onset of dementia by five years resources. today could reduce costs by 36% in 2050. (3) Since 2009, patients with cognitive complaints can be referred to the The majority of all dementia cases, Alzheimer’s dementia (AD), is Centre for Cognitive Impairments at the Department of Neurology, caused by a progressive accumulation of beta-amyloid protein Ljubljana University Medical Centre, Slovenia. At first visit, a detailed plaques and neurofibrillary tangles, which damage synaptic history is taken from all patients, who also undergo a general connections and neurons and lead to the loss of cognitive abilities. In neurological examination, a screening cognitive assessment and are Europe, there are currently no disease modifying treatments (DMT) further referred for extensive laboratory testing and a structural available and treatment of AD is symptomatic, limited to brain scan. Additional examinations are indicated on a case-by-case acetylcholinesterase inhibitors, memantine and other supportive care basis. For selection of potential lecanemab candidates that would measures, which do not slow or stop the progression of the disease. entail lumbar puncture with CSF analyses. In the past two years However, after two decades of clinical trial failures, we finally received (2021-2022), there were 1,461 first visits, 3,133 control visits and 891 the long awaited positive news on a DMT for AD. On January 6, 2023, lumbar punctures performed in persons with a cognitive complaint. lecanemab, an anti-amyloid monoclonal antibody was approved Pathological CSF biomarker profile was present in 257, however, only under an accelerated pathway by the US Food and Drug half (n = 126) were at the stage of MCI or mild AD and thus potential Administration and is currently under review by the European lecanemab candidates. Medicines Agency. (4) In an 18-month study involving participants with mild AD, lecanemab slowed the rate of cognitive decline by 27%. The cost to evaluate 891 patients with neurological assessment, MRI (5) and lumbar puncture would be around €2.5 million, however, in reality, the costs were even higher since some patients also Are we prepared for potential lecanemab approval by European underwent FDG-PET or neuropsychological examination. Medicines Agency (EMA) and Agency for Medicinal Products and Medical Devices of the Republic of Slovenia (JAZMP)? With dementia prevalence data for Slovenia (1) and an estimation of 7.7% of MCI due to Alzheimer’s disease in persons aged 65 year or With the potential approval of lecanemab we can expect huge more, (6, 7) there are 44,278 potentially eligible candidates for lecanemab treatment. With current annual lecanemab’s price of References: approximately €24,000 and all eligible patients receiving the treatment, this would account to €1,06 billion, which is more than an 1. Alzheimer Europe. Prevalence of dementia in Europe. [27.4.2023]. annual cost for all medication in Slovenia (€743 million in 2022). (8) Available from: https://www.alzheimer-europe.org/dementia/prevalence-dementia-europe. Diagnosing all candidates with a neurological assessment, MRI and lumbar puncture would account to almost €125 million. However, 2. Županič E, Wimo A, Winblad B, Kramberger MG. Cost of Diagnosing since 891 assessments were required to yield 126 potential and Treating Cognitive Complaints: One-year Cost-evaluation Study in a candidates, one must realize that the introduction of lecanemab Patient Cohort from a Slovenian Memory Clinic. Zdravstveno varstvo. would greatly increase the direct medical costs in the healthcare 2022;61(2):76-84 DOI: 10.2478/sjph-2022-0011. system even for patients that would never be treated with the drug. 3. Alzheimer's Research UK. The Power to Defeat Dementia It is clearly unrealistic to recognize and treat all the potential [27.4.2023]. Available from: candidates. Besides Centre for Cognitive Impairments in Ljubljana, https://www.alzheimersresearchuk.org/wp-content/uploads/2015/01/Defeat only Maribor has subspecialized outpatient facilities for patients with -Dementia-policy-report.pdf. cognitive impairment, which probably do not exceed Ljubljana’s 4. Eisai. Marketing authorization application for lecanemab as capabilities. The approval of lecanemab would increase the pressure treatment for early Alzheimer’s disease accepted by European Medicines on these two centres and increase the waiting times. Moreover, even Agency. 2023 [27.4.2023]. Available from: if the drug receives regulatory approval, high cost might cause the https://www.eisai.com/news/2023/pdf/enews202311pdf.pdf. national agency to limit the number of treated patients or even refuse reimbursement altogether. The Institute for Clinical and 5. Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Economic Review (ICER), an independent non-profit research Lecanemab in early Alzheimer’s disease. New England Journal of Medicine. organization that assesses expected clinical benefits against potential 2023;388(1):9-21. side-effects and costs, concluded lecanemab’s price would require a 66% to 19% discount to be considered cost-effective. (9) Therefore, at 6. Overton MC. Assessment of cognition in ageing. Investigating internal validity, occurrence and reversion of Mild Cognitive Impairment. current capacity, the Slovenian healthcare system is unable to Data from the general population study “Good Aging in Skåne”: Lund diagnose and select eligible patients for DMT in Alzheimer’s disease. University; 2019. Substantial investments in personnel, infrastructure and medication alone will be required to provide timely diagnosis and enable 7. Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, et treatment with lecanemab. al. Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimer's & Dementia. 2023;19(2):658-70. 8. EFPIA - European Federation of Pharmaceutical Industries and Associations. The Pharmaceutical Industry in Figures. Key data 2022. 2022. Available from: https://www.efpia.eu/media/637143/the-pharmaceutical-industry-in-figures- 2022.pdf. 9. Grace Lin MDW, Abigail Wright, Foluso Agboola, Serina Herron-Smith, Steven D Pearson, David Rind. Antibodies for Early Alzheimer’s Disease: Effectiveness and Value; Evidence Report. Institute for Clinical and Economic Review. 2023 [27.4.2023]. Available from: https://icer.org/wp-content/uploads/2021/12/ICER_Alzheimers-Disease_Revis ed-Evidence-Report_03012023.pdf. Backgrounds Functional brain networks in The increasing prevalence of neurodegenerative disorders worldwide neurodegenerative disorders has fueled scientific efforts to discover cures for these devastating conditions, which can present with dementia or parkinsonian syndromes (1). Despite tremendous investment and effort, only recently have promising disease-modifying drugs for Alzheimer's disease (AD) been released, with none currently available for Tomaž Rus Parkinson's disease (PD) (2). The lack of understanding of the etiology and pathophysiological mechanisms of these disorders, as well as the absence of pathology-based inclusion criteria, has likely contributed to many failed clinical trials. These factors have motivated researchers to seek Abstract biomarkers that can reflect the disease-specific pathological processes. For instance, while biomarkers such as amyloid-beta, tau, Until recently, neurodegenerative disorders such as Alzheimer's and and phosphorylated tau (p-tau) measured in cerebrospinal fluid (CSF) Parkinson's disease had no medication that could impact their or captured by positron emission tomography (PET), together with progression. Many clinical trials may have failed due to a lack of structural neuroimaging (MRI), have been included in research understanding of the underlying pathophysiological mechanisms and criteria for AD (3), there is emerging evidence that different poorly defined inclusion criteria. As a result, researchers have turned neurodegenerative disorders may be differentiated by studying to identifying biomarkers that can reflect disease-specific pathological topographical differences in functional brain networks (4). These processes. One promising approach is studying disease-specific networks can be detected in patients using various imaging methods, changes in functional brain networks. These networks can be among which the most established are [18F]-fluorodeoxyglucose detected in patients using various functional imaging methods, (FDG) PET and resting-state functional magnetic resonance imaging including [18F]-fluorodeoxyglucose (FDG) positron emission (rs-fMRI) (4). These networks allow us to gain insight into disease tomography (PET) and resting-state functional magnetic resonance mechanisms in vivo and to accurately distinguish between similar imaging (rs-fMRI). Both FDG PET and rs-fMRI can detect changes in syndromes. Both FDG PET and rs-fMRI have been shown to be useful functional brain networks in neurodegenerative disorders, providing tools for detecting changes in functional brain networks in insights into the interdependence or connectivity of various brain neurodegenerative disorders. regions, forming a brain network. Functional brain network mapping Functional imaging techniques differ from structural imaging in that they indirectly measure dynamic metabolic processes or brain activity by assessing regional changes or activity of specific molecules or markers. In FDG PET images, the spatial distribution of radioactive FDG, which accumulates in brain tissue according to metabolic demands and correlates with neuronal activity, can be examined (5). By using simple univariate statistical methods, such as statistical parametric mapping (SPM), which compare individual voxels or regions between patients and healthy controls, we can identify the areas that significantly differ between the groups, thus improving image contrast (6). Advanced algorithms not only analyze individual brain voxels or regions but also consider relationships disruption in other neurodegenerative disorders such as progressive between them, providing insights into the interdependence or supranuclear palsy (PSP) and multiple system atrophy (MSA) connectivity of various brain regions, forming a brain network. regardless of the subtype (14). Several analytical methods, such as principal component analysis We further investigated the internal network structure using a graph (PCA) or graph theory, have been developed for this purpose and are theory approach and found ineffective network reorganization with commonly used (7,8). disconnection between vital network hubs. This may explain the severe cognitive decline in CJD despite preserved metabolism and PCA-based analytical methods have been used for several years to relatively sparse histopathological findings in certain classical identify disease-specific metabolic brain networks in cognition-related brain areas (12). neurodegenerative disorders, which have been rigorously validated in diverse clinical populations worldwide. Recent advances in analytical models have enabled the use of similar methods in four-dimensional Functional brain networks in Parkinson’s disease and related rs-fMRI images, using an alternative independent component analysis disorders (ICA) approach (9). While FDG PET captures static metabolic images within a few minutes, rs-fMRI captures transient fluctuations in blood Parkinson's disease (PD) is characterized by stereotypical spread of oxygenation in different brain regions, closely related to neural pathological changes. Accumulation of α-synuclein begins in the activity due to neurovascular coupling. Both modalities are brainstem and pons, followed by midbrain including the substantia complementary. However, while rs-fMRI is cheaper and more easily nigra. In the advanced stages, the cortical regions are affected available, higher noise makes the image contrast less accurate in (15,16). The clinical features of PD correlate with both the intermediate cases. pathological sequence and changes in functional neural networks. The motor network of PD (Parkinson’s Disease-Related Pattern; PDRP) correlates with bradykinesia and rigidity, while the cognitive network of PD (Parkinson’s Disease Cognitive Pattern; PDCP) correlates with Functional Brain Network Alterations in Creutzfeldt-Jakob's cognitive decline (17). Both networks have been identified and Disease: A Model Neurodegenerative Disorder validated in numerous cohorts worldwide, based on FDG PET and rs-fMRI brain imaging. Creutzfeldt-Jakob's disease (CJD) is often regarded as an in vivo model of neurodegeneration due to the well-known mechanism of prion PDRP topographically includes increased activity (relative protein spread throughout the brain. The prion hypothesis has been hypermetabolism) in the basal ganglia, thalamus, and cerebellum, proposed as a possible explanation for the spread of along with decreased activity (relative hypometabolism) in premotor neurodegeneration in the brain (10,11). Furthermore, although the and posterior parietal areas. Its activity can be modulated by final pathological diagnosis is often unknown in neurodegenerative symptomatic treatment, which improves motor symptoms (18,19). diseases due to their long duration, the rapid progression of CJD and the legal obligation to conduct an autopsy allow for the collection of Changes in the cognitive network PDCP appear with a characteristic well-established and pathology-confirmed cases for study. delay of a few years after the PDRP. PDCP topographically involves the ventral default mode network (DMN) with additional areas of the Our research group has recently identified a CJD-specific metabolic cerebral cortex, such as the dorsolateral prefrontal and medial brain network using the SSM-PCA method and validated it on an parietal cortices (20,21). The temporal sequence of PDRP and PDCP independent cohort from a remote center (12). Despite the clinical expression is stereotypical and consistent with the aforementioned heterogeneity of the disease early in its course, the pattern of the pathological sequence as proposed by Braak (17). network was stable and coherent. Although pathological features differed somewhat among different molecular subtypes, metabolic Symptomatic treatments for PD, such as dopaminergic medication or features were consistent regardless of the molecular subtype and surgical techniques like deep brain stimulation, decrease the correlated with the relative disease duration, cognitive, functional, expression of PDRP (4). Detection of brain alterations on a network and neurological decline (13). This finding was somewhat unexpected level holds potential in evaluating the effectiveness of novel but in line with some studies that showed consistent network disease-modifying treatments. Advanced analytical approaches like graph theory not only allow for the study of network expression but differentiation from each other in a specific topographic arrangement also the examination of changes in network structure (22). By doing of changes in brain activity. As the AD is the most prevalent so, variations in information transmission within the network and neurodegenerative disease, ADRP is most studied network validated other connectivity measures can be assessed. These methods have by many groups and characterized by relatively decreased activity in recently demonstrated particular modifications in network the temporoparietal cortex, posterior cingulate, and precuneus, and organization through genetic therapy for PD using AAV2-GAD relatively increased activity in the cerebellum (29). It’s expression application to the subthalamic nuclei and the impact of drugs that correlates with cognitive decline and may be used to predict affect mitochondrial respiratory function. conversion from mild cognitive impairment to dementia making it a reliable biomarker of disease progression. Despite similar clinical presentation in early disease, atypical parkinsonian syndromes, such as MSA, PSP or corticobasal According to the clinical presentation, DLBRP is topographically degeneration (CBD), have different pathophysiological mechanisms characterized by hypometabolism in occipital lobe while the bvFTDRP and sequences of pathological changes. These syndromes are by frontotemporal hypometabolism (30,31). In case of the latter, the characterized by different disease-specific networks: MSA-, PSP and detailed analysis of internal network structure showed consistent CBD-related patterns (23,24). disruption of functional connections between frontal and occipito-parietal hub (31). An important feature of functional brain imaging network analysis using SSM-PCA/ICA approach is that multiple pathological networks can be prospectively calculated on a single FDG PET or rs-fMRI image. Conclusion For example, in a patient with undefined parkinsonism expressions of several parkinsonian networks such as PDRP, MSARP and PSPRP can The advancement of functional network research in also be calculated. Based on the expression of multiple networks, neurodegenerative diseases in recent years has led to the computer algorithms (logistic, SVM, etc.) can calculate probability of development of robust biological markers that have been confirmed individual disease and significantly improve the accuracy of early in various clinical populations using different imaging methods. These diagnosis (25,26). biomarkers can be used for diagnostic and prognostic purposes, monitoring disease progression, and tracking the effect of new drugs. Recent PD research has concentrated on the prodromal phase of the The next challenge is to test these markers in real clinical settings and disease in order to develop early, or even preclinical, diagnostic identify metabolic patterns from rs-fMRI images. However, progress methods. During this phase, individuals may experience non-specific in the field suggests that the use of functional brain networks in symptoms such as olfactory disturbances, constipation, depression, routine diagnostics and clinical research is within reach. and REM Sleep Behavior Disorder (RBD). Patients with RBD typically go on to develop PD or another α-synucleinopathy, such as MSA or dementia with Lewy bodies (DLB). Functional brain imaging studies have demonstrated that PDRP is already present during the prodromal phase (27,28). PDRP and other related networks are being studied as potential presymptomatic biomarkers for PD. Functional brain networks in cognitive disorders As in parkinsonian disorders, specific metabolic brain patterns characterizing pathological functional brain networks have been identified in several neurodegenerative disorders primarily affecting cognition such as AD, DLB and behavioral variant of frontotemporal dementia (bvFTD), so called ADRP, DLBRP and bvFTDRP (29–31). Specific distribution of interconnected metabolic changes enables References 13. Rus T, Mlakar J, Kramberger M, Pirtošek Z, et al. Correlations between brain metabolism and neuropathology in sporadic 1. Feigin VL, Nichols E, Alam T, Bannick MS, Beghi E, Blake N, et al. Creutzfeldt-Jakob disease. In: Matkovič A, Bresjanec M, editors. SNC21 Global, regional, and national burden of neurological disorders, 1990–2016: [Internet]. Ljubljana: SiNAPSA, Slovenian Neuroscience Association; 2021 a systematic analysis for the Global Burden of Disease Study 2016. Lancet [cited 2022 May 27]. p. 23–23. 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Identification and validation of Alzheimer’s disease-related metabolic brain pattern in biomarker confirmed Alzheimer’s dementia patients. Sci Rep. 2022 Dec;12(1):11752. 30. Perovnik M, Tomše P, Jamšek J, Tang C, Eidelberg D, Trošt M. Metabolic brain pattern in dementia with Lewy bodies: Relationship to Alzheimer’s disease topography. Neuroimage Clin [Internet]. 2022 [cited 2022 Jun 24];35(March):103080. Available from: https://pubmed.ncbi.nlm.nih.gov/35709556/ 31. Rus T, Perovnik M, Vo A, Nguyen N, Tang C, Jamšek J, et al. Disease specific and nonspecific metabolic brain networks in behavioral variant of frontotemporal dementia. Hum Brain Mapp [Internet]. 2022 Nov 5 [cited 2022 Nov 8]; Available from: https://pubmed.ncbi.nlm.nih.gov/36334269/ Reproduced with permission 6 European Stroke Journal 6(1) Review article European Stroke Journal Cognitive impairment in patients with Introduction Findings 2021, Vol. 6(1) 5–17 ! European Stroke Organisation Vascular risk factors are recognized as one of the main cerebrovascular disease: A white paper 2021 How to recognize cognitive complaints/impairment Article reuse guidelines: determinants of cognitive impairment associated with from the links between stroke ESO sagepub.com/journals-permissions ageing.1,2 Cognitive impairment (CI) due to cerebro- Cognitive impairment due to CVD can occur in differ- DOI: 10.1177/23969873211000258 vascular disease (CVD) can exist after stroke or in ent settings: after a stroke (PSCI), in the acute stage, in Dementia Committee journals.sagepub.com/home/eso the context of chronic CVD without previous stroke, the recovery stage (while other stroke symptoms representing a leading concern of patients and care- improve), or delayed until months/years after stroke. givers.3 Although acute stroke care has evolved sub- When CI due to CVD follows repetitive or chronic stantially over the last decades, post-stroke cognitive vascular lesions, identification of those symptoms Ana Verdelho1 , Joanna Wardlaw2 , Aleksandra Pavlovic3, impairment (PSCI) remains frequently underdiagnosed may be difficult as they might be quite subtle and mis- leading. Characteristically, and apart from focal cogni- Leonardo Pantoni4 , Olivier Godefroy5, Marco Duering6,7, as it may be overlooked in the presence of other dis- tive symptoms due to stroke itself (such as aphasia and Andreas Charidimou8,9, Hugues Chabriat10 and tressing signs (for instance motor or visual symptoms). hemineglect), the initial symptoms may be hard to iden- Geert Jan Biessels11 Consequently, cognitive impact of acute stroke is often underestimated. Moreover, subtle and progressive tify. These symptoms might include reduced initiative decline might also be caused by vascular lesions (e.g. for usual tasks, slowness, and higher latency to start an answer/action. Patients may accept undertaking either lesions related to small vessel disease (SVD), actions if externally motivated and initiated and more Abstract repetitive minor injuries, or vascular consequences of time may be needed. Because attention is impaired, Purpose: Many daily-life clinical decisions in patients with cerebrovascular disease and cognitive impairment are com-systemic failure as for instance cardiac insufficiency). patients are easily distracted even by irrelevant stimuli. plex. Evidence-based information sustaining these decisions is frequently lacking. The aim of this paper is to propose a Stroke clinicians are well trained in the identification of Multi-tasking can be difficult, not only due to attention practical clinical approach to cognitive impairments in patients with known cerebrovascular disease. stroke, but do not always recognize the myriad of cog- shifting difficulties, but also to difficulty in alternating Methods: The document was produced by the Dementia Committee of the European Stroke Organisation (ESO), nitive and behavioural symptoms that accompany between different tasks and patients may have difficul- based on evidence from the literature where available and on the clinical experience of the Committee members. This stroke in the acute and chronic phases. ties in making decisions. Sometimes, behaviour is pre- paper was endorsed by the ESO. dominantly affected and proxies/families acknowledge Findings: Many patients with stroke or other cerebrovascular disease have cognitive impairment, but this is often not Methods some “personality” changes. Behaviour changes can recognized. With improvement in acute stroke care, and with the ageing of populations, it is expected that more stroke co-exist or even be the only initial manifestation, such survivors and more patients with cerebrovascular disease will need adequate management of cognitive impairment of This paper is a result of an effort of the ESO Dementia as more inflexible behaviour, with reduced tolerance to vascular etiology. This document was conceived for the use of strokologists and for those clinicians involved in cerebro-Committee (2018-2020), under the approval of the ESO changes of routine activities and repetition of the same vascular disease, with specific and practical hints concerning diagnostic tools, cognitive impairment management and Executive Committee, aiming to produce some practi-mistakes (as patients may not be able to correct them- decision on some therapeutic options. cal clinical suggestions on the identification, diagnosis selves). Control of inhibition may be disturbed, loss of Discussion and conclusions: It is essential to consider a possible cognitive deterioration in every patient who experi-and management of CI for clinicians involved in the control of emotional expression, as well as socially ences a stroke. Neuropsychological evaluation should be adapted to the clinical status. Brain imaging is the most management of patients with stroke. Its use is not only inappropriate manifestations (even sexually inappro- informative biomarker concerning prognosis. Treatment should always include adequate secondary prevention. for strokologists, but also for others professionals priate behaviour), although these latter are usually involved in the management of patients with CI due less frequent and occur in more advanced stages. to vascular pathology. Several comprehensive and Keywords Patients may be labelled as “depressed” although usu- updated reviews are available on the topic, acknowl- Stroke, small vessel disease, cerebrovascular disease, cognitive impairment, dementia ally do not complain of sadness, and other key aspects edged throughout this paper, and we did not aim to do of depression are not present. As a result of the symp- Date received: 1 February 2021; accepted: 4 February 2021 an exhaustive or systematic review or to cover all cur- toms above, patients reduce their level of social inter- rent evidence. We tried to incorporate differences of action, quit usual hobbies and sometimes relatives/ approach and access to ancillary investigations, keep- caregivers takeover tasks intuitively. The keystone for ing in mind the standard usual best practice. considering the above symptoms as a manifestation of 7Department of Biomedical Engineering, University of Basel, Basel, Concerning CI in the context of CVD, different ter- CVD is that they represent a change from a previous 1Department of Neurosciences and Mental Health, CHLN-Hospital de Switzerland minologies exist,4–6 and consensus is missing, although way of functioning, implicate an adaptation in daily- Santa Maria, Instituto de Medicina Molecular – IMM e Instituto de Sa ude 8Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research those terms refer broadly to the same or quite similar life, and finally, CVD is the presumed etiology. Ambiental –ISAMB, Faculdade de Medicina, University of Lisbon, Lisbon, Center, Department of Neurology, Massachusetts General Hospital, entities. In order to be practical, for the purpose of this Portugal Harvard Medical School, Boston, MA, USA Evolution might be stepwise, progressive, or fluctuant. 2Centre for Clinical Brain Sciences, UK Dementia Research Institute, 9Department of Neurology, Boston Medical Center, Boston University paper, we will use vascular dementia (VD),4 major vas- If only the patient is interviewed, it is possible to miss University of Edinburgh, Edinburgh, UK School of Medicine, Boston, MA, USA cular cognitive impairment/disorder5 and the more the picture. Interview of a proxy(ies) may be necessary, 3Faculty for Special Education and Rehabilitation, University of Belgrade, 10Department of Neurology, FHU NeuroVasc, Hoˆpital Lariboisiere, recent major vascular neurocognitive disorder but beware of the patient who always looks to the part- Belgrade, Serbia University of Paris, Paris, France 4 (NCD)6 interchangeably, and where less severely ner to answer and the obliging partner who provides all Stroke and Dementia Lab, "Luigi Sacco" Department of Biomedical and 11Department of Neurology, UMC Utrecht Brain Center, University Clinical Sciences, University of Milan, Milan, Italy Medical Center Utrecht, the Netherlands affected, we use mild cognitive impairment/disorder the responses. Separate interview of the informant/rel- 5Department of Neurology, Amiens University Hospital, Laboratory of or mild NCD.5,6 Post-stroke dementia (PSD) or post- atives should be considered whenever interview of both Functional Neurosciences1,6 (UR UPJV 4559), Jules Verne Picardy Corresponding author: stroke cognitive impairment (PSCI) will be used when patient and relative becomes a sensitive point, as rela- University, Amiens, France Ana Verdelho, Department of Neurosciences, Hospital de Santa Maria, it refers to stroke patients, irrespectively of the time 6 tives/caregivers might be uncomfortable giving some Institute for Stroke and Dementia Research, University Hospital, LMU University of Lisbon, Av Prof. Egas Moniz, Lisbon, Portugal. Munich, Germany Email: averdelho@medicina.ulisboa.pt elapsed since stroke. information or describing some details in the presence Reproduced with permission Verdelho et al. 7 8 European Stroke Journal 6(1) of the patient. This separate interview should, never- without clinical stroke, a situation which is especially Table 1. Diagnostic evaluation of patients with CI-CVD. theless, follow usual good practice approaches. encountered in small vessel disease (SVD). Step Aim of investigation Purposefully the VASCOG criteria5 included this situ- Criteria for CI and for CI due to CVD ation and consider the diagnosis of CI due to CVD Risk factor assessment Stroke subtype when deficits in executive functions and/or action Increased risk associated with haemorrhagic (comparing to ischemic strokes) Several sets of criteria for CI due to CVD have been speed are prominent and associated with at least one Increased risk in cardioembolic etiology and large artery atherosclerosis proposed,4,5 most of them requiring to demonstrate the out of three features (gait disturbances, urinary control Clinical assessment Detection of CI and other manifestations (depression, apathy). presence of CI, the presence of cerebral vascular lesions disorders or mood changes). Functional status assessment and a relationship between them. The VASCOG crite- Brain imaging (MRI, if MRI preferred mode of examination ria5 have the advantage to define criteria for both mild contraindications: CT) Differential diagnosis to other conditions causing CI. How to evaluate the neuropsychological status in and major CI (based on the DSM-V)6 and for both Identification of CVD type, location, and extent of CVD patients with stroke and those without stroke. This is stroke patients Laboratory investigations Risk factor identification especially important considering studies showing that a (blood, CSF) Differential diagnosis to other conditions Regarding stroke patients, we will focus on the post- large proportion of patients with CI related to a cere- acute phase, i.e., 3 to 6 months post-stroke. Cognitive CI – cognitive impairment; CVD – cerebrovascular disease; CSF - cerebrospinal fluid; MRI- Magnetic resonance imaging; CT- computerized tomography. brovascular lesion did not have a clinically-evident assessment at the acute stroke onset should be per- stroke.7 formed as part of the neurological examination and The criterion of CI is operationalized in the diagnos- contributes to the diagnosis of the acute condition in found to be associated with PSCI, major CI, in partic- both tests underestimate the impairment in a significant tic criteria of CI due to CVD,4,5 although this opera- the emergency room; in the stroke unit it usually con- ular.10,16,22 A recent study has identified a minimal set proportion of affected patients, i.e. they miss about one tionalization still lacks consensus. Diagnosis of mild CI sists of clinical assessment and screening tests with, of factors for selecting patients at risk of full-spectrum fifth of cognitively impaired patients, a proportion frequently uses the 1.5 standard deviation threshold on when needed, language or hemineglect tests to PSCI.21 The Rankin score represents an important step which increases in mild PSCI. In addition, their specif- cognitive testing following criteria of Winblad et al.8 manage early rehabilitation.12 More detailed informa- provided it is graded with a reliable informant, using a icity is also lower than 100%,28,30,32 indicating that two thresholds have been proposed in the DSM-V (1 tion is already published.12 Although most post-stroke structured interview (including difficulties in instru- mildly decreased scores might be observed in subjects and 2 standard deviations for mild CI and major CI, assessments are now performed within 3-6 months, mental activities of daily living).23 Except in specific with normal comprehensive assessment. Score interpre- respectively).6 In addition, some teams and studies timing of neuropsychological assessment may influence situations (e.g. return to a complex occupation), a com- tation needs to take into account the first language, applied these thresholds to each performance score or the profile of CI: marked improvement in speed and prehensive assessment might be considered to be futile education level (for both tests) and age (for MoCA) to each domain summary scores. Moreover, different 28,33 attention, frontal executive functions, perceptual and in patients having regained all pre-stroke activities ; their scores might also be influenced by sensory- results can be due to the chosen operationalized crite- nominal skills can occur over time, compared to without any concerns (i.e., Rankin score¼0), and in motor deficit, deficits in language and perception ria9 since normative data depend on selection of the stable findings in verbal and visual memory.13,14 bedridden patients (i.e., Rankin score¼5). In the (hemi-neglect). Hence, it important to highlight that controls (volunteers, community or not community, We propose that the initial full neuropsychological same vein, comprehensive assessment is usually unnec- screening tests scores need always to be integrated in with or without brain imaging), which can, per se, evaluation should only be conducted after some stabi- essary for diagnosis in patients with substantial impair- the clinical context and in the whole condition of the limit interpretation of findings. A strict and explicit lization was achieved (possibly as late as 6 months after ment on screening tests. patient, in order not to over value results of the screen- harmonization is needed as the use of different proce- a severe stroke), unless specific cognitive training could The administration of a comprehensive neuropsy- ing tests. dures deeply influences the interpretation (at least in be advised earlier (for instance cognitive intervention chological battery is the gold standard for the diagnosis Assessment of cognitive abilities is difficult in patients with mild impairment) and the false positive for neglect). We do not advise to test and re-test repeat- of CI but may be complex to perform and not feasible patients with severe aphasia. In such cases diagnosis rate.10,11 The use of a global cognitive score summariz- edly, unless specific questions arise (search for associ- in all stroke survivors and requires suitable quiet and of PSCI is usually made on the basis of an aphasia ing all domains and the fifth percentile threshold has ated degenerative disease, driven ability or other legal uninterrupted settings. Hence, the first line of cognitive battery and screening test. Further assessment might been shown to improve sensitivity while controlling for reason, or working difficulties and need for retirement assessment usually relies on clinical examination and be necessary to determine the cognitive profile (i.e. specificity [i.e. false positive rate].10 Whatever the evaluation, for instance). In case re-test is needed for screening tests such as Informant Questionnaire on associated memory disturbances, executive dysfunction chosen procedure, it is essential to ensure that it pro- clinical clarification, an ideal interval of 12 months Cognitive Decline in the Elderly (mainly used to iden- and action slowing). When comprehension abilities vides an optimal sensitivity and controls specificity ade- should be considered to avoid learning bias between tify pre-stroke CI),24 MiniMental Status Examination allow the use of cognitive tests, further cognitive assess- quately. In addition, the selection (volunteers vs evaluations. (MMSE)25 and Montreal Cognitive Assessment ment is usually based in non-verbal tests including general population), demographic characteristics (rep- PSCI is observed in about 50% of stroke survivors, (MoCA).26 These instruments are a first step and visual recognition tests (such as the Doors test, for resentation of older and low education subjects) and two thirds of them corresponding to mild CI, and one may identify different severities of CI. We must more details Table 2 in supplementary material), rea- size sample of normative population influence the third to major CI according to present CI criteria (see acknowledge that MMSE and MoCA do not have soning on visual material (such as Progressive determination of cognitive test cutoff scores. previous section).11,15,16 PSCI has a marked effect on interchangeable results. MoCA tests included more Matrices), visual-motor tests assessing attention and The characteristics of vascular lesions in the brain functional prognosis, risk of institutionalization15,17,18 nonverbal and non-memory items (namely visuospa- processing speed (such as cancellation test, digit are detailed in the subsection ‘Predictors of CI and and risk of recurrence of a major vascular event.19,20 tial/executive functions and attention) compared to symbol modalities subtest). dementia’. The relationship between CI and cerebro- Optimal diagnosis of PSCI should be based on com- MMSE. A recent systematic review indicated good to vascular lesions is typically operationalized by its tem- prehensive cognitive assessment in patients at risk of excellent accuracy, good internal consistency and good Which tests should be used in patients with poral course (i.e., onset within 3 months of diagnosed CI. Although this is always a clinical indication, and reliability of MoCA in differentiating between both suspected CI due to CVD? stroke, abrupt onset, or stepwise progression).4,5 should, in the end, based on the individual level, some mild CI and major CI patients from controls.27 However, abrupt onset is rare in the absence of a cues can be given: this objective can be achieved using a Nevertheless, despite the mildly higher sensitivity of Considering the profile of vascular CI, a comprehen- stroke, and stepwise progression is infrequent owing recently explored strategy based on risk factors of PSCI MoCA as compared to MMSE,27 a low specificity28,29 sive test/battery should assess attention, action speed to better prevention of stroke recurrence. This excludes (Table 1 provided in supplementary material, and still limits its use and both tests have only moderate to (also called psychomotor speed or processing speed), patients with non-acute CI due to vascular lesion “Predictors” section).21 Several factors have been good sensitivity for the diagnosis of PSCI.28–31 Thus, cognitive and behavioural executive functions, episodic Reproduced with permission 10 European Stroke Journal 6(1) Verdelho et al. 9 particular of the Alzheimer‘s disease (AD) type, are the level of education, early-life intelligence (also reflected Table 2. MRI sequences in CI due to CVD should include:59,80 most obvious candidate predictors. An association in type of job), leisure activities, as well as employment Sequence Provides information on: between pre-existing AD pathology detected by amy- and relationship status pre-stroke.10,57–60 loid positron emission tomography (PET) and PSD The Oxford Vascular Study22 is at present the larg- T1-weighted Brain morphology, focal or diffuse atrophy T2-weighted or fluid-attenuated inversion recovery (FLAIR) White-matter hyperintensities, old vascular lesions early after stroke has indeed been shown.49 However, est prospective incidence study for PSD. Stroke severity Diffusion-weighted imaging (DWI) Number, size and location of most recent ischemic lesions several studies do not support a prominent role of amy- as measured by the National Health Institutes Stroke Susceptibility-weighted imaging (SWI)/GRE-T2* Microbleeds, cortical superficial siderosis loid pathology in delayed PSCI50 or PSD,45,51 i.e., CI Scale (NIHSS)61 score was one of the strongest predic- occurring months to years after stroke. tors of PSD. Other factors were age, previous stroke, MRI markers of SVD, such as WMH, lacunes, and recurrent stroke, dysphasia, baseline cognition, low memory, language, and visuo-constructive abilities as predicting cognitive deterioration. While age and initial cerebral microbleeds should be assessed since these all education, pre-morbid dependency, leukoaraiosis - on well as depressive symptoms. When needed, this first clinical status (cognitive and functional assessments) increase the risk of PSCI.52 A large comprehensive sys- brain imaging-, and diabetes. The latter is of particular line of tests should be followed by optional tests assess- already predict future cognitive decline and incident tematic review and meta-analysis clearly demonstrates interest for clinicians, since it was the only vascular risk ing aphasia, hemi-neglect, agnosia, etc. Cognitive dementia to a large extent, brain MRI has added a strong association between increasing severity of factor associated with PSD. This suggests that intensi- testing should anyway be adapted for the age and value.36 Although volumetric measures, such as total WMH (on MRI or CT) and several adverse outcomes fied risk factor management post-stroke might be most sociocultural context, beyond specific stroke deficits. brain volume, white matter volume and hippocampal including subsequent dementia.52 Nevertheless, this effective in the case of diabetes, or reflect that hyper- The battery of tests is now standardized owing to the volume, emerged as the most consistent imaging pre- association becomes less strong with aging, when tension and hyperlipidaemia are already now well man- Harmonization Standards protocol battery.34 This bat- dictors,37,38 their practical use in non-specialized clini- degenerative pathology (AD type) probably superim- aged. Recent data from the same study found that tery has been adapted into multiple languages and cul- cal settings is scarce. Baseline white matter posed on the impact of WMH.53 However, many stud- APOE e4 homozygosity was associated with PSD, rein- tures and interestingly it provides similar cognitive hyperintensities (WMH) and lacunes (cavitated lesions) ies did not account for factors such as premorbid forcing the conviction of the influence of a previous profiles across countries, which sustains evidence for have also been identified as independent predictors.37,39 cognitive ability or resilience/reserve (discussed neurodegenerative pathology.62 the robustness and generalizability of the included More novel markers, such as diffusion (tensor) imaging below), which may partly account for the apparent Still concerning stroke survivors, a combined cogni- tests (detailed tests and references provided in Table 2 and structural network analysis, show potential,40,41 ‘looseness’ of the association between WMH burden tive risk score based on four easily documented factors of supplemental material). Other studies have used neu- but still need further development and simplification and cognition.54 Given these results, the effect of (severity of neurological deficit, presence of multiple ropsychological assessment, albeit different, that per- to be applicable in clinical routine care. some other predictors of delayed PSCI, such as diabe- strokes, multiple deep WMH corresponding to mitted pooled analysis, including the main cognitive tes, might at least in part be mediated by cerebral SVD, Fazekas score 2 and a mild decrease of MMSE domains identified by harmonization standards Neuroimaging predictors of post-stroke cognitive impairment. and is potentially modifiable through better risk factor score, i.e., adjusted MMSE score from 21 to 27) pro- protocol.35 Specific MRI markers as post-ischemic event predic- control. The fact that delayed CI occurs months to vided a very good screening strategy21 but remains to Difficulties in activities of daily living (ADL) should tors have been summarized in a recent review.42 The years after the initial stroke might open a time be tested independently and more widely in other be assessed using scales that can distinguish those dif- most consistent neuroimaging predictors of PSCI, in window for therapeutic interventions, again emphasiz- cohorts before adoption into practice. ficulties due to CI (as needed for a diagnosis of major addition to clinical predictors, were global and medial ing the importance of risk factor treatment after the A last word considering age. Although age is an CI) from those due to sensory-motor deficit and less temporal lobe atrophy.42,43 These data suggest that it acute event. important predictor, PSCI, both acute and delayed, is frequently, to psychiatric disorders,4,5 as physical might be beneficial to use brain imaging (computerized From a practical point of view, infarct volume and not infrequent in young stroke survivors, and consid- impairment can be a confounder for diagnosis.10 As tomography - CT- or MRI) to identify stroke patients location, in combination with WMH, microbleeds and ering relative risk (although not absolute risk), the this distinction (critical for the diagnosis of major CI) with these atrophy patterns. Volume and location of atrophy (globally and medial temporal lobe), may be dementia risk is greater in younger populations.16,22 may be challenging, some studies have used an adap- the infarct (including lacunes) and strategically- the most important neuroimaging predictors of PSCI,51 Inspite of that, predictors of post-stroke cognitive tation of instrumental activities of daily living assess- located infarcts were also found to be major predic- providing added value on top of clinical variables. status in this subpopulation are largely ment, with additional questions and examination that tors.43 Interestingly, data from the large STRIDE Finally, it should be mentioned that predictors of understudied.63,64 identify the mechanism (sensory-motor, cognitive or study suggests that imaging predictors for PSCI may minor and major CI after ischemic stroke and after psychiatric depressive) accounting for the decline of differ depending on the time point of CI symptom intracerebral haemorrhage appear to be largely simi- Complementary investigations not to be missed each activity.10 This poorly investigated area still onset.44 While early PSCI showed the strongest associ- lar,22 with haemorrhagic stroke associated with an ation with infarct features (mostly size and location), The large clinical and neuroimaging heterogeneity of requires additional validation studies. increased risk of PSCI compared with ischemic delayed PSCI was strongly associated with (pre-exist- stroke.48,55 CI due to CVD explains the difficulty of developing a ing) SVD on MRI,45 although these findings await rep- standardized medical evaluation in the clinical setting Predictors of CI lication in other studies. PSCI risk may differ according Clinical predictors. Predictors are of particular interest in for all types of CI due to CVD.65,66 Several factors have been identified as predictive of to stroke subtype, with an increased risk of CI for the context of PSCI, to identify patients at high-risk for It should go without saying that all patients who are future mild or major CI in patients with CVD disease. cardioembolic etiology and large artery atherosclero- CI promptly identified after the acute event. Multiple seen in a CVD clinic have a comprehensive evidence- These factors can be informative for clinicians regard- sis,46,47 while others reported no differences after studies on PSCI identified predictors related to the con- based vascular risk factors assessment67,68 and a work- ing counselling of patients and relatives as well as selec- adjustment for other factors such as stroke severity cept of brain resilience or reserve.44 This concept up for determining the stroke subtype and potential tion of patients for more intensive follow-up and for and premorbid status,48 or noted a significant progres- addresses the phenomenon that the same level of underlying mechanism.69–71 The underlying source of clinical trials. sive trend of CI among patients with small vessel dis- brain pathology leads to different levels of CI depend- vascular brain damage should be pursued in all CI due ease and lacunes up to 5 years after stroke47 (Table 1). ing on the premorbid condition of the brain and pre- to CVD patients72 in order to prevent subsequent/ Neuroimaging predictors of cognitive impairment in small Pre-stroke brain pathology may contribute to cog- sumably its ability to actively compensate for the recurrent strokes. vessel disease. In patients with cerebral SVD (but not nitive decline after stroke by increasing the susceptibil- damage.56 Or. in other words, lower resilience leads Clinical assessment of patients with CI due to CVD necessarily with history of stroke), clinical status and ity to CI. Because of their high prevalence in the to a greater susceptibility for PSCI. Predictive factors should include the analysis of typical cognitive changes brain magnetic resonance imaging (MRI) aid in elderly, SVD and neurodegenerative pathology, in attributable to the concept of resilience or reserve are (described above) but also the recognition of non- Reproduced with permission Verdelho et al. 11 12 European Stroke Journal 6(1) cognitive manifestations of CVD such as depression, evaluation of the likely cause of CI. In this context, Treatment to improve cognition in patients with CI randomized studies),99 but globally, multi-domain apathy, motor disability, gait difficulties, balance prob- the best imaging tool is brain MRI, which can be con- due to CVD interventions, including non-pharmacologic and life- lems, sensorimotor deficit(s), sphincter control dys- sidered as the gold standard for diagnosis of CI due to style modifications showed no consistent benefit in cog- function, parkinsonism, pseudobulbar palsy and all CVD,65 although CT scanning is the most widely avail- Currently, there is no specifically approved treatment nition in stroke survivors.100–103 their possible functional consequences in daily life able method and provides relevant information on for CI due to CVD. A systematic review of cholines- Patients with CI due to CVD should be treated as (Table 1). stroke type and pre-stroke brain changes including leu- terase inhibitors (donepezil, rivastigmine, galantamine) usually recommended after the occurrence of an acute While functional outcome in patients surviving koaraiosis and atrophy. MRI examination should and N-methyl-d-aspartate receptor antagonists (mem- ischemic or haemorrhagic stroke.104 In patients with a acute stroke is well-established, comprising measures include sequences shown in Table 2. antine) suggested that these drugs improved cognition past history of ischemic stroke, there is accumulating of disability (modified Rankin scale score)73 and func- MRI can also show suggestive patterns of lesions in in CI due to CVD, but did not improve behaviour or evidence suggesting that the number of microbleeds on tional independence (Barthel Index),74 other aspects of favor of specific underlying disorders; Cerebral functional status.94,95 It should be noted, however, that MRI imaging should no longer be considered as a activities and functional disturbances in daily living are Autosomal Dominant Arteriopathy with Subcortical due to the limitations of inclusion and diagnostic crite- contra-indication to antithrombotic drugs.105 Recent multifaceted, nuanced, difficult to delineate and not ria, the vascular origin of cognitive impairment could Infarcts and Leukoencephalopathy (CADASIL) is data support that in the vast majority of cases, the well assessed using specific tools.65,66,75–77 Cognitive not be determined in all participants in any of the trials. often associated with temporal pole T2 hyperinten- absolute risk of ischemic events largely exceeds that impairment and executive dysfunction, in particular, More dropouts and adverse events (anorexia, nausea, sities; cerebral amyloid angiopathy (CAA) often leads of haemorrhages. Only the presence of lobar haemor- as well as depression and apathy, may all have a sig- vomiting, diarrhea, and insomnia) occurred with cho- to lobar macro- and microbleeds and cortical superfi- rhage in probable CAA, anticoagulant should be thor- nificant impact on patients’ functional abilities and linesterase inhibitors compared with memantine. In cial siderosis.86,87 Diffusion tensor imaging that can oughly discussed dependent on the level of risk of independence.78 One practical way to assess this CADASIL, a pure form of VD,96 the use of donepezil probe the microstructure of white matter (even in oth- ischemic events. impact is using the interview, with a relative/caregiver. was also found to improve some executive performan- erwise normal appearing brain tissue), as well various Particular attention must be paid to patients with CI The interview should include aspects mentioned before ces but without improving activities of daily living.97 refined MRI modalities (high-resolution MRI systems, due to CVD when cognitive deficits are severe, to assess in “how to recognize cognitive impairment/ Hence, these drugs are not recommended when CI or proton NMR spectroscopy and dynamic contrast- the risk related to therapeutic compliance, including complaints” such as abandonment of leisure activities, dementia is of purely vascular origin. However, they enhanced MRI) can provide information about the errors or misunderstanding regarding the use of antith- change of habits. can be considered at individual level when the vascular tissue status but are not used in daily clinical prac- rombotic treatments.106 In some individuals, a caregiv- component of dementia is associated with a degenera- tice.40,79,88 Neuroimaging acquisition, interpretation er may be needed to control the treatment tive disease such as AD, which might be the case in Laboratory analysis in CI due to CVD and reporting of cerebral SVD are now better stan- administration. When in doubt, treatments that many patients seen in daily practice, particularly expose a high risk of complications might be avoided. No specific laboratory analysis or biomarker in the dardized, and the Standards for ReportIng Vascular older patients. blood or cerebrospinal fluid (CSF) is available yet for changes in nEuroimaging (STRIVE) criteria have No significant effect was detected on CI due to CVD Reperfusion therapies in presence of CI determining the exact vascular injury responsible for CI been proposed to better define MRI lesions.89 In using nimodipine, piracetam, huperzine A, cytidine di- due to CVD.67 However, blood laboratory tests can patients with MRI contraindications, CT scans can phosphocholine and vinpocetine. Other molecules have There is no study examining specifically the potential help identify and monitor vascular risk factors. depict atrophy, intracranial haemorrhage, acute and shown a limited benefit in patients with CI due to CVD of thrombolysis or thrombectomy to treat acute ische- In patients with SVD, CSF studies may help in dif- old infarcts, and, to a lesser degree, lacunes and exten- (dl-3-n-butylphthalide, gingko biloba extract, cerebro- mic stroke in patients with CI due to CVD. However, ferential diagnosis of inflammatory myelin disorders or sive WMH.67 The use of fluorodeoxyglucose -PET is lysin, actogevin).72,98 The results were obtained in small the risk of death and haemorrhage is not increased in to exclude vasculitis.79 CSF protein examination can not helpful for differentiating AD from patients with samples or only in subgroups of individuals and were persons suffering from dementia107 and there is some provide evidence of blood-brain barrier disruption vascular pathology.90 In a recent meta-analysis, PET not replicated at large scale. Therefore, we see no evi- evidence that persons with dementia may benefit as do (increased albumin amyloid positivity (a classical feature in presence of other acute stroke patients from intravenous rt-PA.108 CSF to albuminblood ratio).60,79 dence to recommend these drugs in patients with CI Analysis of CSF markers of cortical neuronal degen- CAA or AD) has been reported in elderly APOE e4 due to CVD. Therefore, thrombolysis or thrombectomy should be eration and amyloid pathology may help in detecting carriers meeting the criteria of VD, and a further In conclusion, the use of cholinesterase inhibitors considered in all acute stroke patients including those mixed etiologies (namely with AD -reduced amyloid increase may be observed in PSD subjects,50,67,91 sug- and memantine might be considered in patients with with CI due to CVD. However, the premorbid level of b1-42 - also detected in amyloid angiopathy - associat- gesting a contribution from AD pathology, and a CI due to CVD only very cautiously and on a case- function, quality of life, social support and life expec- ed with increased phosphorylated-tau).79 Other multi- mixed etiology in older patients with PSD. by-case basis where AD is thought to contribute, tancy should be weighted whenever possible before ple markers are so far of limited value in clinical depending on the authorization available in the coun- deciding to treat as they can be major determining fac- practice,80–83 such as serum and CSF inflammatory Integration of diagnostic information and diagnostic try, the individual tolerance of the treatment and the tors in outcome.107 markers, markers of extracellular matrix breakdown labels perceived benefit during follow-up. Hence, the use of cerebral reperfusion therapies (matrix metalloproteinases) or of neuroaxonal should not be ruled out in patients with CI. Complementary investigations may be needed for the damage (serum neurofilament light chain), markers of Individual decisions of not to treat maybe taken, differential diagnosis of MRI-identified lesions (e.g. Prevention in patients with CI due to CVD hypercoagulable state, oxidative stress as well as other namely in situations where autonomy is already severe- vascular versus demyelinating lesions in younger In patients with CI due to CVD or at risk of developing metabolic markers (e.g., homocysteine). ly affected and when large lesions cannot be significant- patients, or differential diagnosis of white matter CI of vascular origin, it is obviously crucial to prevent ly reduced by the treatment. lesions at different ages)92,93 or for identifying associ- the occurrence of any new stroke event or incident cere- Neuroimaging in CI due to CVD ated disorders, particularly neurodegenerative condi- brovascular lesion. The assessment of the underlying Neuroimaging will have been performed in most tions that develop with aging.79 In hereditary forms Discussion and conclusion CVD and all measures to reduce its progression patients in the acute setting to assess the stroke sub- of CI due to CVD, the patient should be referred to a should be undertaken in all patients. Additional investigations are needed to improve the type, and to plan the secondary prevention strategy at comprehensive center enabling diagnosis of genetic dis- Control of vascular risk factors and lifestyle changes management of cognitive disorders due to cerebrovas- individual level (Table 3 in supplementary materi- eases which can help to reduce unnecessary diagnostic have limited effects at cognitive level, with exception of cular pathology. The development of innovative pre- al).66,72,84,85 This imaging can also support the procedures and implement treatment strategies. hypertension (with suggestions of some benefit from ventive therapies in stroke patients that can further Reproduced with permission Verdelho et al. 13 14 European Stroke Journal 6(1) reduce the risk of vascular brain damage will remain paper and we thank the European Stroke Organization for neurology of stroke. 2nd ed. Cambridge: Cambridge cognitive impairment: a systematic review. Int J the best guarantee for decreasing the risk of cognitive supporting and for the endorsing this initiative. University Press, 2013, pp. 22–31. Geriatr Psychiatry 2019; 34: 1114–1127. decline. Any progress in the management of all types of 13. Hurford R, Charidimou A, Fox Z, et al. Domain-spe- 28. Godefroy O, Fickl A, Roussel M, et al. Is the Montreal CVD will be essential in this context. 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(stroke and cognition consortium): an international con- Funding tical manual of mental disorders. 5th ed. Arlington: 21. Godefroy O, Yaiche H, Taillia H, et al. Who should sortium to examine the epidemiology, diagnosis, and The author(s) received no financial support for the research, American Psychiatric Association, 2013. undergo a comprehensive cognitive assessment after a treatment of neurocognitive disorders in relation to authorship, and/or publication of this article. 7. Vermeer S E, Prins ND, den Heijer T, et al. Silent brain stroke? A cognitive risk score. Neurology 2018; 91: cerebrovascular disease. Alzheimers Dement (Amst) infarcts and the risk of dementia and cognitive decline. e1979–e1987. 2016; 7: 11–23. Ethical approval N Engl J Med 2003; 348: 1215–1222. 22. Pendlebury ST and Rothwell PM. Incidence and prev- 36. Chabriat H, Herve D, Duering M, et al. Predictors of 8. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive alence of dementia associated with transient ischaemic clinical worsening in cerebral autosomal dominant arte- Our institution does not require ethical approval for report- impairment–beyond controversies, towards a consensus: attack and stroke: analysis of the population-based riopathy with subcortical infarcts and leukoencephalop- ing individual cases or case series. report of the international working group on mild cog- Oxford Vascular Study. Lancet Neurol 2019; 18: athy: prospective cohort study. Stroke 2016; 47: 4–11. Informed consent nitive impairment. J Intern Med 2004; 256: 240–246. 248–258. 37. Jouvent E, Duchesnay E, Hadj-Selem F, et al. 9. Pendlebury ST, Mariz J, Bull L, et al. Impact of differ- 23. Godefroy O, Just A, Ghitu A, et al. Rankin scale with Prediction of 3-year clinical course in CADASIL. Informed consent for patient information to be published in ent operational definitions on mild cognitive impair- revised structured interview. Int J Stroke 2012; 7: Neurology 2016; 87: 1787–1795. this article was not obtained because this was an audit. ment rate and MMSE and MoCA performance in 183–184. 38. van Uden IW, van der Holst HM, Tuladhar AM, et al. transient ischaemic attack and stroke. Cerebrovasc Dis 24. Jorm AF. A short form of the Informant Questionnaire White matter and hippocampal volume predict the risk Guarantor 2013; 36: 355–362. on Cognitive Decline in the Elderly (IQCODE): devel- of dementia in patients with cerebral small vessel dis- AV. 10. Barbay M, Taillia H, Nedelec-Ciceri C, et al. Prevalence opment and cross-validation. Psychol Med 1994; 24: ease: the RUN DMC study. J Alzheimers Dis 2016; 49: Contributorship of post-stroke neurocognitive disorders using NINDS- 145–153. 863–873. CSN, VASCOG criteria and optimized criteria of cog- 25. Folstein MF, Folstein SE and McHugh PR. “Mini- 39. Pavlovic AM, Pekmezovic T, Tomic G, et al. Baseline All authors contributed equally to conceive the manuscript, nitive deficit. Stroke 2018b; 49; 1141–1147. mental state”. A practical method for grading the cog- predictors of cognitive decline in patients with cerebral the structure of paper, literature research and writing of the 11. Barbay M, Diouf M, Roussel M, et al, on behalf of the nitive state of patients for the clinician. J Psychiatr Res small vessel disease. J Alzheimers Dis 2014; 42: S37–S43. manuscript. All authors contributed to the different stages of GRECOG-VASC study group. Prevalence of mild and 1975; 12: 189–198. 40. Baykara E, Gesierich B, Adam R, et al. A novel imaging the manuscript, reviewed and edited and finally approved the major post-stroke neurocognitive disorders in hospital- 26. Nasreddine ZS, Phillips NA, Bedirian V, et al. The marker for small vessel disease based on skeletonization final version of the manuscript. based studies: a systematic review and meta-analysis. 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European Stroke Organisation cognitive impairment: A white paper 2021 Article reuse guidelines: Date received: 9 October 2020; accepted: 19 January 2021 from the ESO dementia committee – sagepub.com/journals-permissions DOI: 10.1177/2396987321994294 A practical point of view with suggestions journals.sagepub.com/home/eso for the management of cerebrovascular diseases in memory clinics Introduction Findings Dementia and stroke share several modifiable vascular Clinical expression of cerebrovascular contribution risk factors and are risk factors for each other.1–3 Hence, patients with cognitive impairment (CI) who in CI Ana Verdelho1 , Geert Jan Biessels2, Hugues Chabriat3, are seen at memory clinics frequently present with vas- Cognitive and behavioral manifestations. Once a patient is Andreas Charidimou4,5, Marco Duering6,7, Olivier Godefroy8, cular risk factors and cerebrovascular disease. seen in a memory clinic and the diagnosis of CI has Furthermore, cerebrovascular disease contributes to Leonardo Pantoni9 , Aleksandra Pavlovic10 and been confirmed, the possible presence, coexistence, or clinical symptoms that may aggravate or anticipate relevance of a cerebrovascular component in the etiol- Joanna Wardlaw11 the clinical expression of underlying degenerative ogy of CI should be considered. Identification of cere- brain pathology There is a lack of evidence on the brovascular disease through neuroimaging is quite treatment of cerebrovascular disease in patients with straightforward (see below). However, identification CI.4,5 Uncertainty about management of vascular risk of symptoms and signs of cerebrovascular disease on Abstract factors and cerebrovascular disease in people affected clinical grounds might be less obvious. A synthetic Purpose: Practical suggestions on clinical decisions about vascular disease management in patients with cognitive by CI might lead to heterogeneity in the treatment of impairment are proposed. approach is given in Text Box 1. Over the last years, those patients. In addition, professionals from memory Methods: The document was produced by the Dementia Committee of the European Stroke Organisation (ESO) based there has been much discussion about the potential role clinics may have less experience in the recognition and on the evidence from the literature where available and on the clinical experience of the Committee members. This of neuropsychology in order to differentiate the vascu-in the appropriate management of cerebrovascular dis- paper was endorsed by the ESO. lar from the degenerative component of CI.6 Although ease. The aim of this paper is to help reducing this Findings: Vascular risk factors and cerebrovascular disease are frequent in patients with cognitive impairment. While there is consensus that compromise of some cognitive potential knowledge gap, while waiting for appropriate acute stroke treatment has evolved substantially in last decades, evidence of management of cerebrovascular pathology domains (such as memory) may be more prominent in field trials. beyond stroke in patients with cognitive impairment and dementia is quite limited. Additionally, trials to test some daily-Alzheimer disease (AD) than in cerebrovascular dis- life clinical decisions are likely to be complex, difficult to undertake and take many years to provide sufficient evidence to eases,7 and executive dysfunctions are thought to be produce recommendations. This document was conceived to provide some suggestions until data from field trials are Methods more typical of cerebrovascular pathology, in fact all available. It was conceived for the use of clinicians from memory clinics or involved specifically in cognitive disorders, This document is a white paper produced by the major cognitive domains are affected in small vessel addressing practical aspects on diagnostic tools, vascular risk management and suggestions on some therapeutic options. Dementia Committee members, and endorsed by the disease8 and neuropsychological testing cannot per se Discussion and conclusions: The authors did not aim to do an exhaustive or systematic review or to cover all European Stroke Organization, aiming to give practical differentiate between vascular CI and AD at the current evidence. The document approach in a very practical way frequent issues concerning cerebrovascular disease in clinical suggestions for the management and treatment patients with known cognitive impairment. of cerebrovascular disease in patients with cognitive disorders. It was meant for the use of professionals Text Box 1. Clinical symptoms/signs which should raise possibility involved in the management of patients with CI, of concomitant cerebrovascular disease including medical specialists, general practitioners, but also non-medical professionals interested in CI Cognitive symptoms Slowness of processing speed and dementia, in order to help clinical decisions. Attention deficits 7Medical Image Analysis Center (MIAC AG) and qbig, Department of Content is not a result of a systematic review, but Reasoning problems 1Department of Neurosciences and Mental Health, CHLN-Hospital de Biomedical Engineering, University of Basel, Basel, Switzerland rather based on relevant literature and on the clinical Decision-making difficulties Santa Maria, Instituto de Medicina Molecular – IMM e Instituto de Saude 8Departments of Neurology, Amiens University Hospital, and Laboratory Apathy Ambiental-ISAMB, Faculdade de Medicina. University of Lisbon, Lisbon, experience of the authors of Functional Neurosciences1,6 (UR UPJV 4559), Jules Verne Picardy Behavioral and Mood changes (namely Portugal University, Amiens, France In this paper an effort was made to incorporate dif- 2 psychological depressive symptoms) Department of Neurology, UMC Utrecht Brain Center, University 9Stroke and Dementia Lab, “Luigi Sacco” Department of Biomedical and ferences of approach and access to ancillary investiga- Medical Center Utrecht, Utrecht, the Netherlands symptoms Clinical Sciences, University of Milan, Milan, Italy tions, keeping in mind the standard usual best practice Emotional control problems 3Department of Neurology, FHU NeuroVasc, Hoˆpital Lariboisiere, 10Faculty for Special Education and Rehabilitation, University of Belgrade, Lack of initiative from a cerebrovascular disease perspective. For a prac- University of Paris and INSERM U1141, Paris, France Belgrade, Serbia Apparent change in personality 4Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research 11 tical use, cognitive impairment (CI) include patients Centre for Clinical Brain Sciences, UK Dementia Research Institute, Informant report of cognitive Center, Department of Neurology, Massachusetts General Hospital, University of Edinburgh, Edinburgh, UK with objective cognitive impairment regardless of decline and behavioral changes Harvard Medical School, Boston, MA, USA having or not criteria for dementia. Subjective cogni- Motor and other Gait changes 5Department of Neurology, Boston Medical Center, Boston University Corresponding author: tive impairment refers to subjective complaints of non-cognitive/ School of Medicine, Boston, MA, USA Ana Verdelho, Department of Neurosciences, Hospital de Santa Maria, Urinary problems 6 decline in cognition without confirmation of decline behavioral symptoms Institute for Stroke and Dementia Research (ISD), University Hospital, University of Lisbon, Av Prof. Egas Moniz, Lisbon, Portugal. Finger tapping changes LMU Munich, Germany Email: averdelho@medicina.ulisboa.pt on objective cognitive assessment. Reproduced with permission Verdelho et al. 113 114 European Stroke Journal 6(2) individual level,9 nor clearly outline the presence of a focal neurological symptoms and signs. These latter and neurodegenerative or other brain lesions. They but many patients have global brain atrophy, so in vascular contribution in patients with CI of degenera- should be always searched for, systematically, as they should be assessed for common modifiable vascular practice, atrophy patterns may have limited specificity. tive origin.10 Nevertheless, the combination of the are highly indicative of a cerebrovascular contribution. and lifestyle risk factors to minimize their impact on information driven by neuropsychological testing CI phenotype usually reflects more than one patho- brain and general health (Table 1). MRI and CT scan applications. Brain imaging can be (and remaining clinical evaluation) with brain imaging logical mechanism. Biomarkers (namely imaging for performed with computerized tomography (CT) scan- is the best clue to support a likely cerebrovascular vascular pathology) are able to put in evidence cerebro- ning or magnetic resonance imaging (MRI). MRI contribution. vascular disease. The knowledge of the clinical expres- Neuroimaging might not always be available, or not applicable for Behavioral and psychological symptoms are highly sion of vascular pathology leads to the possibility of General considerations. On neuroimaging, vascular every patient, so clear knowledge about limitations frequent among cerebrovascular disease manifesta- addressing better the specific trigger for CI in a specific lesions include cortical or subcortical infarcts or old and advantages of each technique is needed. tions11,12 and might be different according to the person. Some neurological signs may help in the iden- haemorrhages, signs of SVD including white matter Moreover, CT is of quick realization, which is quite nature of cerebrovascular lesions.13 Those symptoms tification of the etiology of the clinical picture. One hyperintensities (WMH), lacunes and microbleeds, relevant for instance in patients with behavioral might be undervalued by relatives (and interpreted relevant aspect to be outlined is the possibility to sus- and cortical superficial siderosis (cSS).24 Perivascular changes, fear of closed environments or with MRI con- for instance as due to ageing) or overlooked due to pect a vascular component of CI by assessing physical spaces are common in cerebrovascular disease, but traindications (pacemaker or some prostheses, for other concomitant cognitive symptoms. Depressive performance with simple and clinically friendly tools.17 their clinical relevance is currently less clear.25,26 instance). CT is equally accurate as MRI for patholo- symptoms, lack of emotion expression control and Patients with cerebrovascular disease have frequently Brain atrophy occurs in the common neurodegenera- gies such as brain tumours, subdural haematomas, emotionalism, apathy and lack of initiative and gait disturbances with balance difficulties, small steps, tive dementias including AD (particularly of medial many larger infarcts, acute haemorrhages, and can change in personality traits are among those symp- and bradykinesia. Besides those affected by the sequel- temporal lobes), fronto-temporal dementia (of frontal show brain atrophy, moderate to severe white matter toms. There is no ideal short battery for the identifica- ae of previous stroke such as hemiparesis, patients with and temporal lobes), dementia with Lewy Bodies (of lesions (leukoaraiosis), and lacunes.28 Nevertheless, dif- tion of deficits in patients with cerebrovascular disease. SVD have typically a slowed, short-stepped, wide- parietal lobes), but also occurs diffusely in SVD27 ferentiation of old haemorrhages from old infarcts, We should keep in mind that less exhaustive neuropsy- based gait. These patients also have an increased rate and focally after infarcts and haemorrhages. The pat- identification of microbleeds and cSS and some small chological study might fail to put in evidence few cog- of falls. More sophisticated tools for assessing gait per- tern of atrophy may provide clues of the dementia type, acute infarcts is not reliable on CT. MRI is much more nitive deficits and behavioral changes14 formance maybe better but also difficult to implement in memory clinics on a large scale.18 Table 1. Investigations to avoid missing modifiable vascular risk factors. Evolution over time. Apart from detailed evaluation of Finally, there have been data supporting that cognitive testing, there might be other clinical hints changes in other non-cognitive symptoms (as for Measure To detect that suggest the presence of a vascular component in instance urinary troubles early in the course of the dis- Modifiable vascular risk factors a patient with CI. ease) since these are common in patients with vascular Blood pressure Hypertension May need multiple measures, or ambu- Historically, one clinical tool to differentiate the vas- contributions to CI and have an adverse effect on their latory monitoring cular component of the cognitive decline is to apply the daily lives. Cerebral SVD is associated with urinary Blood glucose Diabetes so-called ischemic score published by Hachinski and problems19 and also with abnormalities on neurologi- Blood lipids Hyperlipidaemia co-authors, aiming to differentiate AD from multi- cal examination, such as slowness of finger tapping.20 Body mass index Overweight and obesity infarct dementia.15 The score is today considered Despite the possibility that these features might direct Lifestyle history Excessive alcohol intake, smoking, poor diet, partly out-of-date and is more rarely used than in the the attention of the treating physician towards the pres- inadequate exercise and sedentary habit past; however, it may serve to outline and discuss some Other proxy-risk factors, as Different factors associated with higher vascular If not actively searched be a missed ence of a vascular contribution, other degenerative aspects. According to the original paper, a few charac- obstructive sleep apnea, risk opportunity to be identified pathologies may present with similar findings21,22 . It teristics of the clinical course of the cognitive deterio- homocysteine levels might be reasonable however to search for all these Sources of emboli and evidence of ischaemic cardiovascular disease: ration may indicate the presence of a vascular aspects in each patient arriving at a memory clinic. ECG Cardiac arrhythmias, particularly atrial fibrillation; May need ambulatory monitoring, to component (or cause); these are the abrupt onset, the ischaemic heart disease detect paroxysmal arrhythmias or stepwise deterioration, and a fluctuating course. Subjective cognitive impairment. One last word concerning even an ECG-T (cardiac event However, it should be kept in mind that the original subjective CI, that usually is associated with higher risk recorder) paper was referring to patients with multiple strokes. of dementia, usually of the Alzheimer type (and not Echocardiogram Heart valve disease, atrial septal defects (ASDs) Transoesophageal echo with iv echo- Today, we know that a good proportion of patients with SVD).12 However, among community cohorts, Aortic cross atheroma contrast is more sensitive to ASDs whose CI recognizes a vascular cause - or at least a may represent an increase in the relative risk risk for, than transthoracic vascular component of it -, have small vessel disease Doppler Ultrasound, CT or MR Carotid or vertebral artery extra- or intracranial CT or MR angiography for suspected particularly, CI of vascular origin.23 Clinicians should (SVD),16 and the course of their cognitive decline is angiography stenosis intracranial stenosis keep in mind that patients with subjective complaints not usually stepwise but rather progressive and with Evidence of cerebrovascular disease living in the community are an opportunity to identify MR or CT brain imaginga Acute or old cortical infarcts; T1-weighted, T2-weighted, FLAIR, SWI insidious onset. Other items of the original scale, vascular risk factors in people otherwise well, and rein- Acute or old subcortical infarcts; and DWI sequences are all essential given the current knowledge, appear of limited utility force preventive actions concerning those vascular risk acute or old brain haemorrhage; to assess for the range of cerebro- as they are scarcely discriminative and are also a risk factors. WMH, lacunes, microbleeds, cortical siderosis; vascular disease lesions. factor for AD (more information concerning brain atrophy including regional distribution Hachinski’s score is provided in supplementary What investigation/complementary investigation(s) a material). MRI preferred, as more sensitive for detecting vascular changes. CT will detect non vascular causes and brain atrophy, many infarcts, acute are important? haemorrhage, and moderate to severe WMH and lacunes, but not microbleeds, differentiate old infarct from haemorrhage, and is much less sensitive to SVD lesions than is MRI. CT possibilities discriminated in main text. Motor and non-motor manifestations. More relevant in this Patients presenting to memory clinics should have WMH: white matter hyperintensities; FLAIR: fluid attenuated inversion recovery; SWI: susceptibility-weighted imaging; DWI: diffusion-weighted sense are the history of strokes and the presence of brain imaging that includes assessment for vascular imaging or diffusion imaging. Reproduced with permission Verdelho et al. 115 116 European Stroke Journal 6(2) sensitive to vascular lesions, particularly WMH, micro- reading due to a subclavian artery stenosis. More bleeds and cSS. MRI is also better for detecting and detailed repeated measures of BP in clinic or home Text Box 2. Summary of suggestions for the management of cerebrovascular disease in patients with CI. differentiating sporadic vascular lesions from multiple monitoring may be required but this is out of scope sclerosis, vasculitis, some infections and familial genetic for this paper. Loss of adherence to hypertension treat- Clinical appointments due to CI should be considered as an opportunity to check and better control of vascular risk factors causes of dementia and cerebrovascular disease such as ment should be prevented (namely patients might stop Brain imaging (made in the context of CI) should be reviewed to verify existence of cerebrovascular disease CADASIL. However, when using MRI, the correct medication when values get normal due to treatment), In the case of cerebrovascular component highly suspected/not clear after CT, an MRI should be considered (namely if doubt MRI sequences are required to identify key vascular hence, any attendance at a clinic is a good opportunity about hemorrhagic component including microbleeds and cSS, small acute lesions, specific profiles as familiar -e.g.CADASIL, or pathologies. Many memory clinics use MRI protocols to check that vascular risk management is under con- extension of WMC and SVD) including 3 D T1 and T2, which detect brain atrophy, trol. Patients should also have their blood glucose and Specific investigations should be considered in acute lesions, recurrent and multiple strokes (namely neck and intracranial artery some cortical infarcts, lacunes and can exclude tumours imaging and cardiac study) blood lipids (cholesterol, LDL, HDL) measured if and subdural haematomas, for instance. However, to these have not been performed recently elsewhere, detect key vascular lesions, a fluid attenuated inversion and appropriate management implemented whenever preventive medicine. In patients who experienced a intracerebral haemorrhage (ICH).41 Similarly, lesions recovery (FLAIR) sequence is required for WMH and necessary.31 ischaemic stroke, or transient ischaemic attack, the that are typically considered to be haemorrhagic, in small cortical infarcts, a susceptibility-weighted imag- risk of future vascular events can be reduced by 30– particular, microbleeds, also convey an increased risk ing (SWI or Gradient Echo or T2*) sequence is essen- Ancillary investigations concerning vascular risk fac- 50% through guideline-based treatments and lifestyle tial to detect microbleeds, cSS, and old of ischaemic stroke. For example, in patients who pre- tors. As cholinesterase inhibitors may delay atrial- recommendations.38 Of note, the evidence on which macrohaemorrhages, and diffusion-weighted imaging viously experienced a TIA or ischaemic stroke it has ventricular conduction, an electrocardiogram (ECG) these guidelines are built is largely derived from studies (DWI) is important to detect small acute infarcts. been established that presence of multiple microbleeds is usually requested in memory clinics. When there is on atherosclerotic (large artery) disease. By compari- is associated with a much higher relative hazard ratio evidence of cerebrovascular disease, an ECG will be son, the available evidence specifically concerning Specific hints from neuroimaging. WMH, lacunes, for future ICH than for ischaemic stroke.42 Yet, helpful to identify arrhythmias, and signs of ischaemic microbleeds and atrophy all increase with age.24,25 treatment of cerebral SVD, the commonest form of heart disease or left or right chamber hypertrophy. because the overall rate of ischaemic stroke in these However, a higher than expected burden of WMH vascular brain injury encountered in people with CI, Special attention must be given to patients with patients is several fold higher than that of ICH, even for age, and any lacunes or microbleeds, should trigger is quite limited.29,39 recent focal neurological symptoms or evidence of cere- in patients with multiple microbleeds the absolute risk a search for modifiable risk factors.29 Smith et al. pro- There clearly is an important potential for vascular brovascular lesions on scanning, especially if in multi- of ischaemic stroke is higher than that of ICH.42 These vided a practical schema of WMH severities according prevention strategies in patients with CI. Yet, physi- ple vascular territories: in those patients, ambulatory observations illustrate how difficult it can be to base to age groups, based on MRI, in a recent publication cians should be careful to apply guidelines for second- monitoring may be required to detect paroxysmal indications for antithrombotic agents on patients with (see Figure 7 in).29 Large numbers of WMH and ary prevention after stroke to people with CI and arrhythmias and further investigations such as echocar- these lesions. Practical hints are given in Text Box 3. lacunes in a young patient should raise the possibility so-called “silent cerebrovascular disease”. In this set- diography, and neck or intracranial artery imaging e.g. of a monogenic SVD such as CADASIL. Multiple cor- ting, some treatments that are cornerstones in second- with Doppler ultrasound, CT or MR angiography32 Specific issues in the use of antithrombotic therapy. It is also tical infarcts especially in multiple arterial territories, ary prevention, in particular antithrombotic agents, may be needed. Patients with more complex cerebro- important to consider if the vascular brain injury, as should trigger a search for proximal embolic sources. may be ineffective, or sometimes even harmful. vascular disease as recurrent strokes despite adequate seen on the scan, provides an indication to initiate or Microbleeds are associated with hypertension, where Although some recommendations are published,29 we management and adequate secondary prevention, rare modify antithrombotic therapy. As a general principle they typically occur mainly in deep grey and white try to summarize few practical points in the next lines. causes of stroke (as genetic diseases as CADASIL) and “silent” ischemic lesions, in particular WMH, do not matter, and commonly found in patients with cerebral In all patients with CI and vascular brain injury, patients with recent acute stroke or suspected TIA provide a clear indication for prescription of antith- amyloid angiopathy (CAA) where they typically have a guidelines for primary prevention of cardiovascular should be considered for referral to a stroke clinic. rombotic agents.29 By contrast, it is also questionable lobar distribution and are seen at the cortical- disease apply.40 This includes lifestyle recommenda- if presence of a few microbleeds should be a reason to subcortical junction, although mixed distributions of tions, and encouraging cessation of smoking, if appli- Other life-style and global measures. Tobacco smok- withhold antithrombotic agents in patients in whom microbleeds are common. Microbleeds plus cSS are cable, as mentioned above. To determine if additional ing33 and excess alcohol consumption damage the such agents are otherwise indicated for presence of likely to indicate CAA.30 treatment is needed, or existing treatments should be brain,34 so cessation of those habits should be sug- modified, a pragmatic approach is the following: symptomatic ischaemic vascular disease. An exception gested. Exercise helps to maintain brain vascular may be people with high (e.g. >10) numbers of micro- Vascular risk management First, determine if the patient had a previous ischae- health,35 and a well-balanced diet including recom- bleeds and also people with cSS, particularly if dissem- Vascular risk factors assessment. The main modifi- mic vascular event or other ischemic vascular disease mended amounts of fruit and vegetables,36 avoiding inated (detected in more than 3 sulci). cSS is an able vascular risk factors are hypertension, hyperlipid- elsewhere in the body. If this is the case, this previous excess sodium37 and processed meats, is advisable. emia, diabetes, and sources of emboli or altered cardiovascular disease generally determines the choice indicator of CAA and conveys an absolute risk of Lifestyle advice encourages patient awareness of their cerebral perfusion such as atrial fibrillation or other of antithrombotic agents and blood pressure and cho- future ICH of 11% per year when disseminated.43,44 vascular risk and is part of comprehensive risk cardiac arrhythmias, heart valve disease, and athero- lesterol targets, according to available guidelines.38,40 In all cases, particularly for prescribing or discontin- management. matous internal carotid artery stenosis. Modifiable life- Nevertheless, the memory clinic visit should be taken uing antithrombotic agents, an individualized A synopsis of suggested investigations is given in style risk factors include tobacco smoking, lack of as an opportunity to double check if this treatment is approach is needed. Where possible this should be Table 1, and a summary of relevant suggestions in regular physical exercise and poor diet including appropriately installed. based on weighing the patients estimated absolute Text Box 2. excess dietary sodium and alcohol. Next, determine the nature of the vascular brain risk (and not relative risk which might often be mis- All patients attending memory clinics should have injury. Asses the different lesion types and burden as leading) of both future ischaemic and haemorrhagic their blood pressure measured using an approved and Treatment indicators of risk of future vascular injury. Of note, events. The challenge is that such estimates are still well maintained sphygmomanometer device. Blood Primary and secondary prevention of stroke. Prevention of lesions that are typically considered to be ischemic, imprecise and are largely derived from studies that pressure should be assessed sitting after at least five new vascular events in people with symptomatic car- such as WMH and lacunes, not only convey an did not specifically include patients from memory clin- minutes of rest, and in both arms to avoid falsely low diovascular disease is one of the real success stories of increased risk of future ischemic stroke, but also of ics. This clearly is an area for further study. Reproduced with permission Verdelho et al. 117 118 European Stroke Journal 6(2) References 17. Verwer JH, Biessels GJ, Heinen R, et al.; Utrecht Text Box 3. Practical suggestions concerning treatment of cerebrovascular disease in patients with CI. 1. Rostamian S, Mahinrad S, Stijnen T, et al. Cognitive Vascular Cognitive Impairment (VCI) study group. impairment and risk of stroke: a systematic review and Occurrence of impaired physical performance in memory clinic patients with cerebral small vessel disease. Implement primary and secondary prevention of stroke; primary prevention applies to all patients. Patients who experienced a meta-analysis of prospective cohort studies. Stroke 2014; Alzheimer Dis Assoc Disord 2018; 32: 214–219. stroke should be treated according to secondary prevention guidelines. 45: 1342–1134. 18. Mc Ardle R, Morris R, Wilson J, et al. What can quan- No evidence base to support application of secondary stroke prevention treatment strategies for WMH alone. 2. Pendlebury S, Rothwell P and Study OV. Incidence and titative gait analysis tell us about dementia and its sub- Individualized approach to initiate or modify antithrombotic agents based on weighing the individual patients estimated absolute prevalence of dementia associated with transient ischae-types? A structured review. J Alzheimers Dis 2017; 60: risk of future ischaemic or haemorrhagic events. mic attack and stroke: analysis of the population-based oxford vascular study. Lancet Neurol 2019; 18: 248–258. 1295–1312. 3. Hachinski V. Stoop to conquer: preventing stroke and 19. Poggesi A, Pracucci G, Chabriat H, et al.; on behalf of Conclusion and suggestions for Acknowledgements dementia together. Lancet 2017; 389: 1518. the LADIS Study Group. Urinary complaints in nondis- future research We thank Professor Franz Fazekas, from the Medical 4. Deschaintre Y, Richard F, Leys D, et al. Treatment of abled elderly people with age-related white matter University of Graz, Austria, for his contribution on this vascular risk factors is associated with slower decline in changes: the leukoaraiosis and DISability (LADIS) The interplay between vascular and neurodegenera- paper and we thank the European Stroke Organisation for Alzheimer disease. Neurology 2009; 73: 674–680. study. J Am Geriatr Soc 2008; 56: 1638–1643. tive pathologies in patients with CI and dementia supporting and for endorsing this initiative. 5. Frederiksen KS, Cooper C, Frisoni GB, et al. A 20. Poggesi A, Gouw A, van der Flier W, et al. Cerebral remains an active area of research. In recent years, European academy of neurology guideline on medical white matter changes are associated with abnormalities the notion of potentially significant vascular contri- management issues in dementia. Eur J Neurol 2020; 27: on neurological examination in non-disabled elderly: the butions to CI and dementia in different patient set- Declaration of conflicting interests 1805–1820. LADIS study. J Neurol 2014; 261: 1160–1169. tings is becoming better appreciated by clinicians. The author(s) declared the following potential conflicts of 6. Salvadori E and Pantoni L; on behalf of the Società 21. Jeppesen Kragh F, Bruun M, Budtz-Jørgensen E, et al. However, the mechanisms of how cerebrovascular interest with respect to the research, authorship, and/or pub- Italiana di NeuroGeriatria (SINEG). The role of the neu- Quantitative measurements of motor function in ropsychologist in memory clinics. Neurol Sci 2020; 41: pathophysiology reciprocally interacts with neurode- lication of this article: Olivier Godefroy during the last five Alzheimer’s disease, frontotemporal dementia, and 1483–1488. generation in producing or contributing to cognitive years has served on scientific advisory boards and speaker dementia with lewy bodies: a proof-of-concept study. (Biogen, Astra Zeneca, Novartis) and received funding for 7. Lamar M, Price CC, Giovannetti T, et al. The dysexecu- symptoms and decline are complex and currently elu- Dement Geriatr Cogn Disord 2018; 46: 168–179. travel and meetings from Bristol-Myers Squibb, Roche, tive syndrome associated with ischaemic vascular disease sive. For example, there are many strong epidemio- 22. Kim KJ, Jeong SJ and Kim JM. Neurogenic bladder in Biogen, Teva-sante, Boehringer-Ingelheim, Covidien, Ipsen. and related subcortical neuropathology: a Boston process progressive supranuclear palsy: a comparison with logical links between traditional vascular risk factors The remaining authors declare that there are no conflict of approach. Behav Neurol 2010; 22: 53–62. Parkinson’s disease and multiple system atrophy. and CI, and also a plethora of theoretical pathophys- 8. Hamilton O, Kl Blackhouse EV, Janssen E, et al. interest concerning the paper. Neurourol Urodyn 2018; 37: 1724–1730. iologic crosstalk mechanisms between brain vessels Cognitive impairment in sporadic cerebral small vessel 23. Slot RER, Sikkes SAM, Berkhof J, et al.; SCD-I pathologies and b-amyloid, a hallmark of neurode- disease: a systematic review and meta-analysis. Working Group. Subjective cognitive decline and rates generation pathobiology. Often, age-related CI and Funding Alzheimers Dement. Epub ahead of print 13 November 2020. DOI: 10.1002/alz.12221. of incident Alzheimer’s disease and non-Alzheimer’s dis- dementia represent really a mix of neurodegenerative The author(s) received no financial support for the research, 9. Andriuta D, Roussel M, Barbay M, et al. Differentiating ease dementia. Alzheimers Dement 2019; 15: 465–476. and vascular pathologies. Despite the details and tra- authorship, and/or publication of this article. between Alzheimer’s disease and vascular cognitive 24. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging jectories being largely unknown, this realization gives impairment: is the “memory versus executive standards for research into small vessel disease and its a reason for hope, in that more contributions to CI in Informed consent function” contrast still relevant? J Alzheimers Dis 2018; contribution to ageing and neurodegeneration: a united patients translates to more targets and opportunities approach. Lancet Neurol 2013; 12: 822–838. Informed consent is not applicable to this manuscript. 63: 625–633. to intervene. Such targets might include protection of 10. Mathias JL and Burke J. Cognitive functioning in 25. Debette S, Schilling S, Duperron M, et al. Clinical signif- the endothelium, the blood-brain barrier, other com- Alzheimer’s and vascular dementia: a meta-analysis. icance of magnetic resonance imaging markers of vascu- lar brain injury: a systematic review and meta-analysis. ponents of the neurovascular unit, or targeting CAA. Ethical approval Neuropsychology 2009; 23: 411–423. JAMA Neurol 2019; 76: 81–94. It will also be of interest to assess the independent Ethical approval is not applicable for this manuscript. 11. O’Brien J. Behavioral symptoms in vascular cognitive 26. Francis F, Ballerini L and Wardlaw JM. Perivascular benefit on cognition of commonly used medications impairment and vascular dementia. 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Networks Like physical disability in MS, cognition also worsens during relapses, followed by complete to almost complete recovery. It is not clear how much relapses contribute to decline overall. There are debates in our Tom Fuchs field about how often to test cognitive function. Practice effects could wash out our sensitivity to cognitive deterioration. Even once annual cognitive testing is likely to result in significant practice effects. In MS, we also must be vigilant of confounds specific to the disease. Physical and cognitive fatigue is the most commonly experienced symptom in MS and is often cited as a confound of cognitive performance. Multiple sclerosis is an immunological and neurodegenerative Symptomatic pharmacologic treatment of cognitive dysfunction in MS disease of the central nervous system. This disease, more prevalent is not effective, though medications that control the disease appear in women in northern climates, is typically characterized by a to also reduce cognitive decline. Behavioral treatments are somewhat “relapsing-remitting” phase followed by a more “progressive” phase effective, though few long-term studies exist. Restorative where disability accrues more precipitously. The disease results in rehabilitation techniques seem best suited in early stages of cognitive localized lesions in gray matter and white matter of the central decline, whereas compensatory techniques, like story memory nervous system. Locations of these lesions is non-random, e.g. techniques, are likely better suited for later stages. around venules and more around the lateral ventricles, but locations vary widely from person to person. Because of this varied lesion MRI can be applied to glean interesting insights about the locations, neurologic symptoms also vary widely. Notably though, relationship between the brain and cognition in MS. At the simplest cognitive dysfunction is common. Charcot, a 19th century French level, we can measure central atrophy or the sum of lesion volume – physician, provided broad but accurate descriptions of cognitive and these correlate with cognitive performance. Lesions of the gray dysfunction in multiple sclerosis: “Marked enfeeblement of the matter correlate more strongly but are difficult to view on clinical memory" and "conceptions that formed slowly". MRI. Gray matter atrophy also correlates strongly with cognitive dysfunction in MS and thalamic atrophy has proved to exhibit the In the present age, cognitive impairment is observed in up to 80% of strongest correlations with cognitive function. There are many people with multiple sclerosis in later phases of the disease. potential explanations for this, including the closeness of the However, because the location of damage can vary person to person, thalamus to CSF as well as its robust network connectivity – leaving it so too can the expected cognitive impairments and order of susceptible to damage as axons are affected throughout the bran. impairments. Nonetheless, there are some central expectations. The We can map the locations of lesions and the severity of their damage most commonly measured impairment in MS is slowed cognitive using diffusion-based techniques and identify how such lesions processing speed. We measure this using a test called the Symbol disrupt connections between brain hubs. This network-style Digit Modalities Test. Tests of verbal and visuospatial learning and approach helps us treat MS almost like an ablation model to better memory are also commonly applied ins MS. Although cognitive understand cognition, but from a network-oriented perspective impairment in MS is specific to which brain networks are affected, we rather than considering one brain region at a time. Dysfunction of have investigated the most common order of impairment as the memory affect networks involving hippocampal connections. Lesions disease progresses. Slowing of processing speed is commonly the affecting right-hemispheric parietal temporal connections relate with earliest cognitive dysfunction observed in MS. This is followed by dysfunction in visuospatial memory, and lesions in frontal networks impairment of short-term verbal and visuospatial memory and then correlate with worsened ability to be goal-oriented and organized. by executive dysfunction. Other commonly addressed domains Functional imaging has similarly allowed us to view how the brain include auditory attention and verbal fluency. It is likely that we could adapts to network disruption. For instance, preservation of normal find most any cognitive dysfunction in MS, depending on lesion static functional connectivity, despite structural disruption, appears to be paramount to preservation of cognitive functioning and this preservation of functional connectivity is moderated by cognitive reserve. Failures of usual functional dynamics, such as switching of functional network activation, is also associated with deterioration of cognitive function. Interestingly, higher-function functional networks appear to be most susceptible to change in relation to structural disruption, whereas primary sensory networks show less of a relationship between structural damage and deviation of functional connectivity. CHOLESTEROL HOMEOSTASIS AND MECHANISMS OF STATINS IN AD Statins in patients with Alzheimer's Cholesterol is an essential component of cell membranes, involved in dementia – a friend or a foe? several cognitive processes, including neuronal function and signaling. About a quarter of the whole-body cholesterol content is stored in the brain and is metabolically separated from the peripheral cholesterol pool by a functional blood-brain barrier (1). Dysregulation of central cholesterol homeostasis has been proposed to be involved Bojana Petek in the pathogenesis of AD through different mechanisms, including the effect on the amyloid pathway, vascular impairment or interaction with other metabolic pathways in the brain (2). Moreover, a genetic polymorphism of cholesterol transporter in the brain, ApoE4, represents a major risk factor for late-onset AD. On the other hand, a complex association between peripheral hypercholesterolemia and cognition has been recognized. Hypercholesterolemia in midlife has been linked to a higher risk of AD in late life (3). However, dyslipidemia in late life is thought to reflect a better overall health and is associated with a slower cognitive decline (4). Statins are a group of medications widely used in the prevention of cardiovascular disease which act through a competitive reversible inhibition of enzyme HMG-CoA reductase. In addition to the inhibition of endogenous cholesterol production, they exhibit other pleotropic characteristics, such as anti-inflammatory, anti-oxidant and ABSTRACT neuroprotective abilities (2). The brain penetration of an individual statin has been linked to several factors, such as their individual Several risk factors have been identified in the pathogenesis of lipophilicity, size of the molecule and different transporters (5). Most Alzheimer's dementia (AD), including genetics, age, lifestyle factors, biochemical studies divided statins into two groups regarding their and certain medical conditions, reflecting a multifactorial backround. lipophilicity: a group with a higher lipophilicity which facilitates the Among these factors, a disturbance of cholesterol homeostasis can brain penetration (e.g. simvastatin, atorvastatin, fluvastatin) and a be involved in the pathogenesis of AD. Therefore, possible cognitive hydrophilic group of statins which enter the brain less easily (e.g. effects of cholesterol-modulating medications have lead to an rosuvastatin, pravastatin). Epidemiological studies which compared extensive amount of research, driven by a lack of effective treatment lipophilic to hydrophilic statins were inconsistent and have reported of AD. Statins are a class of cholesterol-lowering medications widely no difference when comparing the cognitive decline in these groups used to prevent and treat cardiovascular disease. In addition to their (6), or a possible benefit of lipophilic statins (7). cholesterol-lowering effects, statins exhibit anti-inflammatory and neuroprotective properties that may be beneficial in the context of The overall cognitive effects of statins on cognition have been linked AD. Epidemiological evidence of potential cognitive benefit of statins to a complex interplay of several factors, such as brain penetration have been inconclusive or controversial in the past two decades. In and function of the blood-brain barrier, the balance of the beneficial this presentation, we will review the current state of knowledge on and harmful effects of statins on several processes in a neurovascular the role of statins in the prevention and treatment of AD as well as unit (8), lenght of treatment and dose of a medication (9), time of potential risks. We will discuss the potential mechanisms underlying treatment in the course of AD pathogenesis (10), patients the effects of statins on cognition. comorbidities and medication interactions, to name a few. PREVIOUS RESEARCH ON STATINS AND AD REFERENCES Since the promising results of first two observational studies almost 1. Gamba P, Staurenghi E, Testa G, Giannelli S, Sottero B, Leonarduzzi G. A crosstalk between brain cholesterol oxidation and glucose metabolism two decades ago (11,12), an extensive amount of consecutive in Alzheimer’s disease. 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Benito-León J, Vega-Quiroga S, Villarejo-Galende A, Bermejo-Pareja F. tools. More recent studies considered several epidemiological biases Hypercholesterolemia in elders is associated with slower cognitive decline: A prospective, population-based study (NEDICES). J Neurol Sci. due to observational nature or a heterogeneous design of studies to 2015;350(1–2):69–74. be important cause of these discrepancies (10). 5. Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: A comparative in vitro study of lipophilicity, CONCLUSION blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimer’s Dis. 2011;23(2):307–18. The cognitive effects of statins on cognition in patients with AD 6. Haag MDM, Hofman A, Koudstaal PJ, Stricker BHC, Breteler MMB. probably result from a complex interplay of several factors, linked to Statins are associated with a reduced risk of Alzheimer disease regardless of the medication (lipophilicity and brain penetration, the lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. cholesterol-lowering and pleotropic effects, lenght of treatment and 2009;80(1):13–7. dose) and individual patient's characteristics (pathogenesis of AD, 7. Lin FC, Chuang YS, Hsieh HM, Lee TC, Chiu KF, Liu CK, et al. Early statin use and the progression of Alzheimer disease: A total function of the blood-brain barrier, comorbidities and comedication). population-based case-control study. Med (United States). 2015; It is biologically plausible and consistent with epidemiological 8. Mendoza-Oliva A, Zepeda A, Arias C. The Complex Actions of Statins evidence that treating dyslipidemia in midlife diminishes the in Brain and their Relevance for Alzheimer’s Disease Treatment: an Analytical metabolic risk factor of hyperlipidemia on cognitive decline in late life. Review. Curr Alzheimer Res. 2014; Most of the recent research does not suggest an overall harmful 9. Olmastroni E, Molari G, De Beni N, Colpani O, Galimberti F, Gazzotti effect of statins on cognitive abilities. Moreover, statins may be M, et al. Statin use and risk of dementia or Alzheimer’s disease: a systematic beneficial to a subgroup of AD patients with central cholesterol review and meta-analysis of observational studies. Eur J Prev Cardiol. 2021 homeostasis disturbance or early in the disease pathogenesis. Dec 6; 10. Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF. Statins, cognition, and dementia-systematic review and methodological commentary. Nat Rev Neurol. 2015;11(4):220–9. 11. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57(10):1439–43. 12. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356(9242):1627–31. 13. Wagstaff LR, Mitton MW, Arvik BML, Doraiswamy PM. Statin-associated memory loss: Analysis of 60 case reports and review of the literature. Vol. 23, Pharmacotherapy. 2003. p. 871–80. 14. Adhikari A, Tripathy S, Chuzi S, Peterson J, Stone NJ. Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies. J Clin Lipidol. 2021 Jan 1;15(1):22-32.e12. 14. Adhikari A, Tripathy S, Chuzi S, Peterson J, Stone NJ. Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies. J Clin Lipidol. 2021 Jan 1;15(1):22-32.e12. 15. Davis KAS, Bishara D, Perera G, Molokhia M, Rajendran L, Stewart RJ. Benefits and Harms of Statins in People with Dementia: A Systematic Review and Meta-Analysis. J Am Geriatr Soc. 2020 Mar 1;68(3):650–8. 16. Poly TN, Islam MM, Walther BA, Yang HC, Wu CC, Lin MC, et al. Association between Use of Statin and Risk of Dementia: A Meta-Analysis of Observational Studies. Neuroepidemiology. 2020 May 1;54(3):214–26. 17. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, Van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77(6):556–63. 18. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956–64. identified as a risk factor for postoperative delirium 23-26. Disparity Association of blood pressure variability between mean BP and BPV can be attributed to the deleterious effects of BPV, which is independent of mean BP 27. The deleterious with delirium in critically ill effects of BPV on cerebral function can be explained by microvascular and blood-brain barrier damage caused by enlarged pulsatile loads, which are inadequately buffered by impaired cerebral autoregulation during acute critical illness 28, 29. Nika Zorko Garbajs ESTABLISHING AN ASSOCIATION BETWEEN BPV AND DELIRIUM IN CRITICALLY ILL We performed two studies in which we aimed to analyze the association between BPV during the first 24 hours after ICU admission and the likelihood of acute delirium during ICU admissions DELIRIUM AND CRITICAL ILLNESS in a large patient cohort. The first study included previously cognitively unimpaired older patients (> 50 years old), voluntary Delirium, an acute fluctuating neurocognitive condition characterized participants of the Mayo Clinic Study of Ageing, and analyzed the by inattention, depressed awareness, and impaired cognition, is associations between BPV, delirium and long-term cognitive commonly found in critically ill patients (from 20% in non-intubated outcomes 30. The second analyzed the association of BPV with to 87% in the mechanically ventilated) 1, 2. The underlying causes for delirium in all adult ICU population 31. Both excluded patients with delirium are presumably multifactorial, including neuroinflammation, primary neurological diseases, as they can affect the reliability of oxidative stress, neuroendocrine dysregulation, and disturbances of delirium evaluation. cerebral vascular regulation 3. Is it associated with numerous adverse outcomes of intensive care unit (ICU) treatment, including increased We evaluated delirium by Confusion Assessment Method of the ICU and hospital mortality rates and lengths of stay, prolonged Intensive Care Unit (CAM-ICU) score in non-sedated patients at least mechanical ventilation duration, increased risk of hospital every 8-12 hours. Long-term cognitive outcome was evaluated readmissions, death after hospital discharge 4, 5, and just as through the changes in the slope of longitudinally assessed global importantly long-term cognitive impairment 6-8. The increased cognitive scores associated with ICU admission (comparing pre- severity of these complications in patients with delirium led to the admission and post-admission assessments). Systolic and diastolic launching of various initiatives to detect and eliminate precipitating blood pressure, measured in 15-minute to 1-hour intervals during risk factors for delirium and to implement interventions for first 24 hours of ICU admission were recorded. The primary BPV modifiable risk factors. To this end, bundle interventions, such as the measure for systolic and diastolic BP each was average real variability ICU Liberation initiative 9, have been introduced to prevent delirium (ARV), representing the average of absolute differences between in patients admitted to an ICU; however, current bundle interventions consecutive measures during the observed time, accounting for the do not include BPV as an intervention target 10. number and order of consecutive measurements 32. BLOOD PRESSURE VARIABILITY AND MORBIDITY The first study included 794 patients with 1,130 ICU admissions. Of these admissions, 185 (16%) manifested with delirium. Compared to Blood pressure variability (BPV) is a complex phenomenon defined as patients who did not experience cognitive disturbance in the ICU, the magnitude and pattern of blood pressure (BP) fluctuations during participants who developed delirium were sicker and had a higher a certain period of time 11. Increased short-term and long-term BPV rate of mechanical ventilation during the first 24 hours. There was a is associated with the development and progression of cardiac, dose-response relationship between 24-hour systolic and diastolic vascular, neurologic, and kidney disease, increased risk of ARV and the development of delirium, meaning higher BPV was cardiovascular events and death 12-17, and long-term cognitive associated with an increased likelihood acute delirium during the first decline in ambulatory populations 18, 19. Additionally, intraoperative day of admission and after. For the assessment of the association of BPV (and not only intraoperative hypotension) 20-22, has been BPV with the change in long-term trajectory of cognition, 371 participants met criteria, with average follow up duration of 2.5 years References: pre- and post- first ICU admission. We found an accelerated global cognitive decline after ICU admission, that was steeper in patients 1. Van Rompaey B, Schuurmans MJ, Shortridge-Baggett LM, Truijen S, Elseviers M, Bossaert L. A comparison of the CAM-ICU and the NEECHAM experiencing delirium during admission (15 - 4.3%), but unaffected by Confusion Scale in intensive care delirium assessment: an observational measures of BPV 30. study in non-intubated patients. Crit Care 2008;12:R16. 2. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, et al. In the second study 66,549 ICU admissions of 54,056 unique patients Evaluation of delirium in critically ill patients: validation of the Confusion were included in our analysis. Delirium was documented in 13,427 Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med (20.2%) ICU admissions. Increased BPV was associated with higher 2001;29:1370-1379. odds of delirium (P<.001) and an increased duration of delirium (P 3. Maldonado JR. Acute Brain Failure: Pathophysiology, Diagnosis, ≤.001). Specifically, a 5-mm Hg increase in systolic ARV was associated Management, and Sequelae of Delirium. Crit Care Clin 2017;33:461-519. with a 34% increase in the odds of delirium (OR, 1.34; 95% CI, 4. Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, 1.29-1.40) 31. et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ 2015;350:h2538. 5. Fiest KM, Soo A, Hee Lee C, Niven DJ, Ely EW, Doig CJ, et al. CONCLUSION Long-Term Outcomes in ICU Patients with Delirium: A Population-based Cohort Study. Am J Respir Crit Care Med 2021;204:412-420. Our studies are the first identifying a relationship between early BPV 6. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, and delirium in the ICU, demonstrating higher BPV during the first 24 Pun BT, et al. Long-term cognitive impairment after critical illness. N Engl J hours of ICU admission is associated with increased risk and duration Med 2013;369:1306-1316. of delirium in critically ill, regardless whether the patients in question 7. Sakusic A, Gajic O, Singh TD, O'Horo JC, Jenkins G, Wilson GA, et al. were elderly or a general ICU population. However, our results do not Risk Factors for Persistent Cognitive Impairment After Critical Illness, Nested prove causality. If our observations are confirmed in future Case-Control Study. Crit Care Med 2018;46:1977-1984. prospective studies, new interventions may be developed and 8. Bulic D, Bennett M, Georgousopoulou EN, Shehabi Y, Pham T, Looi JCL, et al. Cognitive and psychosocial outcomes of mechanically ventilated subsequently assessed in clinical trials to examine whether reducing intensive care patients with and without delirium. Ann Intensive Care BPV can decrease the burden of delirium in patients with critical 2020;10:104. illness. 9. Rose L, Burry L, Agar M, Campbell NL, Clarke M, Lee J, et al. A Core Outcome Set for Research Evaluating Interventions to Prevent and/or Treat Delirium in Critically Ill Adults: An International Consensus Study (Del-COrS). Crit Care Med 2021. 10. Ely EW. The ABCDEF Bundle: Science and Philosophy of How ICU Liberation Serves Patients and Families. Crit Care Med 2017;45:321-330. 11. Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol 2013;10:143-155. 12. Stevens SL, Wood S, Koshiaris C, Law K, Glasziou P, Stevens RJ, et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ 2016;354:i4098. 13. Bennett AE, Wilder MJ, McNally JS, Wold JJ, Stoddard GJ, Majersik JJ, et al. Increased blood pressure variability after endovascular thrombectomy for acute stroke is associated with worse clinical outcome. J Neurointerv Surg 2018;10:823-827. 14. Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Blood Pressure Variability and Clinical Outcome in Patients with Acute Intracerebral Hemorrhage. J Stroke Cerebrovasc Dis 2015;24:1493-1499. 15. Kirkness CJ, Burr RL, Mitchell PH. Intracranial and blood pressure variability and long-term outcome after aneurysmal sub-arachnoid hemorrhage. Am J Crit Care 2009;18:241-251. 16. Rossignol P, Girerd N, Gregory D, Massaro J, Konstam MA, Zannad F. 30. Garbajs NZ, Singh TD, Valencia Morales DJ, Herasevich V, Warner DO, Increased visit-to-visit blood pressure variability is associated with worse Martin DP, et al. Association of blood pressure variability with short- and cardiovascular outcomes in low ejection fraction heart failure patients: long-term cognitive outcomes in patients with critical illness. Journal of Insights from the HEAAL study. Int J Cardiol 2015;187:183-189. Critical Care 2022;71. 17. Saito K, Saito Y, Kitahara H, Nakayama T, Fujimoto Y, Kobayashi Y. 31. Zorko Garbajs N, Valencia Morales DJ, Singh TD, Herasevich V, In-Hospital Blood Pressure Variability: A Novel Prognostic Marker of Renal Hanson AC, Schroeder DR, et al. Association of Blood Pressure Variability Function Decline and Cardiovascular Events in Patients with Coronary Artery with Delirium in Patients with Critical Illness. Neurocritical Care 2022. Disease. Kidney Blood Press Res 2020;45:748-757. 32. Mena LJ, Felix VG, Melgarejo JD, Maestre GE. 24-Hour Blood Pressure 18. Zhou TL, Kroon AA, van Sloten TT, van Boxtel MPJ, Verhey FRJ, Variability Assessed by Average Real Variability: A Systematic Review and Schram MT, et al. Greater Blood Pressure Variability Is Associated With Meta-Analysis. J Am Heart Assoc 2017;6. Lower Cognitive Performance. Hypertension 2019;73:803-811. 19. Tadic M, Cuspidi C, Bombelli M, Facchetti R, Mancia G, Grassi G. Relationships between residual blood pressure variability and cognitive function in the general population of the PAMELA study. J Clin Hypertens (Greenwich) 2019;21:39-45. 20. Wachtendorf LJ, Azimaraghi O, Santer P, Linhardt FC, Blank M, Suleiman A, et al. Association Between Intraoperative Arterial Hypotension and Postoperative Delirium After Noncardiac Surgery: A Retrospective Multicenter Cohort Study. Anesth Analg 2022;134:822-833. 21. Williams-Russo P, Sharrock NE, Mattis S, Liguori GA, Mancuso C, Peterson MG, et al. Randomized trial of hypotensive epidural anesthesia in older adults. Anesthesiology 1999;91:926-935. 22. Langer T, Santini A, Zadek F, Chiodi M, Pugni P, Cordolcini V, et al. Intraoperative hypotension is not associated with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia for surgery: results of a randomized controlled pilot trial. J Clin Anesth 2019;52:111-118. 23. Lizano-Diez I, Poteet S, Burniol-Garcia A, Cerezales M. The burden of perioperative hypertension/hypotension: A systematic review. PLoS One 2022;17:e0263737. 24. Radinovic K, Markovic Denic L, Milan Z, Cirkovic A, Baralic M, Bumbasirevic V. Impact of intraoperative blood pressure, blood pressure fluctuation, and pulse pressure on postoperative delirium in elderly patients with hip fracture: A prospective cohort study. Injury 2019;50:1558-1564. 25. Wang NY, Hirao A, Sieber F. Association between intraoperative blood pressure and postoperative delirium in elderly hip fracture patients. PLoS One 2015;10:e0123892. 26. Hirsch J, DePalma G, Tsai TT, Sands LP, Leung JM. Impact of intraoperative hypotension and blood pressure fluctuations on early postoperative delirium after non-cardiac surgery. Br J Anaesth 2015;115:418-426. 27. de Havenon A, Anadani M, Prabhakaran S, Wong KH, Yaghi S, Rost N. Increased Blood Pressure Variability and the Risk of Probable Dementia or Mild Cognitive Impairment: A Post Hoc Analysis of the SPRINT MIND Trial. J Am Heart Assoc 2021;10:e022206. 28. Rickards CA, Tzeng YC. Arterial pressure and cerebral blood flow variability: friend or foe? A review. Front Physiol 2014;5:120. 29. Goodson CM, Rosenblatt K, Rivera-Lara L, Nyquist P, Hogue CW. Cerebral Blood Flow Autoregulation in Sepsis for the Intensivist: Why Its Monitoring May Be the Future of Individualized Care. J Intensive Care Med 2018;33:63-73. Smernice za zdravljenje trde kapsule, 25 mg, 50 mg, 75 mg, 150 mg, 300 mg pregabalin nevropatske bolečine priporočajo pregabalin kot prvo izbiro zdravljenja. (1) Več jakosti za več možnosti zdravljenja Sestava Ena trda kapsula vsebuje 25 mg, 50 mg, 75 mg, 150 mg ali 300 mg pregabalina. Terapevtske indikacije Nevropatska bolečina Zdravljenje periferne in centralne nevropatske bolečine pri respiratorno funkcijo, bolezen dihal ali živčevja, ledvično okvaro ali sočasno uporabljajo depresorje osrednjega živčevja, in pri starejših lahko obstaja večje tveganje za pojav hude depresije odraslih. Epilepsija Dodatno zdravljenje pri odraslih s parcialnimi napadi, sekundarno generalizacijo ali brez nje. Generalizirana anksiozna motnja pri odraslih Odmerjanje in način uporabe dihanja. Pri bolnikih, ki so se zaradi različnih indikacij zdravili z antiepileptiki, so poročali o samomorilnem razmišljanju in vedenju. Pri bolnikih, ki so dobivali pregabalin v obdobju trženja, so opazili Odmerjanje Razpon odmerjanja je od 150 do 600 mg na dan v 2 ali 3 odmerkih. Nevropatska bolečina Zdravljenje se lahko začne s 150 mg na dan v 2 ali 3 odmerkih. Glede na bolnikov odziv in povečano tveganje za pojav samomorilnega vedenja in smrti zaradi samomora. V obdobju trženja so ob sočasnem jemanju pregabalina in zdravil, ki lahko povzročijo zaprtje, kot so opioidni prenašanje je mogoče čez 3 do 7 dni odmerek povečati na 300 mg na dan, in če je treba, čez nadaljnjih 7 dni na največji odmerek 600 mg na dan. Epilepsija Zdravljenje se lahko začne s 150 mg na analgetiki, poročali o učinkih, povezanih z zmanjšanim delovanjem spodnjega gastrointestinalnega trakta (npr. o črevesni zapori, paralitičnem ileusu, zaprtju). Pri predpisovanju pregabalina dan v 2 ali 3 odmerkih. Glede na bolnikov odziv in prenašanje se odmerek čez 1 teden lahko poveča na 300 mg na dan. Po dodatnem tednu se lahko doseže največji odmerek, to je 600 mg na dan. sočasno z opioidi je potrebna previdnost zaradi tveganja za pojav depresije osrednjega živčevja. Poročali so tudi o primerih nepravilnega jemanja, zlorabe in odvisnosti. Po prekinitvi kratkotrajnega Generalizirana anksiozna motnja Razpon odmerjanja je od 150 do 600 mg na dan v 2 ali 3 odmerkih. Potrebo po zdravljenju je treba redno ocenjevati. Zdravljenje s pregabalinom se lahko začne z ali dolgotrajnega zdravljenja s pregabalinom so pri nekaterih bolnikih opazili odtegnitvene simptome. Med jemanjem pregabalina ali kmalu po prekinitvi se lahko pojavijo krči, vključno z odmerkom po 150 mg na dan. Glede na bolnikov odziv in prenašanje se lahko odmerek po 1 tednu poveča na 300 mg na dan. Še 1 teden zatem se lahko odmerek poveča na 450 mg na dan. epileptičnim statusom in generaliziranimi krči. Predvsem pri bolnikih z osnovnimi stanji, ki lahko izzovejo encefalopatijo, so poročali o primerih encefalopatije. Medsebojno delovanje z drugimi Največji dovoljeni odmerek, ki se lahko doseže 1 teden pozneje, je 600 mg na dan. Ukinitev pregabalina Če je treba jemanje pregabalina prekiniti, ga je v skladu s klinično prakso, ne glede na zdravili in druge oblike interakcij Pregabalin lahko stopnjuje učinke etanola in lorazepama. V obdobju trženja so poročali o primerih odpovedi pljuč in primerih kome pri bolnikih, ki so jemali . indikacijo, priporočljivo zmanjševati postopoma, vsaj 1 teden. Bolniki z ledvično okvaro Očistek pregabalina je neposredno sorazmeren z očistkom kreatinina, zato je treba pri bolnikih z oslabljenim pregabalin in druga zdravila, ki zavirajo delovanje osrednjega živčevja. Kaže, da pregabalin prispeva k okvari kognitivnega in grobega motoričnega delovanja, ki jo povzroča oksikodon. Plodnost, M ledvičnim delovanjem odmerek individualno prilagoditi glede na očistek kreatinina. Pri bolnikih na hemodializi je treba dnevni odmerek pregabalina prilagoditi ledvičnemu delovanju. Poleg nosečnost in dojenje Ženske v rodni dobi morajo med zdravljenjem uporabljati učinkovito kontracepcijo. Jemanje pregabalina v prvem trimesečju nosečnosti lahko povzroči večje prirojene , T dnevnega odmerka morajo bolniki po vsaki 4-urni hemodializi takoj dobiti dodaten odmerek. Bolniki z jetrno okvaro Bolnikom z jetrno okvaro odmerka ni treba prilagajati. Pediatrična populacija napake pri nerojenem otroku. Pregabalin Krka se ne sme jemati med nosečnostjo, razen če je nujno potrebno (če koristi za mater prevladajo nad možnim tveganjem za plod). Pregabalin se izloča Varnost in učinkovitost zdravila pri otrocih in mladostnikih nista bili dokazani. Na podlagi trenutno razpoložljivih podatkov ni mogoče dati priporočil o odmerjanju. Starejši bolniki (po 65. letu) Če v materino mleko. Učinek pregabalina na dojene novorojenčke/dojenčke ni znan. Odločiti se je treba med prenehanjem dojenja in prekinitvijo zdravljenja s pregabalinom, pri čemer je treba je njihovo ledvično delovanje oslabljeno, je treba odmerek zmanjšati. Način uporabe Zdravilo se lahko jemlje s hrano ali brez nje. Kontraindikacije Preobčutljivost za učinkovino ali katerokoli pretehtati prednosti dojenja za otroka in prednosti zdravljenja za mater. Vpliv na sposobnost za vožnjo in upravljanje strojev Zdravilo Pregabalin Krka lahko povzroči omotico in somnolenco pomožno snov v zdravilu. Posebna opozorila in previdnostni ukrepi V skladu s klinično prakso moramo nekaterim bolnikom s sladkorno boleznijo, pri katerih med zdravljenjem s pregabalinom in tako blago ali zmerno vpliva na sposobnost za vožnjo in upravljanje strojev. Bolnikom je treba svetovati, naj ne vozijo, ne upravljajo zapletenih strojev in ne opravljajo drugih potencialno pride do povečanja telesne mase, prilagoditi hipoglikemična zdravila. V obdobju trženja so poročali o preobčutljivostnih reakcijah, vključno z angioedemom. V povezavi z zdravljenjem s nevarnih dejavnosti, dokler ni znano, ali to zdravilo vpliva na njihovo zmožnost opravljanja takšnih dejavnosti. Neželeni učinki Zelo pogosti neželeni učinki so omotica, somnolenca in glavobol. pregabalinom so redko poročali o hudih kožnih neželenih učinkih, vključno s Stevens-Johnsonovim sindromom (SJS) in toksično epidermalno nekrolizo (TEN), ki so lahko življenjsko nevarni ali Pogosto se pojavijo nazofaringitis, povečanje apetita, evforično razpoloženje, zmedenost, razdražljivost, dezorientiranost, nespečnost, zmanjšanje libida, ataksija, poslabšana koordinacija, tremor, , 395401-2023 smrtni. Zdravljenje s pregabalinom je bilo povezano z omotico in somnolenco, ki lahko pri starejših poveča pogostost nezgodnih poškodb (padcev). V obdobju trženja so poročali tudi o izgubi dizartrija, amnezija, okvara spomina, motnje pozornosti, parestezije, hipestezija, sedacija, motnje ravnotežja, letargija, zamegljen vid, diplopija, vrtoglavica, bruhanje, navzeja, zaprtje, driska, zavesti, zmedenosti in poslabšanju mentalnih sposobnosti, zato je treba bolnikom svetovati, naj bodo previdni, dokler ni znano, kako zdravilo učinkuje nanje. V obdobju trženja so poročali o flatulenca, napetost trebušne stene, suha usta, mišični krči, artralgija, bolečine v hrbtu, bolečine v udih, krči v vratu, motnje erekcije, periferni edemi, edemi, nenormalna hoja, padec, občutek neželenih učinkih na vid, vključno z izgubo vida, zamegljenostjo ali drugimi spremembami ostrine vida, ki so bile v večini primerov prehodnega značaja. Poročali so o primerih ledvične odpovedi; pijanosti, nenormalno počutje, utrujenost in povečanje telesne mase. Ostali neželeni učinki se pojavijo občasno, redko ali zelo redko. Imetnik dovoljenja za promet z zdravili Krka, d. d., , 5/2023 ob prekinitvi zdravljenja je bil ta neželeni učinek v nekaterih primerih reverzibilen. Za ukinitev sočasnega jemanja antiepileptičnih zdravil in prehod na monoterapijo s pregabalinom, ko je pri Šmarješka cesta 6, 8501 Novo mesto, Slovenija. Način izdajanja zdravila Samo na zdravniški recept. Oprema 56 trdih kapsul po 25 mg, 50 mg, 75 mg, 150 mg ali 300 mg pregabalina. Datum dodatnem zdravljenju s pregabalinom dosežen nadzor nad napadi, ni zadostnih podatkov. V obdobju trženja so pri nekaterih bolnikih, ki so jemali pregabalin, poročali o primerih kongestivnega zadnje revizije besedila 19. 2. 2023. venija srčnega popuščanja. Takšne reakcije so se večinoma pojavile pri starejših bolnikih s srčno-žilnimi boleznimi, ki so dobivali pregabalin za nevropatsko indikacijo. Pri zdravljenju bolnikov s centralno loS nevropatsko bolečino kot posledico poškodbe hrbtenjače se je povečala pogostost neželenih učinkov, povezanih z osrednjim živčevjem, posebno somnolence. Pri bolnikih, ki imajo zmanjšano 1. Attal N, Cruccu G, Baron R et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European Journal of Neurology 2010, 17: 1113-1-23. Samo za strokovno javnost. Celoten povzetek glavnih značilnosti zdravila je objavljen na www.krka.si. Krka, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija, www.krka.si The 11th COGNITIVE DAY meeting was made possible by Main sponsor Sponsors Krka d.d. ABBVIE d. o. o. Organisers Center for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana BIOGEN Pharma d. o. o. LEK farmacevtska družba d. d. MEDIS d. o. o. Slovenian Neurological Association NOVARTIS Pharma Services INC. STADA d. o. o.