13 th COGNITIVE DAY 9 MAY 2025, LJUBLJANA, SLOVENIA Decoding Lewy Body Dementia: Translating Scientific Discoveries into Clinical Advances 13 th COGNITIVE DAY Decoding Lewy Body Dementia: Translating Scientific Discoveries into Clinical Advances Published by: Centre for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana Date and place of publication: 2025, Ljubljana Edited by: Milica Gregorič Kramberger Access to e-booklet: Preceding was published only in e-version (format PDF) at 13th Cognitive Day meeting on 9 May 2025. It is available for download at: Slovenian Neurological Association, www.zdruzenjenevrologov.si Cognitive Day is an annual scientific meeting with international participation organised 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 235156739 ISBN 978-961-7080-11-7 (PDF) Contents 4 List of authors/ lecturers 5 Preface 6 Program 7 Role of structural MRI in Dementia with Prodromal Dementia with Lewy bodies: What is it 16 and how does it fit in the new neuronal synuclein Lewy Bodies disorder framework? Irena REKTOROVA, Brno, Czech Republic Dag AARSLAND, Stavanger, Norway & London, UK 8 Seeing the Invisible: Mechanisms of hallucinatory 20 Cholinergic white matter and vascular phenomena in Dementia with Lewy Bodies pathology in Dementia with Lewy bodies: Zvezdan PIRTOŠEK, Ljubljana, Slovenia New insights from neuroimaging Cene JERELE, Ljubljana, Slovenia 11 Understanding biology to classify and treat synucleinopathies 23 The role of neurophysiology in diagnosis and Tiago OUTEIRO, Goettingen, Germany treatment of Dementia with Lewy bodies Laura BONANNI, Chieti, Italy 14 Identifying co-pathologies in Dementia with Lewy bodies: the role of fluid biomarkers 25 The role of molecular imaging in Dementia Andreja EMERŠIČ, Ljubljana Slovenia with Lewy bodies Maja TROŠT, Ljubljana, Sovenia List of speakers Cene JERELE MD; PhD student Zvezdan PIRTOŠEK, MD, PhD Consultant in Radiology Professor of Neurology University Medical Center Chair of Neurology Ljubljana, Slovenia Medical Faculty University of Ljubljana and Karolinska Institutet and Department of Neurology, University Medical Center Department of Neurobiology, Care Sciences and Society (NVS) Ljubljana, Slovenia Division of Clinical Geriatrics Huddinge, Sweden Dag AARSLAND MD, PhD Professor of Old Age Psychiatry Director of the Centre for Healthy Brain Ageing, Irena REKTOROVA, MD, PhD Department of Psychological Medicine Professor of Neurology and Head of the NIHR HealthTech Research Centre in Brain Health South Head of the Movement Disorders Centre at the First Department of London Neurology, School of Medicine and of the Applied Neuroscience and Maudsley NHS Foundation Trust, London, United Kingdom Research Group at Central European Institute of Technology (CEITEC), and Director of research at Centre for Age Related Medicine, Stavanger Masaryk University in Brno, Czech Republic University Hospital, Norway. Laura BONANNI, MD, PhD Tiago Fleming OUTEIRO, PhD Professor of Neurology Professor of Aggregopathies, Head of Department of Medicine and Aging Sciences Director of the Department of Experimental Neurodegeneration, Universita degli Studi “. dAnnunzio Chieti-Pescara, Italy University Medical Center Göttingen, Göttingen, Germany Maja TROŠT, MD, PhD Professor of Neurology Andreja EMERŠIČ PhD, Eu SpLM Department of Neurology, University Medical Center Ljubljana Laboratory for CSF diagnostics, and Department of Nuclear Medicine, University Medical Center Ljubljana Neurology Clinic, University Medical Center, Ljubljana, Slovenia and Medical Faculty University of Ljubljana, Slovenia Preface Dear colleagues, It is a great pleasure to welcome you to the 13th Cognitive Day international meeting and to present this selection of scientific articles and abstracts compiled for the occasion. On behalf of the Organizing Committee, I am honored to introduce this year’s meeting, which is dedicated to Dementia with Lewy Bodies (DLB) — a complex, multifaceted, and often underrecognized neurodegenerative disease. DLB is recognized as the second most common cause of degenerative dementia after Alzheimer’s disease. However, its diagnosis and management remain significant clinical challenges. Thanks to continuous research efforts and growing clinical awareness, we are increasingly better equipped to detect, understand, and manage this condition. This meeting brings together leading international experts, Thank you for your participation and your dedication to improving clinicians, researchers, and healthcare professionals, united by a the lives of individuals living with DLB and their families. A special common goal: to share the latest advances, foster new thanks to all the speakers and contributors who made this meeting collaborations, and advance innovation in the diagnosis and care possible. of individuals affected by DLB. We wish you an engaging and fruitful experience. We have prepared a comprehensive program designed to inspire meaningful discussions and provide valuable insights. This booklet Warm regards, contains essential information about the meeting, including the Associate Professor Milica Gregorič Kramberger, MD, PhD program schedule and abstracts. Head of the Organizing Committee Program 08:30 - 09:00 Registration 11:25 - 11:45 Coffee Break 09:00 Welcome and introduction STRUCTURAL IMAGING Milica G. KRAMBERGER, Ljubljana, Slovenia CLINICAL PRESENTATION Irena REKTOROVA, Brno, Czech Republic 11:45 Role of structural MRI in Dementia with Lewy Bodies 09:05 Prodromal Dementia with Lewy bodies: What is it 12:15 Cholinergic white matter and vascular pathology in and how does it fit in the new neuronal synuclein Dementia with Lewy bodies: New insights from disorder framework? neuroimaging Dag AARSLAND, Stavanger, Norway & London, UK Cene JERELE, Ljubljana, Slovenia 09:35 Seeing the Invisible: Mechanisms of hallucinatory Discussion 12:45 - 12:55 phenomena in Dementia with Lewy Bodies Zvezdan PIRTOŠEK, Ljubljana, Slovenia 13:00 - 14:00 LUNCH 10:05 - 10:15 Discussion NEUROPHYSIOLOGY & FUNCTIONAL IMAGING 10:15 BIOMARKERS The role of neurophysiology in diagnosis and 14:00 treatment of Dementia with Lewy bodies Understanding biology to classify and treat Laura BONANNI, Chieti, Italy synucleinopathies Tiago Fleming OUTEIRO, Goettingen, Germany 14:30 The role of molecular imaging in Dementia with Lewy bodies 10:45 Identifying co-pathologies in Dementia with Maja TROŠT, Ljubljana, Sovenia Lewy bodies: the role of fluid biomarkers Andreja EMERŠIČ, Ljubljana Slovenia 15:00 - 15:15 Discussion 11:15 - 11:25 Discussion 15:15 Closing remarks Prodromal Dementia with Lewy bodies: What is it and how does it fit in the new neuronal synuclein disorder framework? Dag Aarsland Like all the major neurodegenerative disorders, dementia with Lewy bodies (DLB) has an extended period of gradually increasing neuropatho- logical changes before clinical symptoms emerge. The earliest pathologi- cal changes in DLB are alpha-synuclein accumulation, which usually starts in the brainstem and olfactory regions, leading to synaptic dysfunction, followed by spread to limbic and cortical areas. This pathol- ogy precedes the onset of full-blown cognitive and motor symptoms by years. The prodromal stage of DLB is less well described compared to Alzhei- mer`s disease and Parkinson`s disease, but research criteria have been proposed (MCKetih et al 2020, 32661072). It is well established that REM sleep behavior disorder (RBD) is an early clinical indicator of subsequent DLB. Similarly, some patients with mild cognitive impairment (MCI), in particular those with non-amnestic MCI and one or more of the core DLB features (eg visual hallucinations, parkinsonism, fluctuating cognition, RBD), will develop DLB rather than Alzheimer`s disease. The opportunity to reliably diagnose alpha-synucleinopathy in CSF has enabled the possibility to accurately diagnose DLB, and potentially also the prodromal and even the pre-clinical stages of DLB. This has led to the proposal of new biological classification systems for DLB and other alphasynuclein disorders, similar to that of Alzheimer`s disease (eg the ATN system). The neuronal synuclein disorder framework (Simuni T et al 2024) ,includes an integrated staging system (NSD-ISS). This system is developed based on evidence in Parkinson`s disease. In this lecture, I will discuss how it might fit with DLB, both manifest and prodromal DLB, and describe an ongoing research project aiming to assess this question. phenomena in Dementia with Lewy Bodies Cognitive neuropsychology has revealed that hallucinations in DLB emerge from a disruption in the dynamic interaction between bottom-up Seeing the Invisible: Mechanisms of hallucinatory Cognitive and Perceptual Mechanisms sensory input and top-down cognitive control. Patients exhibit significant deficits in visuoperception, attention, and executive function, with poor contrast sensitivity, impaired figure-ground discrimination, and difficulty integrating visual information. These perceptual abnormalities create ambiguity, which the brain attempts to resolve — often by generating internally derived interpretations that manifest as hallucinations. Zvezdan Pirtošek Cognitive fluctuations, a defining feature of DLB, further destabilize perceptual reality. Periods of reduced alertness, transient confusion, or dream-like mentation correlate temporally with hallucinatory episodes, suggesting that transient shifts in consciousness enable internally generated images to intrude into waking perception. Abstract Structural and Functional Brain Correlates Hallucinations — perceptions in the absence of external stimuli — repre- sent one of the most striking and clinically significant symptoms in Structural MRI studies consistently demonstrate occipital and parietal Dementia with Lewy Bodies (DLB). Among these, visual hallucinations lobe atrophy in DLB, particularly in visual association areas. Hippocampal (VHs) are particularly characteristic, often appearing early in the disease and temporal lobe involvement also contributes to impaired contextual course, and serving as both a diagnostic hallmark and a window into memory and familiarity misattribution. Functional neuroimaging using deeper neural dysfunction. This lecture explores the multifactorial neuro- FDG-PET and resting-state fMRI reveals occipital hypometabolism, biological, cognitive, and theoretical mechanisms underlying hallucinato- disrupted dorsal attention networks, and increased activity in the default ry phenomena in DLB, integrating empirical findings with recent advances mode network (DMN) — all of which point to a breakdown in perceptual in systems neuroscience and consciousness studies. prediction and attentional control. DLB is further characterized by reduced functional connectivity between frontal executive regions and posterior visual cortices. This results in Clinical and Phenomenological Overview diminished top-down correction of perceptual errors and facilitates the emergence of unfiltered or erroneous percepts. Emerging EEG studies Dementia with Lewy Bodies is the second most common form of neuro- reveal thalamo-cortical dysrhythmia and increased low-frequency degenerative dementia after Alzheimer’s disease, defined by the accumu- oscillations, linking hallucinations to unstable cortical rhythms and lation of α-synuclein pathology in cortical and subcortical structures. impaired sensory gating. Core clinical features include cognitive fluctuations, visual hallucinations, REM sleep behavior disorder (RBD), and parkinsonism. Visual hallucinations affect up to 70–80% of patients and are typically Neurochemical Contributions well-formed, vivid, and recurrent, involving human figures, animals, or objects. Early in the disease, patients may retain insight into their halluci- Neurochemical imbalances play a central role in DLB hallucinations. natory experiences, which gradually diminishes as the disease progress- Severe cholinergic deficits, particularly in the occipital cortex, reduce the es. Unlike hallucinations in psychotic disorders, those in DLB are less brain’s capacity to filter visual noise and sustain attention. Dopaminergic bizarre and often contextual. They are also strongly associated with dysregulation, while crucial for motor function, contributes to overactive caregiver burden, earlier institutionalization, and increased mortality risk. salience attribution and hyperinterpretation of internal stimuli. This aligns DLB in part with psychotic models of hallucination, while maintaining its unique neurodegenerative profile. Serotonergic and noradrenergic systems also modulate arousal and Practical Implications and Clinical Strategies reality testing. Reduced serotonin receptor binding (especially 5-HT2A) in temporal and visual cortices may lower thresholds for hallucinatory Clinically, hallucinations in DLB are more than perceptual curiosities — intrusion. Pharmacological studies show that cholinesterase inhibitors they signal a more rapid cognitive decline and greater disease severity. (e.g., rivastigmine) can reduce hallucinations, while dopaminergic and Their management requires nuanced, interdisciplinary approaches. anticholinergic medications often exacerbate them. Neuroleptic Non-pharmacological interventions should be prioritized, including sensitivity remains a critical clinical issue, with typical antipsychotics reassurance, environmental adaptation (lighting, visual cues), and potentially triggering severe, even fatal, reactions. caregiver education. Medication review is essential, particularly for anticholinergic or dopaminergic agents. Cholinesterase inhibitors remain the mainstay of pharmacological Theoretical Integration: Predictive Coding and Consciousness treatment. When antipsychotic medication becomes necessary, quetiapine may be used cautiously, while clozapine remains an Recent advances in cognitive neuroscience provide novel theoretical alternative under specialist supervision. Pimavanserin, a 5-HT2A inverse frameworks to understand hallucinations as active inferences rather than agonist, holds promise in preliminary studies but is not widely available in passive errors. According to the Bayesian brain hypothesis, perception all regions. results from hierarchical predictions generated by the brain, which are Emerging research into biomarkers — including occipital constantly updated against incoming sensory data. In DLB, degraded hypometabolism, EEG slowing, and neurotransmitter imaging — may bottom-up input (due to visual processing deficits and cholinergic loss) enable earlier identification of hallucination-prone individuals and leads the brain to rely more heavily on internal predictions or priors. personalized therapeutic interventions. When these priors dominate in the absence of reliable error correction, hallucinations occur. This view aligns with Anil Seth’s model of perception as “controlled Conclusion hallucination.” All perception, under this model, is a hallucinatory construction shaped by prior knowledge — constrained by sensory data. Hallucinations in DLB arise from a complex interplay of sensory In DLB, these constraints weaken, resulting in “uncontrolled degradation, cognitive instability, network dysfunction, and hallucinations” where top-down predictions become indistinguishable neurochemical imbalance. They reflect the breakdown of systems from reality. Visual hallucinations thus reveal the predictive nature of responsible for integrating, predicting, and correcting perceptual input — consciousness itself, distorted through neurodegeneration. ultimately revealing how the brain constructs reality. As such, they are not merely pathological, but epistemologically and neurologically revealing. By “seeing the invisible,” both literally and conceptually, we gain insight Evolutionary Perspective on Hallucinatory Phenomena into the architecture of consciousness, the vulnerability of perception, and the necessity of interdisciplinary research. Hallucinations in DLB From an evolutionary standpoint, perception evolved to favor survival offer a unique opportunity to bridge clinical neurology with theoretical over veridical accuracy. A brain primed to detect potential threats — even neuroscience — and to advance both our science and our compassion. at the risk of false positives — may have had adaptive value. Visual systems are evolutionarily ancient, and hallucinations may represent a reversion to more primitive, less supervised forms of perception. As the evolutionarily newer cortical regions (parietal, occipital, prefrontal) deteriorate in DLB, subcortical and limbic systems gain relative dominance, producing vivid percepts without contextual filtering. In this light, hallucinations may be understood as evolutionarily “disinhibited survival heuristics” emerging in the absence of modern neural governance. REFERENCES McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88–100. Aarsland D, Ballard C, Halliday G. Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? Lancet Neurol. 2021;20(5):301–311. Shimizu S, Hanyu H, Asano T, et al. Differentiation of dementia with Lewy bodies from Alzheimer's disease using brain SPECT. Dement Geriatr Cogn Disord. 2005;20(1):25–30. Peraza LR, Taylor JP, Kaiser M. Divergent brain functional network alterations in dementia with Lewy bodies and Alzheimer’s disease. Neurobiol Aging. 2015;36(9):2458–2467. Ballard C, Grace J, McKeith I, et al. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet. 1998;351(9108):1032–1033. McKeith I, Fairbairn A, Perry R, et al. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ. 1994;308(6920):202–203. Sawada H, Oeda T, Umemura A, et al. Cholinesterase inhibitors may reduce hallucinations in dementia with Lewy bodies. Int J Geriatr Psychiatry. 2019;34(4):522–528. Friston K. A theory of cortical responses. Philos Trans R Soc Lond B Biol Sci. 2005;360(1456):815–836. Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ. The computational anatomy of psychosis. Front Psychiatry. 2013;4:47. Collerton D, Perry E, McKeith I. Why people see things that are not there: a novel perception and attention deficit model for recurrent complex visual hallucinations. Behav Brain Sci. 2005;28(6):737–757. Seth AK. Being You: A New Science of Consciousness. London: Faber & Faber; 2021. Seth AK. A predictive processing theory of sensorimotor contingencies: Explaining the puzzle of perceptual presence and its absence in synesthesia. Cogn Neurosci. 2014;5(2):97–118. Barrett LF. How Emotions Are Made: The Secret Life of the Brain. Boston: Hough- ton Mifflin Harcourt; 2017. Pessoa L. The Cognitive-Emotional Brain: From Interactions to Integration. Cambridge: MIT Press; 2013. Understanding biology to classify and treat and the adoption of aberrant conformations, initiating aggregation processes. Some of the resulting aggregated species are thought to be synucleinopathies cytotoxic, leading to neuronal dysfunction and death in neurodegenerative diseases. Protein aggregation is a common feature in various neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and rarer conditions such as prion diseases, all of which have devastating consequences for the brain. A shared hallmark of neurodegenerative diseases, beyond region-specific neuronal death, is Tiago Fleming Outeiro the accumulation of protein aggregates in the brain, and in some cases, even in peripheral tissues. However, it is now widely accepted that protein pathology in the various neurodegenerative diseases is more complex than initially thought and that multiple pathologies/co-pathologies can occur [2], especially with aging. This understanding has strong implications for diagnosis and may prove The molecular process of protein aggregation has been extensively useful also for disease classification. studied in vitro over the years. However, the mechanisms governing protein folding and unfolding in the crowded cellular environment — In PD, dementia with Lewy bodies (DLB), pure autonomic failure (PAF) where concentrations of proteins and other biomolecules are extremely and multiple system atrophy (MSA), collectively referred to as high—remain less understood. This understanding is highly relevant not synucleinopathies, α-synuclein (aSyn) is the key aggregating protein. Its only in the context of normal biology, but also in the context of a variety misfolding and subsequent aggregation into oligomeric and fibrillar of human conditions, ranging from cancer, to diabetes, and neurodegen- species represent central pathogenic events. These aggregates not only erative disorders. disrupt cellular functions but also contribute to the progressive neuronal loss observed in this disorder. Understanding how aSyn misfolds, Cells must tightly regulate protein production, folding, clearance, and aggregates, and interacts with the proteostasis network is therefore disaggregation in order to maintain protein homeostasis, or proteostasis critical for developing effective therapeutic strategies to combat PD and [1]. This includes ensuring proper folding in diverse subcellular compart- related synucleinopathies. ments and detecting and addressing instances of protein misfolding. The cellular proteostasis network encompasses molecular chaperones, PD is understood as a highly complex disorder. While the motor degradation pathways such as the ubiquitin-proteasome system, and symptoms are the hallmark leading to diagnosis, prodromal phases autophagy (Gidalevitz et al., 2010). This network also integrates signaling exhibit signs such as hyposmia, REM sleep disturbances, gastrointestinal pathways that allow cells to respond to environmental perturbations that and behavioral changes. These early symptoms implicate multiple brain disrupt proteostasis, thereby mitigating damage and preventing cellular regions and even peripheral organs, such as the gut, before involvement toxicity. of the dopaminergic substantia nigra. This region of the brain experiences extensive neuronal loss in PD, with the resulting dopamine By targeting the molecular triggers of protein misfolding, it may be deficiency contributing to the motor deficits characteristic of the disease. possible to interfere with the progression of protein aggregation at its earliest stages. Therefore, developing biomarkers capable of detecting Advances in understanding of genetic factors, environmental factors, and these preclinical molecular changes would also enable early intervention, factors contributing to neurodegeneration suggest that PD should not be providing a promising avenue for the discovery of disease-modifying considered a singular homogeneous condition but rather a complex therapies (DMTs). multifaceted group of related disorders arising due to the combination of Under various conditions, including environmental stressors, genetic various complex components (i.e. ‘Parkinson’s diseases’). Importantly, mutations, post-translational modifications, or simply the aging process, various pathophysiological mechanisms have been associated with PD the proteostasis network may fail. This can lead to protein misfolding and they are likely preferentially associated with specific factors. Consequently, there is an increasing need for a broad set of criteria to classify and define PD based on biological markers rather than relying solely on descriptive, often subjective, clinical criteria. The development of seeding amplification assays (SAA) has emerged as a powerful tool for detecting the presence of misfolded and aggregated proteins associated with neurodegenerative diseases [3-5]. These assays exploit the ability of pathological protein aggregates to induce the misfolding of their soluble monomeric counterparts, amplifying even minute amounts of disease-related species for detection. SAAs, such as Real-Time Quaking-Induced Conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA), have demonstrated remarkable sensitivity and specificity in identifying disease-associated aggregates in various biological samples, including cerebrospinal fluid, blood, and even skin biopsies [3, 4, 6, 7]. Recent studies further highlight the potential of these techniques to advance the understanding of disease heterogeneity and identify reliable biomarkers for early diagnosis [8, 9]. Several groups of international leaders have proposed classification systems neurodegenerative diseases, beginning with AD [10, 11] and most recently including PD. These PD-related proposals, initially designed for research purposes, are meant to serve as a foundation for diagnosis and differentiation between distinct PD subtypes [12-14]. As new biomarkers become available, these classification systems will continue to evolve and it is likely, and desirable, they become integrated in routine clinical practice. In summary, the scientific community has made tremendous progress in our understanding of molecular mechanisms involved in neurodegenerative diseases. While laboratory models are essential for testing basic molecular mechanisms, it has also become evident that we need to use and develop more complex models that aim to recapitulate the genetic and cellular context of cells in the complex environment of the human brain. In turn, this requires the development of disease classification systems that capture the underlying biology/pathobiology so that we can attempt to recapitulate disease in model systems. Ultimately, the hope is that we can diagnose diseases early to maximize our chances of therapeutic success. REFERENCES 14. Simuni, T., et al., A biological definition of neuronal alpha-synuclein disease: towards an integrated staging system for research. Lancet Neurol, 2024. 1. Balch, W.E., et al., Adapting proteostasis for disease intervention. Science, 23(2): p. 178-190. 2008. 319(5865): p. 916-9. 2. Spires-Jones, T.L., J. Attems, and D.R. Thal, Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol, 2017. 134(2): p. 187-205. 3. Frey, B., et al., Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer's disease brain. Acta Neuro- pathol Commun, 2023. 11(1): p. 181. 4. Huang, J., et al., Pathological alpha-synuclein detected by real-time quaking-induced conversion in synucleinopathies. Exp Gerontol, 2024. 187: p. 112366. 5. Vascellari, S., C.D. Orru, and B. Caughey, Real-Time Quaking- Induced Conversion Assays for Prion Diseases, Synucleinopathies, and Tauopathies. Front Aging Neurosci, 2022. 14: p. 853050. 6. Concha-Marambio, L., et al., Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc, 2023. 18(4): p. 1179-1196. 7. Vivacqua, G., et al., Salivary alpha-Synuclein RT-QuIC Correlates with Disease Severity in de novo Parkinson's Disease. Mov Disord, 2023. 38(1): p. 153-155. 8. Coysh, T. and S. Mead, The Future of Seed Amplification Assays and Clinical Trials. Front Aging Neurosci, 2022. 14: p. 872629. 9. Mok, T.H., et al., Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease. Brain, 2023. 146(6): p. 2570-2583. 10. Jack, C.R., Jr., et al., Revised criteria for diagnosis and staging of Alzhei- mer's disease: Alzheimer's Association Workgroup. Alzheimers Dement, 2024. 20(8): p. 5143-5169. 11. Jack, C.R., Jr., et al., A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology, 2016. 87(5): p. 539-47. 12. Hoglinger, G.U., et al., A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol, 2024. 23(2): p. 191-204. 13. Lang, A.E., et al., Initial biological classification of Lewy body diseases: No consensus on terminology. Alzheimers Dement, 2024. Identifying co-pathologies in Dementia with Corroborating previous findings, we observed decreased CSF Aβ42/40 ratio in 49%, and the A+T+ profile (decreased CSF Aβ42/40 ratio with Lewy bodies: the role of fluid biomarkers increased phosphorylated tau (p-tau)) in 34% of our patients with probable DLB; CSF profile consistent with underlying amyloid or AD co-pathology in DLB was associated with poorer performance on mini-mental state examination (MMSE). Since newly developed blood-based biomarkers offer promising, less invasive tools for early and accurate AD diagnosis, we further evaluated plasma p-tau217 and brain-derived tau performance in our memory clinic cohort. Brain-derived tau and p-tau217 correlated with CSF Aβ42/40 ratio, total tau, and CSF Andreja Emeršič p-tau181 and detected amyloid co-pathology in DLB with 73% and 83% accuracy, respectively. Similarly, higher plasma p-tau181 and p-tau231 concentrations were found in European-DLB Consortium cohort participants with abnormal CSF Aβ42 levels and associated with lower baseline MMSE scores and more rapid MMSE decline over time in this multicentric study (9). Most patients with neurodegenerative dementia receive only one diagno- sis during life; however, more than half exhibit multiple pathologies at Contrary to AD, the impact of coexistent TDP-43 proteinopathy in DLB is autopsy that likely contributed to their clinical presentation, rate of less investigated because we lack reliable biomarkers to identify cognitive decline, and mortality (1–3). Because current evidence is pathological TDP-43 aggregation during life (1). The real-time largely derived from retrospective neuropathological data, our under- quaking-induced conversion technique has been adapted to CSF TDP-43 standing of the impact of concomitant pathologies in dementia with protein but not studied in DLB (10). Nevertheless, neuropathological Lewy bodies (DLB) is still limited. Cerebrospinal fluid (CSF) or studies have shown that TDP-43 pathology is associated with greater blood-based biomarkers that reflect underlying co-pathologies may Lewy pathology burden, occurs more frequently in the presence of inform the prediction of disease progression and improve clinical trial concomitant AD, and might reduce the likelihood of a clinical DLB design in the future (1,4). diagnosis (1,11–13). To conclude, comorbid proteinopathies are prevalent and likely affect DLB, the second most common neurodegenerative dementia, is charac- clinical presentation and disease progression in DLB. Combined terized by the intracellular accumulation of α-synuclein aggregates in the assessment of α-synuclein disease-specific biomarkers and biomarkers form of Lewy bodies and Lewy neurites (5,6). Neuropathological studies of concomitant pathologies could facilitate early, accurate diagnosis and have demonstrated a high prevalence of concomitant Alzheimer’s guide potential treatment approaches. disease (AD), TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathology in DLB (1). Intermediate or high levels of AD neuropathology, reported in up to 50% of patients with autopsy-confirmed Lewy body disease, have been associated with greater α-synuclein burden and worse prognosis (1,4). Poorer performance in memory tests, more rapid attention decline, and shorter life expectancy have been reported in DLB individuals with AD neuropathologic change or AD CSF biomarker profile compared to patients with Lewy body pathology alone (1,2,7,8). Further- more, amyloidosis (decreased CSF Aβ42/40 ratio) and AD CSF profile which were more common among the patients with Lewy body disease and dementia (71% and 43%, respectively) compared to those at mild cognitive impairment stage (48% and 9%, respectively), suggest the frequency of AD co-pathology in DLB increases with the severity of cognitive impairment (2). REFERENCES 12. Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta 1. Toledo JB, Abdelnour C, Weil RS, Ferreira D, Rodriguez-Porcel F, Pilotto A, Neuropathol. 2007;114(3):221–9. et al. Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design. Alzheimer’s Dement. 2023;19(1):318–32. 13. McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. 2. 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TDP-43 real-Time quaking induced conversion reaction optimization and detection of seeding activity in CSF of amyotrophic lateral sclerosis and frontotemporal dementia patients. Brain Commun. 2020;2(2):1–14. 11. Buciuc M, Whitwell JL, Boeve BF, Ferman TJ, Graff-radford J, Savica R, et al. TDP-43 is associated with a reduced likelihood of rendering a clinical diagnosis of dementia with Lewy bodies in autopsy- confirmed cases of transitional/diffuse Lewy body disease. J Neurol. 2020;267(5):1444–53. Role of structural MRI in Dementia with volumes, worse cognition, and faster cognitive decline, a subtype with low GM volumes in fronto-occipital regions, and a subtype of younger Lewy Bodies patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations. A specific brain-clinical signature which predicted conversion to fully developed DLB over 4 years was described in patients with isolated REM sleep behavioural disorder (iRBD) using partial least squares between brain deformation and 27 clinical variables (Rahayel et al., 2021). The pattern consisted of deformation of both cortical and subcortical regions, including mainly the basal ganglia, thalamus, corona Irena Rektorova radiata, amygdala, frontal and temporal lobes, and cerebellum, while expansion was additionally described in the ventricular system and subarachnoid cisterns. The deformation score predicted conversion to DLB with odds ratio = 4.7. Many authors explored atrophy in specific brainstem structures and Based on biological definition of neuronal α-synuclein diseases (Simuni basal forebrain to evaluate losses of dopaminergic, noradrenergic and et al., 2024) or on SynNeurGe classification of Parkinson’s disease cholinergic neurons and pathways. Nucleus basalis of Meynert (NBM) (Höglinger et al., 2024), imaging will be utilized particularly for evaluating volume has been consistently reduced in cognitively impaired patients neurodegeneration. So far, dopaminergic imaging using PET or SPECT with Parkinson’s disease (PD) and it was shown utility as a prognostic and cardiac scintigraphy has been particularly implicated for diagnostic indicator of future cognitive decline (Slater et al., 2024). Atrophy of the purposes in dementia with Lewy bodies (DLB) (McKeith et al., 2017). NBM was repeatedly reported also in DLB patients and in early prodromal However, MRI has a great potential to serve as a suitable, relatively DLB (Schumacher et al., 2021, Woo K et al. 2025), while the mean cheap, non-invasive and widely available marker for detection of specific functional connectivity from the nucleus to occipital cortex was degeneration patterns for DLB subtyping and stratification, for assessing increased (Schumacher et al., 2021). Similar functional compensatory microstructural changes, evaluating loss of dopaminergic, cholinergic mechanisms have been described from the basal ganglia structures to and noradrenergic neurons and integrity of particularly cholinergic and lateral temporal cortices in patients with mild cognitive impairment with dopaminergic pathways, and for screening for potential comorbidities. Lewy bodies (MCI-LB) (Novakova et al., 2024), i.e. a prodromal, Longitudinal MRI studies enable its use not only for diagnostic purposes pre-dementia stage of DLB. While NBM atrophy was describe in both but also for monitoring disease progression and potential treatment prodromal and fully blown DLB, based on longitudinal examination, GM effects. atrophy progressed in regions with significant cholinergic innervation, with widespread and accelerated rates of atrophy in patients who progress to probable DLB (Kantarci et al., 2022). Structural MRI alterations Loss of dopaminergic neurons in substantia nigra pars compacta (SNc) While earlier studies particularly pointed out atrophy and cortical thinning and noradrenergic neurons in locus coeruleus (LC) have been studied of insula, anterior cingulate and medial frontal structures in early prodro- using neuromelanin sensitive (NMS) MRI. It is a T1 fast spin echo mal DLB subjects (Blanc et al. 2015, Roquet et al., 2017), later studies sequence. Both dopaminergic neurons and noradrenergic neurons describe specific DLB patterns of early atrophy containing rather occipi- contain a pigment neuromelanin (NM). Source of the NM contrast is NM tal and posterior temporal cortices (Cohen et al. 2025, Wang D, 2024, bind to iron which is paramagnetic. Therefore, NM signal is decreased in Galli et al. 2023). Atrophy patterns may differ between males and patients with DLB, already in early prodromal stages of the disease and in females (Oltra et al., 2023). Various DLB subtypes were reported using iRBD, particularly in the LC (Železníková et al. 2025, Ehrminger et al. cluster analysis based on demographic and clinical data, Alzheimer’s 2016). Iron sensitive susceptibility weighted imaging (SWI) or T2* disease (AD) and cerebrovascular biomarkers at baseline, and cognitive relaxometry can be used to visualize dorsal nigral hyperintensity decline over 3 years of follow up (Inguanzo et al., 2023). The clusters (so-called swallow tail sign) in individual healthy subjects. It evaluates included an older subtype with reduced cortical grey matter (GM) nigrosome-1 as an ovoid hyperintense region in the dorsolateral part of the SNc (Theis et al. 2024). Decreased or loss of the signal is present in Other comorbidities may co-exist in DLB, and cerebrovascular changes already 2/3 of iRBD patients (De Marzi et al. 2016). Although it is easy to manifested as high white matter hyperintensities () loads were reported evaluate, it provides only a qualitative assessment. Based on a to be present in 43% (more than 300 DLB cases evaluated). The WMH systematic review and meta-analysis (Tseriotis et al. 2024), 3T MRI scans were associated with medial temporal atrophy, however, this association showed pooled sensitivity and specificity of 82% to distinguish DLB lost its significance when β-amyloid was included in the model (Rennie et patients from healthy controls and other types of degenerative al. 2024). dementias. The authors concluded that loss of the swallow tail sign (STS) may thus serve as a supportive marker for diagnostic purposes. Another recent review demonstrated that diagnostic accuracy of STS Acknowledgement: loss for DLB differentiation from other dementias was 76–90% (Tseriotis et al. 2025). More precise quantitative susceptibility mapping uses a Supported by EU Joint Program-Neurodegenerative Disease (JPND) multi-echo GRE sequence to map iron deposition in SNs and other project entitled “TACKLing the Challenges of PREsymptomatic Sporadic subcortical and cortical regions (Theis et al. 2024). The trend of Dementia (TACKL-PRED),” project number 8F22005, and by National increasing susceptibility in SNc from controls to iRBD and MCI-LB, and to Institute for Neurology Research (Programme EXCELES, ID Project No. DLB suggests that iron deposition in the substantia nigra starts to LX22NPO5107, Funded by the European Union – Next Generation EU). increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity (Chen et al. 2021). Postmortem data suggest that QSM values are associated with both glial density and tau burden (Wang et al. 2023). However, challenges remain in standardizing QSM processing algorithms to ensure consistent results across different studies. Microstructural changes assessed by MRI using free water imaging Free water imaging uses a bi-tensor diffusion model to assess early microstructural changes, i.e. increased free water in the posterior parts of the SNc in Parkinson’s disease and early DLB stages (Ofori et al. 2017, Burciu et al. 2017). Further alterations can be observed with the disease progression in additional regions including insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial and Rolandic operculum regions over 12 months (Chiu et al. 2024). Free water was increased in the cholinergic NBM in both DLB and AD. However, free water along the pedunculopontine-thalamus tract was increased only in DLB and related to visual hallucinations (Schumacher et al. 2023). Screening LBD co-pathologies While mesial temporal lobe atrophy is rare in pure DLB and intact hippocampi may serve as a supportive feature to distinguish DLB from AD (McKeith et al. 2017), atrophy of the hippocampus or distinct hippocampal subfields is present in coexisting AD-related co-pathology (Ye et al. 2024, Sakurai et al. 2025) which is present in up to 80% of all developed DLB subjects. REFERENCES Schumacher J, Taylor JP, Hamilton CA, et al. In vivo nucleus basalis of Meynert degeneration in mild cognitive impairment with Lewy bodies. Neuroimage Clin. Simuni T, Chahine LM, Poston K, et al. A biological definition of neuronal α-synu- 2021;30:102604. doi: 10.1016/j.nicl.2021.102604. clein disease: towards an integrated staging system for research. Lancet Neurol. 2024 Feb;23(2):178-190. doi: 10.1016/S1474-4422(23)00405-2. Woo KA, Kim H, Kim R, et al. Cholinergic degeneration and early cognitive signs in prodromal Lewy body dementia. 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Rennie A, Ekman U, Shams S, et al. Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias. Brain Commun. 2024 Aug 28;6(5):fcae290. doi: 10.1093/braincomms/fcae290. pathology in Dementia with Lewy bodies: Cholinergic Pathway Involvement New insights from neuroimaging Cholinergic white matter and vascular Key Findings from Recent Research Patients across the Lewy body (LB) continuum exhibited significantly higher WMSA burdens in cholinergic white matter compared to controls, particularly affecting the external capsule, while the cingulum showed more subtle involvement. These findings suggest a preferential vulnerability of certain cholinergic pathways to CVD co-pathology in DLB. The external capsule involvement was detected by both CHIPS and Cene Jerele tractography-based mean diffusivity measures, while cingulum changes were only detected by the more sensitive tractography method. Disease-Specific vs. Age-Related Changes Background While global WMSA (assessed by Fazekas scale and FreeSurfer) reflected primarily age-related changes, cholinergic white matter Dementia with Lewy bodies (DLB) is the second most common neurode- abnormalities represented disease-specific findings in DLB. This generative dementia, frequently presenting with cerebrovascular disease distinction is clinically significant, suggesting that cholinergic pathways (CVD) co-pathology that contributes to both neurodegeneration and may be particularly vulnerable to WMSA in DLB, independent of overall clinical symptoms.[1] White matter signal abnormalities (WMSA) on white matter burden. magnetic resonance imaging (MRI) represent key markers of CVD, with their extent and localization potentially affecting cognitive function.[2] Particularly important are WMSA affecting cholinergic white matter Association with Regional Brain Atrophy pathways, which play a crucial role in cognition across various neurode- generative conditions, including DLB.[3,4] Cholinergic pathways are CHIPS scores were associated with frontal atrophy in LB patients but not affected early in DLB,[5] yet the relationship between WMSA and the with medial temporal or posterior atrophy, suggesting that CVD-related cholinergic system in DLB remains poorly understood. cholinergic damage may specifically contribute to frontal neurodegeneration in DLB. In contrast, medial temporal atrophy appeared to be influenced by a combination of global CVD burden and possible Neuroimaging Approaches to Assess Cholinergic Integrity Alzheimer's disease co-pathology. The Cholinergic Pathway Hyperintensities Scale (CHIPS) offers a feasible clinical tool for assessing WMSA in cholinergic pathways on MRI.[6] This Diagnostic Performance semiquantitative visual rating scale evaluates WMSA in both medial (cingulum) and lateral (external capsule) cholinergic pathways, previously CHIPS assessment of the posterior external capsule demonstrated high applied in Alzheimer's disease and Parkinson's disease but less studied diagnostic performance (>80% sensitivity and specificity) for in DLB. Our recent research compared CHIPS with other regional and discriminating DLB patients from controls, comparable to research-grade global WMSA evaluation methods such as probabilistic tractography, tractography measures. This suggests potential clinical utility for CHIPS FreeSurfer automated segmentation and Fazekas clinical scale to investi- as an accessible biomarker. gate the relationship between cholinergic white matter integrity, vascular pathology, and clinical manifestations in DLB.[7] Clinical Implications These findings highlight the significant role of CVD co-pathology in cholinergic degeneration along the LB continuum. The association between cholinergic WMSA and frontal atrophy suggests that vascular changes may contribute to the clinical presentation of DLB beyond what would be expected from pure synucleinopathy.The differential involvement of cholinergic pathways—with earlier and more severe disruption of external capsule fibers compared to cingulum—aligns with recent evidence suggesting that cholinergic degeneration in Lewy body disease follows a posterior-to-anterior pattern.[8] This structured progression may have implications for the clinical staging and management of DLB. CHIPS presents an accessible clinical tool for assessing cholinergic white matter integrity, potentially aiding in the radiological characterization of DLB patients. Its strong correlation with more complex research methods like tractography supports its validity for clinical application. Conclusion Cerebrovascular co-pathology appears to be an important contributor to cholinergic degeneration in DLB, with a particular impact on the external capsule cholinergic pathway and frontal neurodegeneration. The CHIPS visual rating scale provides a clinically feasible method for assessing cholinergic white matter integrity in DLB, potentially enhancing diagnostic accuracy and treatment planning. These findings emphasize the importance of addressing vascular health in DLB management and suggest that targeted interventions for cerebrovascular risk factors might help preserve cholinergic function across the LB continuum. REFERENCES 1. Watson R, Colloby SJ. Imaging in Dementia with Lewy Bodies: An Over- view. J Geriatr Psychiatry Neurol. 2016;29(5):254-260. doi:10.1177/0891988716654984 2. De Reuck J, Maurage CA, Deramecourt V, et al. Aging and cerebrovascular lesions in pure and in mixed neurodegenerative and vascular dementia brains: A neuropathological study. Folia Neuropathol. 2018;56(2):81-87. doi:10.5114/fn.2018.76610 3. Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O’Brien JT. Progression of white matter hyperintensities in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia: a comparison with normal aging. Am J Geriatr Psychiatry. 2006;14(10):842-849. doi:10.1097/01.JGP.0000236596.56982.1C 4. Schumacher J, Ray NJ, Hamilton CA, et al. Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer’s disease. Alzheimer’s & Dementia. Published online March 15, 2023. doi:10.1002/alz.13034 5. Bohnen NI, Grothe MJ, Ray NJ, Müller MLTM, Teipel SJ. Recent Advances in Cholinergic Imaging and Cognitive Decline—Revisiting the Cholinergic Hypothe- sis of Dementia. Curr Geriatr Rep. 2018;7(1). doi:10.1007/s13670-018-0234-4 6. Bocti C, Swartz RH, Gao FQ, Sahlas DJ, Behl P, Black SE. A new visual rating scale to assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke. 2005;36(10):2126-2131. doi:10.1161/01.STR.0000183615.07936.b6 7. Jerele C, Tzortzakakis A, et al. Cerebrovascular co-pathology and choliner- gic white matter pathways along the Lewy body continuum. Manuscript accepted for publication in Brain Communications, 2025. 8. Okkels N, Grothe MJ, Taylor JP, et al. Cholinergic changes in Lewy body disease: implications for presentation, progression and subtypes. Brain. 2024;147(7):2308-2324. doi:10.1093/BRAIN/AWAE069 The role of neurophysiology in diagnosis and On EEG recordings, theta activity has previously been associated with the presence of cognitive decline, cognitive fluctuation (CF), and visual treatment of Dementia with Lewy bodies hallucinations (VHs) 11 . CF are clinically defined as spontaneous episodes of alterations in cognition, alertness, and attention, characterized also by hypersomnolence and impaired awareness of surroundings12,13. Notably, CF may occur in all forms of dementia, but its prevalence tends to increase up to 90% in case of DLB14,15. According to the most recent diagnostic criteria, CF is considered as a core clinical feature for DLB, together with VHs, parkinsonism, and REM sleep behavior disorder (RBD)10. However, CF has recently been designed to be more common Laura Bonanni, Anita D’Anselmo, Abhimanyu Mahajan, and specifically related to DLB than clinical features as parkinsonism or Alberto Jaramillo Jimenez VHs16. Therefore, the prominence of CF in DLB patients, as well as in Parkinson’s disease with dementia (PDD), has strictly been correlated to Lewy body pathology and more recently to thalamic dysfunction, namely thalamocortical dysrhythmia (TCD)11,14. Electroencephalogram (EEG) is considered as an accurate biomarker for Nowadays, the diagnosis of DLB remains suboptimal and commonly detecting neural changes related to dementia. The diagnostic potential of misdiagnosed as AD. A critical point is to distinguish these two diseases EEG is mainly due to its non-invasiveness, low cost, and high temporal at the earliest stages of dementia, since DLB patients are more sensitive rhythm activity at millisecond levels. However, its spatial resolution is acetylcholinesterase inhibitors, and present a faster disease 17–19 lower in comparison to other diagnostic techniques and, in clinical resolution, which provides functional information in terms of cortical to neuroleptic drugs, experience different responses to progression . Therefore, considering the common difficulties in practice, qualitative EEG findings are subjected to visual interpretation by detecting DLB clinical symptoms such as CF, EEG reveals to be a clinicians1. promising and an effective diagnostic tool for reaching this goal, also at early stages of disease. In neurodegenerative diseases, EEG exhibits a relevant role in detecting cognitive decline, also at early stages, and in discriminating different This talk will describe both spectral analysis approach and QEEG findings types of dementia2–5. In general, a common EEG finding in dementia is an in DLB patients as a helpful guideline for clinicians to improve the increased slow activity together with a decreased rhythm in alpha application of this methodology in clinical setting. The concepts of TCD frequency6. and QEEG analysis will be briefly introduced and, then, the results of QEEG in DLB, also at its prodromal stage, will be discussed. Among all dementing disorders, dementia with Lewy bodies (DLB) represents the second most common cause of dementia after Alzhei- A promising non-pharmacological intervention is transcranial electrical mer’s disease (AD)7. Nevertheless, slowing activities revealed by qualita- stimulation that has become so widespread in recent years, a tive EEG are non-specific to DLB and may be observed in other neurode- non-invasive neurophysiological technique capable of modulating generative diseases or clinical conditions (e.g., alteration of state of cortical excitability. Among the electrical stimulation techniques in consciousness, drug administrations)8. As a result, the introduction of particular, alternating current stimulation offers the possibility of quantitative EEG (QEEG), based on a computational approach to analyze modifying brain oscillations at specific frequencies through the EEG signals, has remarkably enhanced the diagnostic accuracy of this application of a sinusoidal current that is able to induce a consequent methodology9. Indeed, prominent posterior slow-wave activity on resting effect on cognitive functions. Several studies have shown that the alpha state EEG with periodic fluctuations in the pre-alpha/theta range has rhythm is associated with various attentional mechanisms and in fact it recently been included as a supportive biomarker for DLB diagnosis10. has been seen that the application of alpha tACS can improve attentional performance20, 21. 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Neurology. 2004;62(2):181-187. doi:10.1212/WNL.62.2.181 The role of molecular imaging in Dementia Clinically, the presence of occipital hypoperfusion or hypometabolism on SPECT/PET is now recognized as a supportive biomarker for DLB in with Lewy bodies consensus criteria (1) . Notably, the imaging profiles of DLB and PDD are largely overlapping given that they share the “core” pathology, namely α-synuclein deposits. Both DLB and PDD usually demonstrate reductions in occipital lobe activity on functional imaging and relatively mild medial temporal atrophy compared to ADD. Several studies showed greater cortical atrophy in DLB compared to PDD, even though the extent of these changes is heterogenous between studies and some studies found no differences (4). Note that the current diagnostic criteria suggest Matej Perovnik, Maja Trošt following a so-called “one-year-rule” for differentiating between DLB and PDD, i.e. if the onset of dementia and parkinsonism occurs within one year, the patients should be diagnosed with DLB. There is some evidence that FDG PET might be of clinical use also for differentiation between DLB and PDD, while examining “only” regional changes. A longitudinal FDG PET-based study showed a marked decline in brain metabolism in Introduction posterior cortical regions in patients with DLB and in one of its prodromal forms, i.e. mild cognitive impairment due to LB (MCI-LB) compared to acterized by a combination of cognitive decline and parkinsonian predominant subcortical, including the thalami, basal ganglia and (6) features, with core clinical signs including fluctuations in cognition and Dementia with Lewy bodies (DLB) is a neurodegenerative disorder char- healthy individuals (5). While a previous study suggested a more hippocampus, changes in patients with PDD . However, if cortical vs visual hallucinations. In the diagnostic workup of DLB, multiple neuroim- subcortical predominance could separate DLB from PDD cases remains aging modalities are employed for both exclusion of other pathologies to be investigated in the future. and identification of characteristic imaging features. Conventional structural imaging (CT or MRI) can reveal patterns of atrophy (notably a For the practicing neurologist, these imaging observations have practical relative preservation of medial temporal lobe structures) that may implications: preserved hippocampi on MRI or FDG PET or a prominent support the diagnosis of DLB over dementia due to Alzheimer’s disease occipital hypometabolism on PET in a demented patient should raise (ADD). Functional imaging plays an important role in the next step of the suspicion for DLB over typical AD, while an abnormal dopamine diagnostic work-up. Positron emission tomography (PET), especially with transporter scan would support DLB/PDD over AD. 18F-fluorodeoxyglucose (FDG), can demonstrate metabolic deficits characteristic of DLB, and imaging of dopaminergic system, either with PET or single-photon emission computed tomography (SPECT), are Metabolic brain network imaging frequently used to differentiate DLB from other dementias (1,2). Beyond region-by-region findings, advanced multivariate imaging analyses have recently provided a more integrated picture of brain Metabolic brain imaging changes in DLB. Scaled Subprofile Modeling with Principal Component Analysis (SSM/PCA) is a network analysis technique that identifies Neuroimaging reveals both overlaps and important differences between covarying patterns of brain activity across subjects. Applied to FDG-PET DLB and other dementias like ADD and Parkinson’s disease dementia scans, SSM/PCA can extract disease-specific metabolic networks whose (PDD). FDG PET scans in DLB characteristically show hypometabolism in expression can be then calculated at individual patient level (7). Using the occipital lobes and in parieto-temporal regions, with relative sparing this approach, a so called DLB-related metabolic pattern (DLBRP) was of the posterior cingulate cortex – a phenomenon known as the “cingu- identified. The DLBRP is characterized by a prominent hypometabolism late island sign” (3). This topography helps differentiate DLB from ADD, in posterior cortical areas (notably the occipital cortex and inferior which usually presents with temporoparietal hypometabolism that parietal lobes) coupled with relative hypermetabolism (persevered includes the posterior cingulate without the involvement of the occipital metabolic activity) in subcortical and limbic regions, such as the basal cortex (3). ganglia (putamen, pallidum), medial temporal structures (including the hippocampi and parahippocampi), and the cerebellum. Importantly, the However, recent advances in understanding of pathology (17) have DLBRP shares partial topography with known AD and PD metabolic revealed that lower PiB uptake accurately distinguishes cases with Lewy patterns, yet it bears distinct topographic characteristics (8). This is body disease (LBD) from cases with AD or mixed pathology. The severity consistent with DLB having elements of both AD (amyloid/tau of diffuse amyloid pathology is therefore the primary contributor to co-pathology contributing to cortical hypometabolism) and PD elevated PiB uptake in LBD. (α-synuclein pathology driving subcortical network changes). Expression of the DLBRP can discriminate DLB patients from healthy controls with It has been discovered that AD co-pathology in LBD (DLB+) is associated high accuracy, and also separates DLB from ADD (8). The clinical with poorer cognition, greater medial temporal lobe atrophy and a relevance of identifying this network extends beyond diagnosis: the reduced prevalence of visual hallucinations and parkinsonism in degree to which an individual expresses the DLB pattern correlates with cross-sectional studies. However, the relationship between Aβ and tau disease severity and has been linked to shorter survival time (8). biomarkers and longitudinal disease trajectory in LBD is less clear, with Interestingly, a metabolic brain pattern related to cognitive dysfunction in some studies reporting poorer outcome and some not (12). Pathology PD, so called PD-cognitive pattern (PDCP) is topographically unrelated to studies have shown increased mortality in LBD+ compared to LBD- as DLBRP and is characterized by a more prominent frontal hypometabolic well as seven years shorter overall survival (12). There was also an changes (9). Network imaging analysis offers an additional information association between increased amyloid and tau burden in LBD and and provide a tool for precise quantification of disease-specific changes accelerated MMSE decline. Interestingly, this is not so clear for PD (12). at an individual level. This is also reflected in the most recent joint statement of the Society of Nuclear Medicine and Molecular Imaging and Imaging studies too, confirm strong evidence that greater amyloid PET the EANM, which lists multivariate image analysis, based on SSM/PCA, positivity is associated with accelerated cognitive and functional decline as a possible aid for FDG PET image analysis (10). in DLB. A robust study demonstrated an association between greater tau accumulation in specific brain regions and cognitive decline in DLB (18). Given that amyloid β radiotracer binding correlates well with neuritic Amyloid PET plaque and neurofibrillary tangle burden in LBD, the PET literature suggests accelerated disease progression in LBD+. A shared feature of neurodegenerative diseases causing dementia including DLB is the abnormal accumulation and spreading of CSF studies report discrepant findings and limited number of plasma pathological protein aggregates. They affect the selective vulnerable biomarker studies in LBD currently preclude from making a definitive functional circuits in a disease-specific pattern (11). DLB has extensive conclusion. clinical, pathological and genetic overlap with PDD and it commonly co-exists with AD neuropathology, which is characterized by the Although there are some discrepancies in the literature no studies abnormal accumulation of amyloid beta (Aβ) plaques and neurofibrillary reported an association of AD co-pathology and better outcomes. The tangles of hyperphosphorylated tau (tau) (12). Between 51 and 73% of most reported outcome was cognitive decline. The estimated mean patients with Lewy body dementias (LBD), i.e. either DLB or PDD, meet difference between LBD+ and LBD- ranged from 0.53 to 2.9 additional consensus criteria for AD at autopsy (13,14). Amyloid plaques can be MMSE points/year (12). LBD+ demonstrated increased cognitive decline, visualized in patient’s brain by amyloid PET in vivo. functional decline, mortality and poorer response to treatment compared to LBD-. These results suggest that AD co-pathology in LBD accelerates Amyloid PET has been established as an important imaging tool in early disease progression in a clinically significant manner. and specific diagnosis of AD. It is also part of the biomarker screening in the AD diagnostic criteria and can help differentiate from other Regarding α-synuclein (α-syn) neuropathology studies have established dementias (15). There are several amyloid PET tracers currently available that greater α-syn burden is correlated with conversion to dementia (19,20) for use, namely 11C-Pittsburgh compound–B (PiB), 18F-flutemetamol, and disease duration independently of AD co-pathology in LBD. Similarly, 18F-florbetaben, 18F-florbetapir that bind to Aβ plaques and have been a big majority of studies that quantified α-syn, found this to be validated through autopsy studies. However, we must be aware that significantly correlated to poorer clinical outcomes. This raises the amyloid PET cannot be easily used for the differential diagnosis of AD question of the role of AD co-pathology. It may accelerate α-syn and DLB, that are two of the most common types of dementia (16). aggregation, but AD co-pathology may also be an independent driver of neuronal dysfunction and death. Dopamine transporter imaging DLB often features nigrostriatal dopaminergic degeneration that can be detected in vivo using 123I-FP-CIT dopamine transporter single photon emission computed tomography (DaT SPECT). Clinically, this dopamine transporter imaging has become an important supportive biomarker to distinguish DLB from other dementias. In DLB, the DaT SPECT typically shows significantly reduced striatal uptake of the tracer, reflecting loss of dopamine transporters, whereas in AD, a normal striatal DAT binding is observed. Thus, an abnormal DaT SPECT strongly favors a LBD over AD, and studies over the past decade consistently demonstrate high diagnostic accuracy for DLB (sensitivity ~85–88%, specificity ~90–100%) when differentiating it from AD (4). By contrast, PDD shows a similar marked reduction in striatal DAT binding as DLB (4). 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Available from: http://jnm.snmjournals.org/lookup/- Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of doi/10.2967/jnumed.124.268754 dementia in Lewy body diseases. Neuropathol Appl Neurobiol [Internet]. 2016 Aug 2;42(5):436–50. Available from: https://onlinelibrary.wiley.com/- 11. Ni R, Nitsch RM. Recent Developments in Positron Emission Tomography doi/10.1111/nan.12294 The 13th COGNITIVE DAY meeting was made possible by Main sponsor Main sponsor ABBVIE d.o.o. Biogen Pharma d.o.o. Organisers Center for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana Sponsors ALKALOID - FARM d.o.o. KRKA d.d. Slovenian Neurological Association MEDIS d.o.o. STADA d.o.o. TEVA / PLIVA LJUBLJANA d.o.o.