Dementia With Lewy Bodies Research Articles

Current Landscape of Clinical Diagnosis in Multiple System Atrophy: A 15-Year Analysis From 2008 to 2022.

Clinical diagnosis of multiple system atrophy (MSA) is challenging. In 2022, new diagnostic criteria for MSA were proposed. We hypothesized that the positive predictive value (PPV) of clinical diagnosis of MSA improved because of advanced diagnostic tools, including brain MRI. This study aimed to understand temporal changes in PPV of MSA. We conducted a retrospective analysis of patients clinically diagnosed with MSA whose brains were examined in the Mayo Clinic brain bank from 2008 to 2022. PPV was compared between 2 periods (2008-2017 and 2018-2022) and successively with a 4-year moving average. PPV for each clinical subtype (parkinsonism type [MSA-P] and cerebellar type [MSA-C]) was assessed. This study included 321 patients (136 women, age at death 68 ± 9 years) with a clinical diagnosis of MSA. Among them, 225 were pathologically confirmed as MSA, resulting in an overall PPV of 70%. The remaining 30% had alternative pathologic diagnoses including Lewy body disease (18%), progressive supranuclear palsy (4%), cerebrovascular disease (1%), corticobasal degeneration (1%), and others (6%). PPV improved from 63% in 2008-2017 to 78% in 2018-2022 (odds ratio [OR] 2.0 [1.2-3.5], p = 0.005). Linear analysis also demonstrated increased PPV over time (r = 0.66 [0.14-0.89], p = 0.02). Brain MRI scans were more frequently performed in 2018-2022 compared with 2008-2017 (91% vs 80%; OR 2.4 [1.2-5.0], p = 0.012). PPV was higher in patients with brain MRI compared with those without (73% vs 52%; OR 2.5 [1.3-4.9], p = 0.0057). PPV for MSA-C was similar in both groups (87% in 2008-2017 and 93% in 2018-2022), while that for MSA-P improved from 59% in 2008-2017 to 72% in 2018-2022 (OR 1.8 [1.0-3.2], p = 0.04). This study demonstrates an improvement in the PPV of MSA in recent years, potentially attributed to the increased use of brain MRI. Nevertheless, it also highlights that it remains difficult to make a correct diagnosis for some patients based on their clinical presentation. These findings provide a baseline for future clinicopathologic research on MSA.

A General Neurologist's Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders: A Consensus Statement.

The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral. We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals. We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases.

Cognitive impairment in Parkinson's disease and other parkinsonian syndromes.

In this narrative review, we address mild cognitive impairment, a frequent complication of Parkinson's disease (PD) and atypical parkinsonian disorders (APDs). Recent diagnostic criteria have blurred the lines between PD and dementia with Lewy bodies (DLB), particularly in the cognitive domain. Additionally, atypical parkinsonian syndromes like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) often present with significant cognitive decline. Even multiple system atrophy (MSA) can be associated with cognitive impairment in some cases. Several biomarkers, including imaging techniques, such brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET), as well as pathological proteins either of the cerebrospinal fluid (CSF), such as Tau, amyloid beta, and synuclein, or of the serum, such as neurofilament light chain (Nfl) are more and more often utilized in the early differential diagnosis of APDs. The complex interplay between these conditions and the evolving understanding of their underlying pathologies highlight the need for further research to refine diagnostic criteria, possibly incorporate the new findings from the biomarker's field into the diagnostic criteria and develop targeted therapeutic strategies.

Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity

Lewy body diseases, including Parkinson's disease (PD), are characterized by the spread of alpha-synuclein (αSyn) between neurons across synapses, a process crucial for understanding their pathophysiology and developing effective treatments. In this study, we aimed to investigate the role of neuronal activity in releasing αSyn from human induced pluripotent stem cell-derived dopaminergic neurons. We examined human induced pluripotent stem cell-derived dopaminergic neurons, both healthy and those with the αSyn gene mutation associated with PD. We employed pharmacological agents and optogenetic techniques and demonstrated that increased neuronal activity, induced by bicuculline or optogenetic stimulation, significantly enhances αSyn release. However, suppression of neuronal activity with cyanquixaline reduces αSyn secretion. These findings underscore the pivotal role of neuronal activity in αSyn transmission between neurons, showing its potential impact on the spread of Lewy pathology in patients with neurodegenerative diseases like PD. Therefore, this study advances our understanding of PD and opens new avenues for therapeutic strategies to mitigate Lewy body disease progression.

Lewy-MSA hybrid fold drives distinct neuronal α-synuclein pathology.

The ordered assembly of α-synuclein protein into filaments encoded by SNCA characterizes neurodegenerative diseases called synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal α-synuclein pathology and multiple system atrophy (MSA) predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that structures of α-synuclein filaments from LBD differ from MSA and juvenile onset synucleinopathy (JOS) caused by a 21-nucleotide duplication in the second exon of one allele of SNCA gene 1-3 . Importantly, a rare subtype of MSA, called atypical MSA 4 shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that in addition to the MSA fold, α-synuclein can form a new Lewy-MSA hybrid fold in the same brain region, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs) and conformational stability assay (CSA), are also linked to cytopathological differences (e.g. neuronal or oligodendroglial). We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.

Clinical Utility and Safety of an Ultrasonic Head Stimulator in Dementia With Lewy Bodies.

The potential of Ultra-Ma, an ultrasonic head stimulator, for the supplementary treatment of dementia with Lewy bodies (DLB) was evaluated in patients with various symptoms under poor control by drug therapy. Patients with DLB treated with choline esterase inhibitor or L-DOPA, either alone or in combination, and who met inclusion criteria were enrolled. Four weeks of placebo stimulation was followed by 8 weeks of active ultrasonic stimulation and a 4-week follow-up. Primary endpoints were the effects of ultrasonic head stimulation on both cognitive dysfunction and behavioral and psychological symptoms of dementia (BPSD). Cognitive dysfunction was evaluated using the Japanese versions of the Mini-Mental State Examination and Montreal Cognitive Assessment, and BPSD was assessed using the Neuropsychiatric Inventory Brief Questionnaire Form. For cognitive fluctuations, the Cognitive Fluctuation Inventory served as an index. Improvements in parkinsonism, activities of daily living, and caregiver burden were examined as secondary endpoints. Twelve patients were enrolled. The primary endpoint was significantly improved during the active stimulation period, as were secondary endpoint ratings for parkinsonism and caregiver burden. No notable adverse events occurred. The findings suggest that ultrasonic head stimulation has supplementary potential when combined with drug treatment in DLB.

Prevalence of mixed neuropathologies in age-related neurodegenerative diseases: A community-based autopsy study in China.

Despite extensive studies on mixed neuropathologies, data from China are limited. This study aims to fill this gap by analyzing brain samples from Chinese brain banks. A total of 1142 brains from six Chinese brain banks were examined using standardized methods. Independent pathologists conducted evaluations with stringent quality control. Prevalence and correlations of neurological disorders were analyzed. Significant proportions of brains displayed primary age-related tauopathy (PART, 35%), limbic-predominant age-related TDP-43 encephalopathy (LATE, 46%), and aging-related tau astrogliopathy (ARTAG, 12%). Alzheimer's disease neuropathological change (ADNC, 48%), Lewy body disease (LBD, 13%), and cerebrovascular disease (CVD, 63%) were also prevalent, often co-occurring with regional variations. CVD emerged as the potential most early contributor to neuropathological changes. This analysis highlights the prevalence of PART, LATE, ARTAG, ADNC, LBD, and CVD, with regional differences. The findings suggest CVD may be the earliest contributing factor, potentially preceding other neuropathologies. Highlights The prevalence of primary age-related tauopathy (PART), limbic-predominant age-related TDP-43 encephalopathy (LATE), aging-related tau astrogliopathy (ARTAG), Alzheimer's disease neuropathologic change, Lewy body disease, and cerebrovascular disease (CVD) in China, increasing with age, is comparable to other countries. Significant regional differences in the prevalences of diseases are noted. CVD develops prior to any other disorders, including PART, LATE, and ARTAG.

Brain-derived and in vitro-seeded alpha-synuclein fibrils exhibit distinct biophysical profiles

The alpha-synuclein (αSyn) seeding amplification assay (SAA) that allows the generation of disease-specific in vitro seeded fibrils (SAA fibrils) is used as a research tool to study the connection between the structure of αSyn fibrils, cellular seeding/spreading, and the clinicopathological manifestations of different synucleinopathies. However, structural differences between human brain-derived and SAA αSyn fibrils have been recently highlighted. Here, we characterize the biophysical properties of the human brain-derived αSyn fibrils from the brains of patients with Parkinson’s disease with and without dementia (PD, PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and compare them to the ‘model’ SAA fibrils. We report that the brain-derived αSyn fibrils show distinct biochemical profiles, which were not replicated in the corresponding SAA fibrils. Furthermore, the brain-derived αSyn fibrils from all synucleinopathies displayed a mixture of ‘straight’ and ‘twisted’ microscopic structures. However, the PD, PDD, and DLB SAA fibrils had a ’straight’ structure, whereas MSA SAA fibrils showed a ‘twisted’ structure. Finally, the brain-derived αSyn fibrils from all four synucleinopathies were phosphorylated (S129). Interestingly, phosphorylated αSyn were carried over to the PDD and DLB SAA fibrils. Our findings demonstrate the limitation of the SAA fibrils modeling the brain-derived αSyn fibrils and pay attention to the necessity of deepening the understanding of the SAA fibrillation methodology.

Brain-derived and in vitro-seeded alpha-synuclein fibrils exhibit distinct biophysical profiles.

The alpha-synuclein (αSyn) seeding amplification assay (SAA) that allows the generation of disease-specific in vitro seeded fibrils (SAA fibrils) is used as a research tool to study the connection between the structure of αSyn fibrils, cellular seeding/spreading, and the clinicopathological manifestations of different synucleinopathies. However, structural differences between human brain-derived and SAA αSyn fibrils have been recently highlighted. Here, we characterize the biophysical properties of the human brain-derived αSyn fibrils from the brains of patients with Parkinson's disease with and without dementia (PD, PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and compare them to the 'model' SAA fibrils. We report that the brain-derived αSyn fibrils show distinct biochemical profiles, which were not replicated in the corresponding SAA fibrils. Furthermore, the brain-derived αSyn fibrils from all synucleinopathies displayed a mixture of 'straight' and 'twisted' microscopic structures. However, the PD, PDD, and DLB SAA fibrils had a 'straight' structure, whereas MSA SAA fibrils showed a 'twisted' structure. Finally, the brain-derived αSyn fibrils from all four synucleinopathies were phosphorylated (S129). Interestingly, phosphorylated αSyn were carried over to the PDD and DLB SAA fibrils. Our findings demonstrate the limitation of the SAA fibrils modeling the brain-derived αSyn fibrils and pay attention to the necessity of deepening the understanding of the SAA fibrillation methodology.

Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer and Lewy body disease.

Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression and potentially differential responses to targeted treatments, though the diagnosis of AD+LBD can be challenging given overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD+LBD pathologies. We hypothesize that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with positron emission tomography (PET), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ vs. A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found A+S+ patients had parieto-occipital 18F-Fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer pathologies in MED, though our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. A+S+ patients had posterior mismatch with excessive 18F-Fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuron integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD+LBD etiologies harbor a unique metabolic PET mismatch signature.

Whole-genome sequencing to identify rare variants in East Asian patients with dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common form of age-related dementia, following Alzheimer’s disease (AD). DLB is associated with a worse prognosis than AD and is characterized by a more rapid progression of cognitive impairment and a poorer quality of life. In addition, the pathogenesis of DLB is less understood than that of AD, and only three genes—SNCA (α‐synuclein), APOE (apolipoprotein E), and GBA1 (glucosylceramidase beta 1)—have been convincingly demonstrated to be associated with DLB. In this study, we utilized whole-genome sequencing data from 1744 Japanese individuals, comprising 45 DLB patients and 1699 cognitively normal older adults, aiming to identify new genes associated with DLB. Our genome-wide association studies of genes with potentially deleterious mutations identified the CDH23 gene as being associated with DLB, reaching a Bonferroni-corrected significance (P = 7.43 × 10−4). The gene contained three ethnicity-specific heterozygous missense variants (rs181275139, rs563688802, and rs137937502). CDH23 has been linked to deafness syndromes, and DLB patients carrying these mutations displayed symptoms of subjective hearing loss, suggesting a potential association between DLB onset and auditory impairment. Additionally, we explored human leukocyte antigen (HLA) genotypes associated with DLB but found no significant associations. This result suggests that the pathology of DLB differs from that of Parkinson’s disease, which has been reported to have an association with HLA. Although a limitation of this study is the lack of replication of our findings, which require further validation in independent cohorts, our study enhances the understanding of the etiology of DLB in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders.

The abnormal deposition and intercellular propagation of disease-specific protein play a central role in the pathogenesis of many neurodegenerative disorders. Recent studies share the common observation that the formation of protein oligomers and subsequent pathological filaments is an essential step for the disease. Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) are neurodegenerative diseases characterized by the aggregation of the α-synucleinprotein in neurons and/or in oligodendrocytes (glial cytoplasmic inclusions), neuronal loss, and astrogliosis. A similar mechanism of protein Tau-dependent neurodegeneration is a major feature of tauopathies, represented by Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PD). The specific inhibition of the protein misfolding and their interneuronal spreading represents a promising therapeutic strategy against both disease pathology and progression. The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation.

Memories and mimics: unveiling the potential of FDG-PET in guiding therapeutic approaches for neurodegenerative cognitive disorders.

Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) imaging can help clinicians pursue the differential diagnosis of various neurodegenerative diseases. It has become an invaluable diagnostic tool in routine clinical practice in conjunction with computed tomography (CT) imaging, magnetic resonance imaging (MRI), and biomarker studies. We present a single-institution case series and systematic literature review, showing how FDG-PET imaging has helped physicians diagnose neurodegenerative diseases and their mimickers and how patient care was amended. A single institution analysis and comprehensive literature search were completed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. These medical subjects' headings (MeSH) terms were used: "FDG-PET" AND "dementia" OR "Alzheimer's" OR "neurodegeneration" OR "frontotemporal dementia" OR "atypical parkinsonian syndrome" OR "primary progressive aphasia" OR "lewy body dementia." The inclusion criteria included studies with uncertain diagnoses of neurocognitive disease resolved with FDG-PET, PET/MRI, or PET/CT hybrid imaging. A literature search resulted in 3,976 articles. After considering inclusion and exclusion criteria, 14 case reports and 1 case series were selected, representing 19 patients. The average age of patients was 70.8 years (range: 54-83 years). Five of the 19 patients were females. Dementia with Lewy bodies (DLB) had the highest propensity for being misidentified as another neurodegenerative disease, followed by Alzheimer's disease (AD) and frontotemporal dementia (FTD). Without accurate molecular imaging, neurodegenerative diseases may be missed or misdiagnosed. Our single-institution case series and literature review demonstrate how FDG-PET brain imaging can be used to correct and clarify preexisting clinical diagnoses of neurodegenerative disease.

Association of dementia with the 28-day mortality of sepsis: an observational and Mendelian randomization study.

Observational research suggests that individuals with dementia who have sepsis face a higher likelihood of death. However, whether there is a causal relationship between the two remains unknown. We analyzed data from patients diagnosed with sepsis and dementia, extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. To examine the correlation between dementia and 28-day mortality in sepsis, we utilized Cox proportional hazards models. Following this, we performed a Mendelian randomization (MR) study with two samples to investigate the potential link between dementia and mortality within 28 days in sepsis. This study included a total of 22,189 patients diagnosed with sepsis, among whom 1,346 cases (6.1%) had dementia. After adjusting for multiple confounding factors, dementia was associated with an increased risk of 28-day mortality in sepsis (HR = 1.25, 95% CI = 1.12-1.39, p < 0.001). In the MR analysis, there appeared to be a causal relationship between genetically predicted dementia with Lewy bodies (DLB) (OR = 1.093, 95% CI = 1.016-1.177, p = 0.017) and 28-day mortality in sepsis. However, there was no evidence of causality between any dementia (OR = 1.063, 95% CI = 0.91-1.243, p = 0.437), Alzheimer's disease (AD) (OR = 1.126, 95% CI = 0.976-1.299, p = 0.103), vascular dementia (VD) (OR = 1.008, 95% CI = 0.93-1.091, p = 0.844), and the risk of 28-day mortality in sepsis. In the observational analysis, dementia was associated with an increased risk of 28-day mortality in septic patients. However, in the MR analysis, only DLB was associated with increased 28-day mortality in septic patients, with no observed correlation for other dementia subtypes.

Early Changes in the Locus Coeruleus in Mild Cognitive Impairment with Lewy Bodies.

Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking. The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts. A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes. The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). The right LC-CR decrease was associated with impaired visuospatial memory in the MCI-LB group. Only the caudal part of the LC exhibited significant LC-CR decreases in MCI-LB patients compared to HCs on both sides (P < 0.0001). This is the first study that focuses on LC-CRs in MCI-LB patients and analyzes the LC subparts, offering new insights into the LC integrity alterations in the initial stages of DLB and their clinical correlates. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Retraction: Selective Molecular Alterations in the Autophagy Pathway in Patients with Lewy Body Disease and in Models of α-Synucleinopathy.

Retraction: Selective Molecular Alterations in the Autophagy Pathway in Patients with Lewy Body Disease and in Models of α-Synucleinopathy.

Retraction: Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease.

Retraction: Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease.

Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells.

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX's neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.

Medial temporal atrophy predicts the limbic comorbidities in lewy body disease.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

Acute introduction of monomeric or multimeric α-synuclein induces distinct impacts on synaptic vesicle trafficking at lamprey giant synapses.

Synaptic aggregation of α-synuclein often occurs in Parkinson's disease (PD), dementia with Lewy bodies (DLB) and other synucleinopathies and is associated with cognitive deficits and dementia. Thus, it is important to understand how accumulation of α-synuclein affects synapse structure and function. Native, physiological α-synuclein comprises a mixture of tetramers and related physiological oligomers (60-100kDa) in equilibrium with monomeric α-synuclein. We previously demonstrated that acutely increasing the levels of physiologicalα-synuclein impaired intracellular synaptic vesicle trafficking and produced a pleiotropic phenotype, raising questions about which aspects of the synaptic phenotype were due to multimeric versus monomeric α-synuclein. Here, we address this by taking advantage of the unique features of the lamprey giant reticulospinal (RS) synapse, a vertebrate synapse that is amenable to acute perturbations of presynaptic processes via microinjection of purified proteins. α-Synuclein monomers and multimers were purified from HEK cells and separately introduced to lamprey synapses. Ultrastructural analysis revealed that both multimeric and monomeric α-synuclein impaired intracellular vesicle trafficking, leading to a loss of synaptic vesicles and buildup of endosomes. However, while monomeric α-synuclein additionally induced atypical fusion/fission at the active zone and impaired clathrin-mediated endocytosis, multimeric α-synuclein did not. Conversely, multimeric α-synuclein led to a decrease in synaptic vesicle docking, which was not observed with monomeric α-synuclein. These data provide further evidence that different molecular species of α-synuclein produce distinct and complex impacts on synaptic vesicle trafficking and reveal important insights into the cell biological processes that are affected in PD and DLB. KEY POINTS: α-Synuclein accumulation at synapses is associated with cognitive decline and dementia in Parkinson's disease and other synucleinopathies. We previously showed that acute introduction of excess human brain-derived α-synuclein to lamprey giant synapses caused pleiotropic phenotypes on synaptic vesicle trafficking, probably due to the mixture of molecular species of α-synuclein. Here, we dissected which aspects of the synaptic phenotypes were caused by monomeric (14kDa) or multimeric (60-100kDa) α-synuclein by purifying each molecular species and introducing each one separately to synapses via axonal microinjection. While monomeric α-synuclein inhibited clathrin-mediated synaptic vesicle endocytosis, multimeric α-synuclein primarily impaired endosomal trafficking. These findings reveal that different molecular species of α-synuclein have distinct impacts on synapses, suggesting different cellular and molecular targets.