Dementia With Lewy Bodies Cases Research Articles

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Distinguishing Lewy Body Dementia from Alzheimer's Disease using Machine Learning on Heterogeneous Data: A Feasibility Study.

Dementia with Lewy Bodies (DLB) is the second most common form of dementia, but diagnostic markers for DLB can be expensive and inaccessible, and many cases of DLB are undiagnosed. This work applies machine learning techniques to determine the feasibility of distinguishing DLB from Alzheimer's Disease (AD) using heterogeneous data features. The Repeated Incremental Pruning to Produce Error Reduction (RIPPER) algorithm was first applied using a Leave-One-Out Cross-Validation protocol to a dataset comprising DLB and AD cases. Then, interpretable association rule-based diagnostic classifiers were obtained for distinguishing DLB from AD. The various diagnostic classifiers generated by this process had high accuracy over the whole dataset (mean accuracy of 94%). The mean accuracy in classifying their out-of-sample case was 80.5%. Every classifier generated consisted of very simple structure, each using 1-2 classification rules and 1-3 data features. As a group, the classifiers were heterogeneous and used several different data features. In particular, some of the classifiers used very simple and inexpensive diagnostic features, yet with high diagnostic accuracy. This work suggests that opportunities may exist for incorporating accessible diagnostic assessments while improving diagnostic rate for DLB. Clinical Relevance- Simple and interpretable high-performing machine learning algorithms identified a variety of readily available clinical assessments for differential diagnosis of dementia offering the opportunities to incorporate various simple and inexpensive screening tests for DLB and addressing the problem of DLB underdiagnosis.

Nuclear alpha-synuclein is present in the human brain and is modified in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSynNuc) is evident in many models, the dysregulation of which is associated with altered DNA integrity, transcription and nuclear homeostasis. However, the presence of aSynNuc in human brain cells remains controversial, yet the determination of human brain aSynNuc and its pathological modification is essential for understanding synucleinopathies. Here, using a multi-disciplinary approach employing immunohistochemistry, immunoblot, and mass-spectrometry (MS), we confirm aSynNuc in post-mortem brain tissue obtained from DLB and control cases. Highly dependent on antigen retrieval methods, in optimal conditions, intra-nuclear pan and phospho-S129 positive aSyn puncta were observed in cortical neurons and non-neuronal cells in fixed brain sections and in isolated nuclear preparations in all cases examined. Furthermore, an increase in nuclear phospho-S129 positive aSyn immunoreactivity was apparent in DLB cases compared to controls, in both neuronal and non-neuronal cell types. Our initial histological investigations identified that aSynNuc is affected by epitope unmasking methods but present under optimal conditions, and this presence was confirmed by isolation of nuclei and a combined approach of immunoblotting and mass spectrometry, where aSynNuc was approximately tenfold less abundant in the nucleus than cytoplasm. Notably, direct comparison of DLB cases to aged controls identified increased pS129 and higher molecular weight species in the nuclei of DLB cases, suggesting putative pathogenic modifications to aSynNuc in DLB. In summary, using multiple approaches we provide several lines of evidence supporting the presence of aSynNuc in autoptic human brain tissue and, notably, that it is subject to putative pathogenic modifications in DLB that may contribute to the disease phenotype.

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two major neurocognitive disorders in the spectrum of Lewy body diseases that overlap in many clinical and neuropathological features, although they show several differences. Clinically distinguished mainly based on the duration of parkinsonism prior to development of dementia, their morphology is characterized by a variable combination of Lewy body (LB) and Alzheimer's disease (AD) pathologies, the latter usually being more frequent and severe in DLB. ObjectiveThe aims of the study were to investigate essential neuropathological differences between PDD and DLB in a larger cohort of autopsy cases. Methods110 PDD autopsy cases were compared with 78 DLB cases. The major demographic, clinical (duration of illness, final MMSE) and neuropathological data were assessed retrospectively. Neuropathological studies used standardized methods and immunohistochemistry for phospho-tau, β-amyloid (Aß) and α-synuclein, with semiquantitative assessment of the major histological lesions. ResultsPDD patients were significantly older at death than DLB ones (mean 83.9 vs. 79.8 years), with a significantly longer disease duration (mean 9.2 vs. 6.7 years). Braak LB scores and particularly neuritic Braak stages were significantly higher in the DLB group (mean 5.1and 5.1 vs. 4.2 and 4.4, respectively), as were Thal Aβ phases (mean 4.1 vs. 3.0). Diffuse striatal Aβ plaques were considerable in 55% and moderate in 45% of DLB cases, but were extremely rare in PDD. The most significant differences concerned the frequency and degree of cerebral amyloid angiopathy (CAA), being significantly higher in DLB (98.7 vs. 50%, and mean degree of 2.9 vs. 0.72, respectively). Worse prognosis in DLB than in PDD was linked to both increased Braak neuritic stages and more severe CAA. InterpretationThese and other recent studies imply the association of CAA, more severe concomitant AD pathology, and striatal Aβ load with cognitive decline and more rapid disease process that distinguishes DLB from PDD, while the influence of other cerebrovascular diseases or co-pathologies in both disorders was not specifically examined. The importance of both CAA and tau pathology in DLB and much less in PDD supports the concept of a pathogenetic continuum from Parkinson's disease (PD) - > PDD - > DLB - > DLB + AD and subtypes of AD with LB pathology within the spectrum of age-related proteinopathies.

The association of APOE ‐ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging features in α‐synucleinopathies

The ε4-allele of apolipoprotein E (APOE-ε4) presents an elevated risk not only for Alzheimer's disease (AD), but also for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). Indeed, the independent influence of APOE-ε4 on the promotion and exacerbation of α-synuclein pathology has recently been suggested. However, the precise phenotypic associations of APOE-ε4 in α-synucleinopathies are variable. The primary objective of this first, comprehensive systematic review was to identify biomarkers, phenotypes, or other clinicopathological characteristics that reliably associate with APOE-ε4 in α-synucleinopathies [Parkinson's disease (PD), DLB, PDD, and multiple system atrophy (MSA)], which may in turn uncover important pathophysiological mechanisms.Electronic databases were systematically searched from January 1st , 1995 through December 31st , 2020, as per the PRISMA guidelines. Studies evaluating the association of APOE-ε4 with clinicopathological, cognitive, neuropsychiatric, and neuroimaging phenotypes in clinically and/or pathologically diagnosed cases of PD, PDD, DLB, and MSA cases were reviewed.A total of 136 studies were eligible for inclusion (Figure). APOE-ε4 was found to be consistently associated with: 1) lower cerebrospinal fluid levels of amyloid-β 1-42 in PDD and DLB, 2) cognitive deficits in the memory domain in PD, PDD, and DLB, 3) mediotemporal cortical atrophy primarily in DLB, 3) cerebral amyloid angiopathy, shorter survival, and accelerated decline in global cognition in DLB, as well as 4) the co-occurrence of AD-type neuropathological features. Furthermore, APOE-ε4 was associated, albeit inconsistently, with: 1) the presence and severity of diffuse neocortical Lewy body pathology and, 2) elevated tracer retention on amyloid positron emission tomography in PD, PDD, and DLB, 3) greater odds of dementia in PD, and 4) other genetic and pathophysiological factors to enhance the cumulative risk for DLB. APOE-ε4 was not associated with disease risk or α-synuclein pathology in MSA. Studies also highlighted the relationship of APOE-ε4 with neuropsychiatric, epigenetic (DNA methylation), sleep, immunohistochemical, and biochemical factors in α-synucleinopathies, which will be presented.In addition to its role in AD, APOE-ε4 influences the disease presentation and progression particularly in PDD and DLB. Guided by reliable biomarkers, further research to unravel the underlying mechanisms will assist in developing early prevention strategies targeting the APOE protein.

Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging

AbstractBackgroundLewy body dementia (LBD) and Alzheimer’s disease (AD) are the two most common neurodegenerative causes of dementia. Autopsy studies report many cases with these clinical diagnoses having mixed pathology with alpha‐synuclein, tau and amyloid proteinopathies. There is limited research in trying to distinguish these potential mixed pathology conditions prior to death. We used functional neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate clinically diagnosed subjects with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present.MethodEighteensubjects (all Caucasian, male/female ratio 15:3) so far were recruited from Ohio State University Memory Disorder and Movement Disorder Clinics in this currently enrolling study. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing including Mini‐Mental State Examination (MMSE) and Self‐Administered Gerocognitive Examination (SAGE) were performed. Neuroimaging evaluations performed by neuroradiology faculty were blinded to clinical diagnosis.ResultNine subjects with clinical diagnosis of Lewy body disease (5 DLB and 4 PD) and nine subjects with clinical diagnosis AD were compared. The Lewy body subjects were 71.3 ± 7.4 years old, MMSE 22.3 ± 5.4, and SAGE 9.7 ± 4.8. AD subjects were 67.1 ± 9.6 years old, MMSE 18.6 ± 5.2, and SAGE 9.0 ± 5.2. One subject (11%) of the clinical AD cases showed mixed LBD and AD features, one subject (11%) of the clinical AD cases was negative for amyloid with normal DaTscan uptake, two subjects (40%) of the clinical DLB cases showed mixed LBD and AD features, one subject (20%) of the clinical DLB cases was positive for amyloid with normal DaTscan uptake, and all four subjects with clinical PD showed neuroimaging findings consistent with PD.ConclusionBased on functional neuroimaging, 21% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 14% were misdiagnosed. Although the sample size is small, functional neuroimaging studies revealed possibly incomplete or incorrect diagnoses in about one third of subjects clinically diagnosed by subspecialists using standard clinical diagnostic criteria. Larger studies are required to confirm these findings.

Pathology-associated change in levels and localization of SIDT2 in postmortem brains of Parkinson's disease and dementia with Lewy bodies patients

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that share commonalities in their pathology involving the formation of Lewy bodies, the main component of which is α-synuclein protein. Aberrancy and dysfunction in lysosomes have been suggested to play critical roles in the pathogenesis of Lewy body diseases. We recently identified a novel lysosomal degradation pathway in which various macromolecules, including α-synuclein protein, are directly imported into lysosomes and degraded. In this study, we analyzed the levels and localization of the lysosomal membrane protein SIDT2, a key factor in this pathway, in the postmortem brains of patients with PD and DLB. The levels of SIDT2 protein were significantly higher in the anterior cingulate cortex (ACC) of both PD and DLB cases than in age-matched control subjects, but this difference was not observed in the inferior frontal gyrus. The levels of SIDT2 also showed a strong correlation with α-synuclein levels in the ACC of all subjects, including controls. SIDT2 was colocalized with aggregates positive for phosphorylated α-synuclein protein, which is a hallmark of Lewy bodies, in all examined cases of both PD and DLB. These observations suggest that changes in the levels and localization of SIDT2 occur at the lesion site of Lewy body diseases in accordance with the progression of Lewy body pathology. Our findings provide mechanistic insights into the pathogenesis of Lewy body diseases, as well as other neurodegenerative disorders, and may provide clues for improved diagnosis, prevention, and therapeutic intervention for such diseases.

Phantom boarder symptom in elderly Japanese.

Phantom boarder symptom (PBS) is classified as a delusional misidentification syndrome, and is often encountered in elderly individuals who have mild or major neurocognitive disorders. With the ageing of society, patients presenting with PBS are increasing in Japan. This retrospective study was conducted to examine the aetiology and identify significant predictors of PBS. The records of 511 consecutive patients who visited our hospital with suspicion of dementia between September 2013 and September 2019 were retrospectively examined. From those, 16 patients who presented with PBS (1 male, 15 females; mean age 79.9 ± 4 years) were selected and case features were investigated in detail. Clinical symptoms, background factors, and final diagnoses were noted. PBS was most common in patients affected by dementia with Lewy bodies (DLB). Predictive factors were evaluated using multiple logistic regression analysis. The final diagnosis of the 16 subjects was DLB in 7, Alzheimer's disease in 3, delusional disorder in 3, unspecified dementia in 2, and vascular dementia in 1. Analysis limited to DLB cases showed that a low Mini-Mental State Examination (MMSE) score and living alone were related to higher risk for PBS. Various types of dementia, especially DLB, as well as cognitive impairment and living alone were found to be strong predictors of PBS.

Locus Coeruleus Pathology Indicates a Continuum of Lewy Body Dementia.

Lewy body dementia (LBD) has two main phenotypes: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), separated by the 'one-year-rule'. They also show different symptom profiles: core DLB features include fluctuating cognition, REM-sleep behaviur disorder, and visual hallucinations. These symptoms are sometimes present in PDD, representing an intermediate 'PDD-DLB' phenotype. DLB-like features may reflect deficits in the functions of the noradrenergic nucleus locus coeruleus (LC). Therefore, we compared the LC in the LBD phenotypes, PD, and controls. 38 PD, 56 PDD, 22 DLB, and 11 age-matched control cases from the Parkinson's UK tissue bank were included. LC tissue sections were immunostained for tyrosine-hydroxylase (TH), α-synuclein, tau, and amyloid-β. TH-neurons were quantified and pathologic burden calculated by %-coverage method. The LC shows a stepwise reduction in neuron count from controls, PD, PDD, to DLB. PDD-DLB cases showed an intermediate clinical phenotype that was reflected pathologically. Cell counts were significantly reduced in DLB compared to PDD after correction for demographic factors. LC degeneration contributed significantly to the onset of all DLB symptoms. While α-synuclein was not significantly different between PDD and DLB cases, DLB exhibited significantly less tau pathology. DLB and DLB-like symptoms represent noradrenergic deficits resulting from neuronal loss in the LC. PDD and DLB are likely to represent a clinical continuum based on the presence or absence of DLB-like symptoms mirrored by a pathological continuum in the LC.

Platelet miRNA Biosignature Discriminates between Dementia with Lewy Bodies and Alzheimer's Disease.

Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia, after Alzheimer’s disease (AD), and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a seven-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based biosignature, which distinguishes DLB from AD.

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies.

Background:Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.Objective:We tested if genetic variants in part explain the heterogeneity in DLB.Methods:We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer’s disease (AD-PRS) and Parkinson’s disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer’s dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1–42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.Results:We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.Conclusion:These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges.

Dementia with Lewy bodies (DLB) is one of the most common causes of dementia and belongs to the group of α-synucleinopathies. Due to its clinical overlap with other neurodegenerative disorders and its high clinical heterogeneity, the clinical differential diagnosis of DLB from other similar disorders is often difficult and it is frequently underdiagnosed. Moreover, its genetic etiology has been studied only recently due to the unavailability of large cohorts with a certain diagnosis and shows genetic heterogeneity with a rare contribution of pathogenic mutations and relatively common risk factors. The rapid increase in the reported cases of DLB highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods proposed by the International DLB consortium rely on a list of criteria that comprises both clinical observations and the use of biomarkers. Herein, we summarize the up-to-now reported knowledge on the genetic architecture of DLB and discuss the use of prodromal biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.

Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson\u2019s disease and dementia with Lewy bodies

Definitive diagnosis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSynD) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSynD aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSynD across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSynD in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSynD aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSynD in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSynD in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSynD in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSynD as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.

Hybrid imaging in dementia: A semi-quantitative (18F)-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging approach in clinical practice.

Neurodegenerative disorders may demonstrate typical lobar and regional patterns of volume loss with corresponding decreased glucose metabolism. In this retrospective study, we correlated semi-quantitative volumetric changes utilizing NeuroQuant morphometric analysis with decreased fluorodeoxyglucose (FDG) uptake age-matched calculated z-scores utilizing 18F-FDG positron emission tomography/magnetic resonance imaging (PET/MRI). Eighty-nine patients (mean age 71.4) with clinical findings suggestive of various subtypes of dementia underwent PET/MR brain imaging. Cases were categorized as follows: Alzheimer's dementia (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). NeuroQuant software provided semi-quantitative assessment of lobar-specific patterns of volume loss compared to age-matched controls. MIMneuro software provided semi-quantitative FDG uptake data, with metabolic z-scores generated in comparison to age-matched controls. Volumetric and metabolic data were then correlated for statistical significance. In 29 AD cases, Pearson correlation coefficient between z-score and lobar volume was 0.3 (P = 0.120) and 0.38 (P < 0.05), for parietal and temporal lobes, respectively. In 34 FTLD cases, it was 0.35 (P = 0.051) and 0.02 (P = 0.916), for frontal and temporal lobes, respectively. In 14 DLB cases, it was 0.42 (P = 0.130), 0.5 (P = 0.067), and 0.22 (P = 0.447) for the occipital lobes, middle occipital gyrus, and parietal lobes, respectively. In 12 CBD cases, it was 0.58 (P < 0.05) for the superior parietal lobule. Semi-quantitative (F18)-FDG PET/MRI analysis demonstrated a positive relationship between volumetric loss and hypometabolism within certain lobar-specific regions, depending on neurodegenerative disorder subtype. Our findings may add diagnostic confidence in the accurate imaging diagnosis of neurodegenerative disease.

Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia.

α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF). The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synuclein-targeted therapeutics.

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy

BackgroundAlpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies.MethodsGuinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases.ResultsVaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study.ConclusionsThese vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.

Proteomic Characterization of the Olfactory Molecular Imbalance in Dementia with Lewy Bodies.

Olfactory dysfunction is one of the prodromal symptoms in dementia with Lewy bodies (DLB). However, the molecular pathogenesis associated with decreased smell function remains largely undeciphered. We generated quantitative proteome maps to detect molecular alterations in olfactory bulbs (OB) derived from DLB subjects compared to neurologically intact controls. A total of 3214 olfactory proteins were quantified, and 99 proteins showed significant alterations in DLB cases. Protein interaction networks disrupted in DLB indicated an imbalance in translation and the synaptic vesicle cycle. These alterations were accompanied by alterations in AKT/MAPK/SEK1/p38 MAPK signaling pathways that showed a distinct expression profile across the OB–olfactory tract (OT) axis. Taken together, our data partially reflect the missing links in the biochemical understanding of olfactory dysfunction in DLB.

Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

This study investigated clinical and neuropathological differences between DLB and PDD. 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. CAA was more common in DLB than in PDD (P=0.003). The severity of CAA was greater in DLB than in PDD (P=0.009), with significantly higher CAA scores in the parietal lobe (P=0.043), and the occipital lobe (P=0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer's pathology in autopsy-confirmed Parkinson's disease and Dementia with Lewy bodies.

Growing evidence suggests overlap between Alzheimer's disease (AD) and Parkinson's disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)-most commonly manifesting during life as PD-have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. In the first stage of our study, 127 consecutive autopsy-confirmed cases of PD or DLB from a single center were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In these 127 training set individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and tenfold cross-validation to estimate performance. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci), with an area under the receiver operating curve (AUC) of 0.751 in our training set. In the replication stage of our study, we assessed model performance in a separate test set of the next 81 individuals genotyped in our center. In the test set, the AUC was 0.781, and individuals with ADNC-RS in the top quintile had four-fold increased likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. Finally, in the validation stage of our study, we applied our ADNC-RS model to 70 LBD individuals from 20 Alzheimer's Disease Research Centers (ADRC) whose autopsy and genetic data were available in the National Alzheimer's Coordinating Center (NACC) database. In this validation set, the AUC was 0.754. Thus, in patients with autopsy-confirmed PD or DLB, a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.