Dementia With Lewy Bodies Cases Research Articles

Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease

AbstractThe creatine‐phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age‐matched controls were analyzed using antibody‐based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP‐dependent processes, such as the glutamate‐glutamine cycle. As CKB and the creatine‐phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early‐stage energy deficits in AD.

Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

BackgroundNeuroinflammation and Alzheimer’s disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.MethodsThe morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.ResultsMorphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.ConclusionsIn conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

Prevalence, distribution, and severity of cerebral amyloid angiopathy differ between Lewy body diseases and Alzheimer’s disease

Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies.

LRP10 and α-synuclein transmission in Lewy body diseases.

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and dementia with Lewy bodies

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+ and SV2A+ puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

Application of Suggestive Biomarkers in Dementia With Lewy Bodies With Masking of Typical Clinical Symptoms by Alzheimer Disease-type Pathology.

Dementia with Lewy bodies (DLB) is strongly associated with Alzheimer disease (AD)-type pathology and tends to mask the core clinical features of DLB. Therefore, there may be cases of undiagnosed DLB without suggestive biomarkers of DLB. We describe the case of a 63-year-old woman who was initially diagnosed as having AD and later diagnosed with DLB based on suggestive biomarkers of DLB. In this case, transient sleep talking with physical movements for several days led to the assessment of suggestive biomarkers for DLB in the absence of the core clinical features of DLB. For clinicians, diagnosing DLB in patients with AD-type pathology is challenging. However, the application of biomarkers suggestive of DLB to all patients with dementia is not realistic. To overcome the difficulties of clinical diagnosis of DLB, further research is needed regarding strategies for the application of suggestive biomarkers for DLB to appropriately diagnose DLB.

A deep learning model for the detection of various dementia and MCI pathologies based on resting-state electroencephalography data: A retrospective multicentre study

Dementia and mild cognitive impairment (MCI) represent significant health challenges in an aging population. As the search for noninvasive, precise and accessible diagnostic methods continues, the efficacy of electroencephalography (EEG) combined with deep convolutional neural networks (DCNNs) in varied clinical settings remains unverified, particularly for pathologies underlying MCI such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and idiopathic normal-pressure hydrocephalus (iNPH). Addressing this gap, our study evaluates the generalizability of a DCNN trained on EEG data from a single hospital (Hospital #1). For data from Hospital #1, the DCNN achieved a balanced accuracy (bACC) of 0.927 in classifying individuals as healthy (n = 69) or as having AD, DLB, or iNPH (n = 188). The model demonstrated robustness across institutions, maintaining bACCs of 0.805 for data from Hospital #2 (n = 73) and 0.920 at Hospital #3 (n = 139). Additionally, the model could differentiate AD, DLB, and iNPH cases with bACCs of 0.572 for data from Hospital #1 (n = 188), 0.619 for Hospital #2 (n = 70), and 0.508 for Hospital #3 (n = 139). Notably, it also identified MCI pathologies with a bACC of 0.715 for Hospital #1 (n = 83), despite being trained on overt dementia cases instead of MCI cases. These outcomes confirm the DCNN's adaptability and scalability, representing a significant stride toward its clinical application. Additionally, our findings suggest a potential for identifying shared EEG signatures between MCI and dementia, contributing to the field's understanding of their common pathophysiological mechanisms.

Associations between neuropsychiatric symptoms, pathology in neuropathological cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies

AbstractBackgroundNeuropsychiatric symptoms (NPS) are frequent in Alzheimer’s Disease dementia (ADD) but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co‐occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). Previous studies have shown that both ADLB and DLB cases have faster cognitive and/or functional decline compared to AD. However, the differences in NPS severity over disease course and survival in these pathologic subgroups is not well understood.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a final neuropathologic diagnosis of DLB (±AD co‐pathology; n = 65), ADLB (n = 89), AD (without LB) (n = 140), and controls (no neuropathological diagnosis) (n = 82) were included. Total NPI‐Q (scores ranging from 0‐36) at time of enrollment and within 2.5 years of death were calculated for all groups. Statistical analysis utilizing ANCOVA (adjusting for age, sex, baseline MMSE and cognitive symptom duration) with pairwise comparisons, and Kaplan‐Meier curves were completed.ResultAge at onset of cognitive symptoms was not different between pathology groups. NPI‐Q scores at enrollment were highest in ADLB (7.33 ± 4.85), and higher (p<0.001) than DLB (5.10 ± 3.37), AD (4.54 ± 3.63) and controls (1.78 ± 1.70). At final evaluation, NPI‐Q scores were highest in DLB (10.04 ± 6.28), followed by ADLB (8.0 ± 4.), and ADD (7.61 ± 5.05) when compared to controls (2.78 ± 3.97) (all p<0.001). DLB and AD demonstrated significant increases in NPI‐Q severity during follow up (p < 0.001). AD had longer survival time (5.8 years) compared to ADLB (4.0 years) and DLB (3.9 years). Subjects with NPS had a shorter median survival time (3.4 years) compared to subjects without NPS (6.5 years; p = 0.002).ConclusionA higher NPS burden and shorter survival is seen in both DLB and ADLB, as compared with AD. This suggests that diffuse neocortical LB pathology is not the major driver of either NPS or survival.

Red flags and symptom overlap in anti‐IgLON5 disease and dementia with Lewy bodies – a systematic review

AbstractBackgroundAnti‐IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is a type of autoimmune encephalitis (AE) but unlike other AEs anti‐IgLON5 disease has an insidious onset and prominent tau pathology. Anti‐IgLON5 disease mimics neurodegenerative disorders and multiple symptoms overlap with the second most common cause of neurodegenerative dementia, Dementia with Lewy bodies (DLB). The purpose of this review was to assess the overlap in features between anti‐IgLON5 disease and DLB and to identify potential red flags for anti‐IgLON5 disease in patients undergoing diagnostic evaluation for DLB.MethodWe conducted a systematic review of reports on features of anti‐IgLON5 disease from full‐text articles in MEDLINE, Web of Science, and Embase. The reviewed data was compared to consensus criteria for DLB.ResultWe included 57 studies with a total of 125 cases of anti‐IgLON5 disease. The median age was 61 years at diagnosis, with a median symptom duration of 3.5 years. Ten % (13/113 cases) presented with cognitive dysfunction. REM‐sleep disorder was diagnosed in 43% (17/39 cases), and movement disorders were present in 73% (80/110 cases) of which parkinsonism was identified in 21% (18/85 cases). In 47% (25/59 cases), psychiatric disturbances were reported, and hallucinations were observed in 37% (11/30 cases). Dysautonomia was reported in 56% (42/75 cases). Regarding red flags for anti‐IgLON5 disease, bulbar symptoms were observed in 75% (82/109 cases) and respiratory insufficiency was in 60% (32/66 cases). Brain MRI was normal in 56% (40/72 cases) and routine cerebrospinal fluid examination was normal in 63% (36/57 cases). Anti‐IgLON5 antibodies were positive in serum in all cases, where serum was tested and positive in cerebrospinal fluid in 96% (71/75 cases).ConclusionWe found a significant overlap between symptoms in anti‐IgLON5 disease and DLB including cognitive dysfunction, REM‐sleep disorders, parkinsonism, and an insidious onset over several years. We propose that anti‐IgLON5 disease should be considered in atypical DLB cases with bulbar or respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti‐IgLON5 disease.

ATN Cerebrospinal Fluid Biomarkers in Dementia with Lewy Bodies: Initial Results from the United States Dementia with Lewy Bodies Consortium

AbstractBackgroundNeuropathological hallmarks of AD, amyloid plaques and neurofibrillary tangles, have been described in dementia with Lewy bodies (DLB). Less is known about changes in pre‐mortem cerebrospinal fluid (CSF) amyloid and tau biomarker status in DLB. CSF biomarkers for amyloid (A), tau (T), and neurodegeneration (N) can be utilized to define pre‐mortem pathological status. The overall aim of this investigation was to utilize the ATN research framework to characterize pre‐mortem AD‐related pathology longitudinally in a rigorously characterized cohort of DLB from the Dementia with Lewy Bodies Consortium (DLBC) study. Our hypothesis was that ATN biomarkers would identify DLB with coexistent AD and ATN status would remain the same after 12 months.MethodCerebrospinal fluid (CSF) samples from an AD/ADRD cohort were obtained from the Cleveland Alzheimer’s Disease Research Center (CADRC), Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (CBH‐biobank) and DLBC. CSF Aβ40, Aβ42, Aβ42/40 (A), p‐Tau181 (T), and t‐Tau (N), were evaluated. The cohort was subtyped by CSF ATN category and sub‐group of DLB cases were neuropathologically evaluated. A sub‐cohort of DLB cases had longitudinal data with an evaluation at baseline and 12 months later.ResultDLB patients who were positive for both CSF Aβ42/40 (A+) and p‐Tau181 (T+) remained positive from baseline to 12 months. In contrast, some DLB patients who were positive for CSF Aβ42/40 (A+), but negative for p‐Tau181 (T‐), changed from CSF Aβ42/40 positive to negative at 12 months (p‐value = 0.0153) in the A+T‐N‐ and A+T‐N+ group. Findings from a small DLB subgroup with post‐mortem neuropathologic analyses indicated that most of the cases that were p‐Tau181 positive (T+) also had high Braak stage.ConclusionThese findings suggest that DLB patients who are positive for CSF Aβ42/40 (A+), but negative for p‐Tau181 (T‐), may have CSF Aβ42/40 levels that can fluctuate over time. In the small DLB subgroup with post‐mortem neuropathologic analysis, there appeared to be a relationship between AD pathologic change and ATN findings that warrants further study in a larger autopsied cohort to fully understand the relationship between ATN status and underlying AD neuropathologic change in DLB.

Associations between neuropsychiatric symptoms, pathology, and survival in an autopsy-confirmed cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies (S39.008)

Associations between neuropsychiatric symptoms, pathology, and survival in an autopsy-confirmed cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies (S39.008)

Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging (P6-12.002)

<h3>Objective:</h3> To distinguish between Alzheimer’s disease, Lewy body dementia and Parkinson’s disease using functional neuroimaging. <h3>Background:</h3> Lewy 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. <h3>Design/Methods:</h3> 43 subjects were recruited from Ohio State University Memory Disorder and Movement Clinics. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing performed included MMSE and SAGE. We used neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate subjects diagnosed with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present. The neuroimaging evaluations were blinded to clinical diagnosis. <h3>Results:</h3> 28 subjects with clinical diagnosis of Lewy body disease (15 DLB and 13 PD) and 15 subjects with clinical diagnosis AD were compared. The Lewy body subjects were 69.5 ± 7.2 years old, MMSE 26.6 ± 4, and SAGE 18.4 ± 4.7. AD subjects were 68.4 ± 9.3 years old, MMSE 16.3 ± 6.4, and SAGE 7.4 ± 6.1. 5 subjects (33%) of the clinical AD cases showed abnormal DAT scan uptake, 3 subjects (20%) of the clinical AD cases were negative for amyloid with normal DaTscan uptake, 3 subjects (20%) of the clinical DLB cases showed mixed LBD and AD features, 2 subjects (13%) of the clinical DLB cases were positive for amyloid with normal DaTscan uptake, and 1 (8%) subject with clinical PD had normal DAT scan. <h3>Conclusions:</h3> Based on functional neuroimaging, 26% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 25% were misdiagnosed. <b>Disclosure:</b> Dr. Bouchachi has nothing to disclose. Ms. Truelove has nothing to disclose. Ms. Rawson has nothing to disclose. Mrs. Icenhour has nothing to disclose. Michael Knopp has nothing to disclose. Prof. Wright has a non-compensated relationship as a Board of Directors Member with American Board of Science in Nuclear Medicine that is relevant to AAN interests or activities. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BrainTest, Inc. Dr. Scharre has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vascular Scientific. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Hickman &amp; Lowder Co.. The institution of Dr. Scharre has received research support from InSightec. The institution of Dr. Scharre has received research support from Alzheimer’s Therapeutic Research Institute (ATRI). The institution of Dr. Scharre has received research support from Eisai. The institution of Dr. Scharre has received research support from vTv Therapeutics. The institution of Dr. Scharre has received research support from National Institute of Health. The institution of Dr. Scharre has received research support from Eli Lilly. The institution of Dr. Scharre has received research support from Johns Hopkins. The institution of Dr. Scharre has received research support from Biogen. The institution of Dr. Scharre has received research support from Roche. The institution of Dr. Scharre has received research support from AZ Therapies. The institution of Dr. Scharre has received research support from Biohaven. The institution of Dr. Scharre has received research support from Novartis. The institution of Dr. Scharre has received research support from Avanir. The institution of Dr. Scharre has received research support from PrecisionMed, Inc. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care.

NPC1 variants are not associated with Parkinson’s disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement–sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.

The Proteome of Neuromelanin Granules in Dementia with Lewy Bodies.

Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson's disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SNSurr.) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB.

A proposal for a new concept in psychiatric phenomenology: The "Yume-Utsutsu" (dreamy or half-asleep) phenomenon in patients with dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) present with a variety of physical and mental symptoms, including visual hallucinations, delusions, depression, rapid eye sleep movement behavior disorder, and olfactory dysfunction. This study describes another interesting psychiatric symptom, which seems to be characteristic of DLB, in many patients who visited the author's psychogeriatrics department for neurocognitive disorders or psychogeriatric diseases. The clinical courses of seven representative cases of DLB, each of which included episodes of this interesting psychiatric symptom, are described to clarify the commonalities they shared. After examining the characteristic symptoms of these cases, a novel term was proposed for a new concept in psychiatric phenomenology, the "Yume-Utsutsu" (dreamy or half-asleep) phenomenon. "Yume-Utsutsu" is a Japanese word that means a mental state in which dreams are indistinguishable from reality. This phenomenon is different from visual hallucinations, fluctuating cognition, rapid eye sleep movement behavior disorder, delirium, and epilepsy-related automatism. The "Yume-Utsutsu" (dreamy or half-asleep) phenomenon proposed as a novel psychiatric concept in this article is useful for diagnosing and clarifying the psychopathology of DLB.

Characteristics of very late-onset schizophrenia-like psychosis as prodromal dementia with Lewy bodies: a cross-sectional study

BackgroundThis study aimed to identify cases of potential prodromal DLB in very late-onset schizophrenia-like psychosis (VLOSLP), using indicative biomarkers of dementia with Lewy bodies (DLB), and to evaluate the characteristics of psychosis as prodromal DLB.MethodsData of patients with VLOSLP without dementia and Parkinsonism, who underwent testing for at least one indicative biomarker of DLB, were retrospectively collected from the database of the psychiatry clinic at the Osaka University Hospital. Patients were divided into two groups based on the positive (VLOSLP+LB) and negative (VLOSLP–LB) results of the indicative biomarkers of DLB. Age, gender, cognitive battery scores, prevalence of each type of delusions and hallucinations, cerebral volume, and cerebral perfusion were compared between the two groups.ResultsEleven VLOSLP+LB and 23 VLOSLP–LB participants were enrolled. There were no significant differences in age, proportion of females, and MMSE scores between the two groups. The standardized score of the digit symbol substitution test was significantly lower in the VLOSLP+LB than in VLOSLP–LB group (6.9 [3.1] vs. 10.0 [2.7], p = 0.005). The prevalence of visual hallucinations was significantly higher in the VLOSLP+LB group than in the VLOSLP-LB group (81.8% vs. 26.1%, p = 0.003). Auditory hallucinations were prevalent in both groups (43.5% in VLOSLP–LB, and 45.5% in VLOSLP+LB). Among patients with auditory hallucinations, auditory hallucinations without coexistent visual hallucinations tended to be more prevalent in VLOSLP–LB (7 out of 10) than in VLOSLP+LB patients (1 out of 5). Although cerebral volume was not different in any region, cerebral perfusion in the posterior region, including the occipital lobe, was significantly lower in the VLOSLP+LB group.ConclusionsPsychomotor slowing, visual hallucinations, and reduced perfusion in the occipital lobe may be suggestive of prodromal DLB in VLOSLP patients, even though the clinical manifestations were similar in many respects between VLOSLP+LB and VLOSLP–LB. Although auditory hallucinations were prevalent in both groups, most patients in VLOSLP+LB complained of auditory hallucinations along with visual hallucinations. Future studies with a larger number of patients without selection bias are desirable.

Gender differences in Parkinson's disease with dementia and dementia with Lewy bodies

BackgroundGender differences for dementia with Lewy bodies (DLB), usually considered an intermediate disease between Alzheimer disease (AD), Parkinson disease (PD), and Parkinson disease with dementia (PDD), is controversial. The present study investigated gender differences in DLB and PDD using demographic and pharmacologic treatment strategies in a retrospective data analysis. MethodData of confirmed cases of DLB and PDD between 2015 and 2020 were collected from the PRISMA dementia data-base registry. Data from 7594 PDD patients and 608 DLB patients were analyzed using logistic regression analysis to determine demographic and pharmacologic factors associated with DLB and PDD patients. ResultIn the adjusted analysis, central acetylcholinesterase inhibitors (ChEIs) including donepezil, galantamine, rivastigmine were associated with DLB. Second generation antipsychotics (SGAs) such as risperidone (odd ratio(OR)=1.900, 95% confidence interval (CI),1.192–3.030, P = 0.007) was associated with females with DLB while aripiprazole (OR=0.195,95% CI,0.06–0.631, P<0.006), and a selective serotonin receptor inhibitor (SSRIs) including escitalopram (OR=0.651, 95% CI,0.468–0.906, P = 0.011), and demographic factors including tobacco use (OR=0.620, 95% CI,0.444–0.866, P<0.005) and increasing age (OR =1.042, 95% CI, 1.025–1.058, P<0.001), were associated with females that present with PDD. Olanzapine (OR=2.871, 95% CI, 1.902–4.334, P<0.001), escitalopram (OR=1.444, 95% CI, 1.079–1.932) and tobacco use (OR=1.424, 95%CI, 1.075–1.887, P = 0.014) were associated with males with DLB. African American males (OR= 0.249, 95% CI, 0.088–0.703, P = 0.009) with a history of ethyl alcohol (ETOH) use (OR= 0.371, 95% CI, 0.260–0.531, P<0.001) treated with aripiprazole (OR=0.581, 95%CI, (0.302–1.118), P = 0.004) were associated with PDD. ConclusionOur findings reveal similarities and differences in demographic and pharmacologic factors associated with DLB and PDD. Investigating the effect of identified factors on DLB or PDD in future studies can help improve the care of DLB and PDD patients.

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.