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BACKGROUND: Few rare variants have been identified in genetic loci from genome‐wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty‐six rare missense or loss‐of‐function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)‐휀4 was the only variant segregating. However, in 60.3% of families, APOE 휀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE 휀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease.Missense or loss of function variants were found segregating in nearly 7% of families.APOE‐휀4 was the only segregating variant in 29.7% in familial Alzheimer's disease.In Hispanic and non‐Hispanic families, different variants were found in segregating genes.No coding variants were found segregating in many Hispanic and non‐Hispanic families. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The National Institute on Aging – Alzheimer's Association (NIA‐AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre‐mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aβ42/40 after 12 months in the A+T− group. Post mortem neuropathologic analyses indicated that most of the p‐Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T− may need to be monitored to determine whether they remain A+ or ever progress to T positivity. Highlights: Some A+T‐ DLB subjects transition from A+ to negative after 12‐months.Clinically diagnosed DLB with LBP‐AD (A+T+) maintain their positivity.Clinically diagnosed DLB with LBP‐AD (A+T+) maintain their positivity.Monitoring of the A+T‐ sub‐type of DLB may be necessary. [ABSTRACT FROM AUTHOR]

Objective: To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods: Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers. Results: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older. Interpretation: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4. [ABSTRACT FROM AUTHOR]

Background: Hippocampal and amygdala subfields variably affect cognitive impairment in neurodegenerative diseases. Subfields of these regions can be well segmented using modern neuroimaging tools but their role in neurodegenerative disease is under active investigation. In this study, we identified hippocampal and amygdala subregions predictive of cognitive performance and motor symptoms severity measured by MoCA (Montreal Cognitive Assessment) and MDS‐UPDRS III, respectively, in patients with dementia with Lewy Bodies (DLB). Method: We selected all participants with probable DLB (N = 48, mean age = 71±7 years, 15% female) enrolled in the Dementia with Lewy Bodies Consortium (DLBC) as of July 2022, with concurrent measures of 3D T1 MRI sequence, MoCA, and MDS‐UPDRS III scores. We performed cortical reconstruction and volumetric segmentation of hippocampal subfields and nuclei of the amygdala using FreeSurfer (v 7.2). We used combat harmonization to account for site and scanner differences. We trained and applied a bootstrapped, bidirectional stepwise regression model of 29 predictor variables comprised of sub‐fields and mean cortical thickness against MoCA and MDS‐UPDRS III, respectively, with an 80‐20 train‐test split ratio, and 5000 repetitions, corrected for age and sex. Result: Subfield segmentation is shown in Figure 1A. The best fitting model for MoCA included mean cortical thickness, parasubiculum, hippocampal and amygdala transition area, corticoamygdaloid transition area, and CA3 body (Figure 1B, adjusted R2 = 0.51). The best fitting model for MDS‐UPDRS III included the cortical nucleus of the amygdala and CA1 body (Figure 1C, adjusted R2 = 0.22). This model was considered a poor fit. We considered MoCA for further analysis and closely predicted scores in our 20% partitioned test sample (Figure 2A, R2 = 0.38). Conclusion: We report model‐based selection of hippocampal and amygdala subfields to predict MoCA scores in DLB. Atrophy in these regions has been associated with global cognitive deficit in mild cognitive impairment and Alzheimer disease cohorts. The model fit for MDS‐UPDRS III scores was poor, providing evidence that these brain regions do not serve a role in motor control. [ABSTRACT FROM AUTHOR]

Background: The application of machine learning (ML) tools in electronic health records (EHRs) can help reduce the underdiagnosis of dementia, but models that are not designed to reflect minority population may perpetuate that underdiagnosis. Method: To address the underdiagnosis of dementia in both Black Americans (BAs) and white Americans (WAs), we sought to develop and validate ML models that assign race‐specific risk scores. These scores were used to identify undiagnosed dementia in BA and WA Veterans in EHRs. More specifically, risk scores were generated separately for BAs (n = 10K) and WAs (n = 10K) in training samples of cases and controls by performing ML, equivalence mapping, topic modeling, and a support vector‐machine (SVM) in structured and unstructured EHR data. Scores were validated via blinded manual chart reviews (n = 1.2K) of controls from a separate sample (n = 20K). AUCs and negative and positive predictive values (NPVs and PPVs) were calculated to evaluate the models. Result: Among Veterans with undiagnosed dementia who underwent chart review, those diagnosed by expert clinician reviewers with possible/probable dementia had higher ADRD ML risk scores compared to those diagnosed with no dementia (0.45 [0.38] vs. ‐0.02 [0.51] for BAs, and 0.38 [0.41] vs. ‐0.02 [0.47] for WAs; (see figure 1). Of the 1,200 Veterans who underwent chart review, 15.3% (n = 92) of BAs and 9.5% (n = 57) of WAs were identified with possible/probable dementia. However, adjusting for oversampling of Veterans with higher scores, the adjusted estimated prevalence was 4.1% for BA Veterans and 3.6% for WA Veterans. There was a strong positive relationship between risk scores and the prevalence of undiagnosed dementia (Figure 2). As anticipated, for Veterans with scores below the 90th percentile, the percentages of undiagnosed dementia were low: 3.9% for BA and 2.9% for WA Veterans. Among Veterans with scores above the 90th percentile, we found that a higher percentage of BA Veterans had undiagnosed dementia than WA Veterans: 25.6% vs. 15.3%. Conclusion: Our findings suggest that race‐specific ML models can assist in the identification of undiagnosed dementia, particularly in BAs. Future studies should investigate implementing EHR‐based risk scores in clinics that serve both BA and WA Veterans. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are challenging to differentiate. Mobile health devices that measure motor and sleep domains between clinic visits may improve differential diagnosis. Method: Participants with probable AD and probable DLB wore ActiGraph triaxial wGT3X‐BT actigraphy devices on their nondominant wrists for 2 weeks and multichannel Sleep ProfilerX8TM EEG devices on their foreheads for 2 consecutive nights.3 Actigraphy data were processed and scored using GGIR and activity counts in R. The Sleep Profiler characterizes abnormal slow‐wave sleep and non‐REM hypertonia (NRH). Result: At baseline, participants with DLB (n = 9) had higher UPDRS scores and a higher likelihood of psychosis than participants with AD (n = 8; see Table 1). Using univariate Wilcoxon Rank‐Sum tests, we found that at baseline participants with DLB had lower daily activity counts, higher % time in NRH, and lower % time in REM sleep than participants with AD (unadjusted p‐values < 0.05; See Figure 1). In a recent 6‐month followup, activity levels were lower on average than baseline activity levels for both DLB (n = 5) and AD (n = 5). at 6‐months, the differences in % sleep in NRH increased between DLB participants (n = 5) and AD participants (n = 3) as average % NRH increase 6% in DLB and decreased 1% in AD (see Table 2). These 6‐month differences are not statistically significant, but data collection are ongoing. An exploration of methods for processing and scoring actigraphy data revealed that processing can result in wide range of findings. As a result, we have focused on actigraphy outcomes which are more suitable to older participants with dementia. Conclusion: Participants with DLB demonstrated lower baseline physical activity and higher rates of baseline sleep disturbances than participants with AD; sleep differences between DLB and AD appeared to increase over 6 months. Actigraphy and sleep‐monitoring devices are well tolerated in participants with dementia and they can reliably collect valid, useful activity and sleep data in between clinic visits. [ABSTRACT FROM AUTHOR]

Background: Several genetic models that recapitulate neurodegenerative features of Parkinson's disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non‐human vertebrates. Objective: To describe the genetic and pathological findings of three Yellow‐crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype. Methods: The phenotype of the three parrots included severe ataxia, rigidity, and tremor, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their severe impairment, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteasome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents. Results: The brains of affected parrots exhibited neuronal loss, spongiosis, and widespread Lewy body‐like inclusions in many regions including the midbrain, basal ganglia, and neocortex. Proteasome activity was significantly reduced in these animals compared to a control (P < 0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid within the pleckstrin homology (PH) domain of the calcium‐dependent secretion activator 2 (CADPS2) gene. Conclusions: Our data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy body‐like pathology in parrots. Although CADPS2 variants have not been reported to cause PD, further investigation of the gene might provide important insights into the pathophysiology of Lewy body disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Introduction: The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study (NIA‐LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). Methods: Recruitment focused on families with two living affected siblings and a third first‐degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome‐wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results: APOE genotype modified the age‐at‐onset in many large families. Novel variants and known variants associated with early‐ and late‐onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion: The NIA‐LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age‐at‐onset provides opportunities to investigate the complexity of familial AD. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) is difficult to differentiate from Alzheimer's disease (AD) in clinical settings. Actigraphy and sleep‐monitoring devices have the potential to generate data in between clinic visits to help improve the identification of DLB. Objective: We will assess the feasibility of measuring activity and sleep, including day/night reversal, in participants with DLB (n=5) and AD (n=4). Method: Participants were asked to wear actigraphy devices on their wrists for 2 weeks and sleep‐monitoring EEG devices on their foreheads for 2 nights. Actigraphy recording errors were detected by logging instances in which the majority of acceleration values approached the maximum; reliability was evaluated by logging 15‐minute actigraphy and 1‐hour sleep‐monitoring periods with at least some valid data. Actigraphy tolerability was evaluated by examining non‐wear times. Ten variables were selected to evaluate day/night reversal. Result: Averaged across all individuals, only 0.02% of the 15‐minute actigraphy recording periods had a recording error, 100% of the 15‐minute periods had at least some valid data, and only 0.15% of the periods reflected non‐wear times. For the sleep‐monitoring device, an average of 78% of each nightly recording were considered valid. Of the ten day/night reversal variables, two sleep‐monitor variables showed the strongest differences between DLB and AD: sleep efficiency (mean [SD] = 0.56 [0.19] for DLB; mean [SD] = 0.74 [0.11] for AD; see Fig. 1) and percent sleep in REM (mean [SD] = 6.83 [9.16] for DLB; mean [SD] = 18.3 [4.13] for AD; see Fig. 2). The ratio of nighttime to daytime activity as measured by actigraphy (mean [SD] = 0.37 [0.18] for DLB; mean [SD] = 0.38 [0.08] for AD) showed strong differences in the variability of measurements between AD and DLB (see Fig. 3). Conclusion: These findings suggest that actigraphy and sleep‐monitoring devices are tolerable for participants with dementia and that the devices can reliably collect valid activity and sleep data in between clinic visits. Sleep efficiency and percentage REM sleep were lower in participants with DLB than in participants with AD. Larger studies should further explore the promise of actigraphy and sleep‐monitoring devices for differentiating DLB and AD. [ABSTRACT FROM AUTHOR]

SUICIDE PREVALENCE IN LBD, PD, AND DEMENTIA Suicide The prevalence of SI, suicide attempts, and suicide in LBD are not well researched. Implications for LBD Younger individuals with LBD and those of white race may be at a higher risk of suicide based on studies in PD and dementia (Table 1). Research suggests, though, that most individuals with dementia do not access palliative care or access it only in the last weeks of life.80 In a recent study of end of life in LBD, survey respondents said that hospice was used by 78% of individuals with LBD (higher than prior dementia studies), but 40% had hospice initiated less than a month before death.18 Additionally, some caregivers of individuals who died with LBD reported that they were never told that LBD could be terminal. [Extracted from the article]

Background: Neuropathological 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. Method: Cerebrospinal 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. Result: DLB 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. Conclusion: These 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. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy Bodies (DLB) is defined by abnormal deposits of alpha‐synuclein (Lewy bodies), in the brain. DLB may be accompanied by variable co‐pathology, especially Alzheimer's Disease (AD). DLB is diagnosed clinically, with definitive diagnosis only possible at autopsy. Misdiagnosis may occur due to overlapping symptoms in different dementias. The alpha‐synuclein (αSyn) seed amplification assay (SAA) is a qualitative test that detects misfolded aggregates of αSyn in synucleinopathies, including DLB, with high sensitivity and specificity. In autopsy‐confirmed AD with limbic or neocortical synuclein pathology, SAA was positive even when DLB phenotypic features were mild (Arnold et al., 2022). We are now evaluating SAA in cerebrospinal fluid (CSF) samples and clinical features in patients with DLB followed through a multi‐Center DLB Consortium (NINDS U01NS100610), which is part of the NINDS Parkinson's Disease Biomarkers Program (PDBP). Method: CSF from 3 groups: 1) analytical controls: youngest available age, no neurological symptoms, normal neurological exam; 2) clinical controls: no symptoms/signs, age and gender match to DLB; 3) DLB. SAA will be run blind to diagnosis using standardized assay methods by Amprion. We will compare Core clinical features of DLB patients and SAA. We hypothesize that SAA‐ patients will have less clear clinical features for DLB, and will be likely to meet clinical and/or CSF biomarker criteria for other diagnoses, e.g., AD. Core clinical features will be defined as strongly or weakly present, e.g., REM Sleep Behavior Disorder: PSG‐proven (strong); +questionnaire (weak); Parkinsonism: ≥ 2 cardinal features (strong); 1 feature (weak). Hallucinations and fluctuations are described in standardized rating scales/interviews. CSF AD biomarkers (Aβ42, t‐Tau and p‐Tau181) were analyzed for almost all DLB subjects. Sensitivity and specificity of each Core clinical feature will be calculated in relation to SAA+ and SAA‐ results. Result: Subjects were recruited at 8 clinical sites across the USA from 2017‐2021. Demographics of subjects with available CSF are shown in Table 1. Demographics, clinical features and CSF AD biomarker results will be presented in SAA+ and SAA‐ groups. Conclusion: Results will inform how well different core clinical features predict pathological αSyn (CSF SAA+) in people diagnosed with DLB. [ABSTRACT FROM AUTHOR]

Objective: Autosomal‐dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early‐onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild‐type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ1–40 compared to controls, indicating abnormal γ‐secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age‐matched control brain. Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk. [ABSTRACT FROM AUTHOR]

Background: Epidemiological study shows that posttraumatic stress disorder (PTSD) has been linked to increased risk of Alzheimer's disease (AD). However, longitudinal study of Holocaust survivors does not show accelerated cognitive decline in those with PTSD. We compared cross‐sectional and longitudinal cognitive function in a cohort of African American (AA) veterans with combat PTSD to that in a cohort of elderly AA males without PTSD to determine if PTSD was associated with a more rapid cognitive decline. Method: Eighteen male AA Veterans with the combat PTSD who received treatment at the VA Puget Sound Health Care System in Seattle, participated in a longitudinal study of aging at UW ADRC between 2007‐16. Fifty‐four male AA subjects without PTSD were selected from the National Alzheimer's Coordinating Center (NACC) dataset and matched by age (± 4 years), education (± 1 year), and MMSE score (± 2 points) as a comparison group (Table 1). Longitudinal data were available for 16 PTSD+ and 40 PTSD‐ participants. All participants were free of dementia or Mild Cognitive Impairment (MCI) and were assessed using the NACC Uniform Data Set version 2 (UDS 2.0) neuropsychological test battery. Linear mixed effects regression was used to estimate mean cognitive outcome at baseline and mean slope of change over follow‐up. Result: As shown in the Figure 1, mean MMSE score at baseline and slope of change did not significantly differ between those with and without PTSD (p ≥.35). The mean immediate and delayed recall scores from the Wechsler Memory Scale‐Revised Logical Memory were similar at baseline (p >.98) and showed no difference in change from baseline (p >.69). Similarly, there were no statistical differences in means at baseline or slope of change by group for Digit Span Forward and Backward, Category Fluency (animals and vegetables), WAIS‐R Digit Symbol test, and Trail Making Test (A and B) (all p‐values >.27). Conclusion: Cognitive function in AA veterans with combat PTSD was comparable to AA men without PTSD over an average of 4 years. These findings need to be replicated in a larger cohort with a longer duration of follow‐up. [ABSTRACT FROM AUTHOR]

Introduction: Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person's risk of developing both Alzheimer's disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD. Methods: Genomic DNA from postmortem brain tissues (frontal lobe and cerebellum) of neuropathological pure (np) controls and npAD, LBD + AD, and npLBD subjects were bisulfite pyrosequenced. DNA methylation levels of two APOE subregions were then compared for these groups. Results: APOE DNA methylation was significantly reduced in npLBD compared with np controls, and methylation levels were lowest in the LBD + AD group. Discussion: Given that npLBD and npAD postmortem brains shared a similar reduction in APOE methylation, it is possible that an aberrant epigenetic change in APOE is linked to risk for both diseases. [ABSTRACT FROM AUTHOR]

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Of recent interest is the finding that certain cerebrospinal fluid (CSF) biomarkers traditionally linked to Alzheimer's disease (AD), specifically amyloid beta protein (Aβ), are abnormal in PD CSF. The aim of this exploratory investigation was to determine whether genetic variation within the amyloid precursor protein (APP) processing pathway genes correlates with CSF Aβ42 levels in Parkinson's disease (PD).Methods: Parkinson's disease (n = 86) and control (n = 161) DNA were genotyped for 19 regulatory region tagging single-nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP. The SNP genotypes were tested for their association with CSF biomarkers and PD risk while adjusting for age, sex, and APOE ɛ4 status.Results: Significant correlation with CSF Aβ42 levels in PD was observed for two SNPs, (APP rs466448 and APH1B rs2068143). Conversely, significant correlation with CSF Aβ42 levels in controls was observed for three SNPs (APP rs214484, rs2040273, and PSEN1 rs362344).Conclusions: In addition, results of this exploratory investigation suggest that an APP SNP and an APH1B SNP are marginally associated with PD CSF Aβ42 levels in APOE ɛ4 noncarriers. Further hypotheses generated include that decreased CSF Aβ42 levels are in part driven by genetic variation in APP processing genes. Additional investigation into the relationship between these findings and clinical characteristics of PD, including cognitive impairment, compared with other neurodegenerative diseases, such as AD, are warranted. © 2015 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Of recent interest is the finding that certain cerebrospinal fluid (CSF) biomarkers traditionally linked to Alzheimer's disease (AD), specifically amyloid beta protein (Aβ), are abnormal in PD CSF. The aim of this exploratory investigation was to determine whether genetic variation within the amyloid precursor protein (APP) processing pathway genes correlates with CSF Aβ42 levels in Parkinson's disease (PD). Methods Parkinson's disease (n = 86) and control (n = 161) DNA were genotyped for 19 regulatory region tagging single-nucleotide polymorphisms (SNPs) within nine genes ( APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP. The SNP genotypes were tested for their association with CSF biomarkers and PD risk while adjusting for age, sex, and APOE ɛ4 status. Results Significant correlation with CSF Aβ42 levels in PD was observed for two SNPs, ( APP rs466448 and APH1B rs2068143). Conversely, significant correlation with CSF Aβ42 levels in controls was observed for three SNPs ( APP rs214484, rs2040273, and PSEN1 rs362344). Conclusions In addition, results of this exploratory investigation suggest that an APP SNP and an APH1B SNP are marginally associated with PD CSF Aβ42 levels in APOE ɛ4 noncarriers. Further hypotheses generated include that decreased CSF Aβ42 levels are in part driven by genetic variation in APP processing genes. Additional investigation into the relationship between these findings and clinical characteristics of PD, including cognitive impairment, compared with other neurodegenerative diseases, such as AD, are warranted. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative disease (NDD) is associated with sleep disturbances, including decreased stage N3 and REM sleep and reduced spindle activity. Further, supine sleep position may impact NDD risk by altering glymphatic clearance. This study evaluated conventional and exploratory sleep metrics in the differentiation of subjects with normal cognition (NC) and patients with Alzheimer's disease dementia (AD) and alpha‐synucleinopathies (α‐Syn). Method: Home sleep data were acquired across multiple study sites using the self‐applied Sleep ProfilerTM, including 44 NC subjects (age=69+5.0), 22 patients diagnosed with AD (age=75+7.1) and 25 with α‐Syn (Parkinson's disease=14, Parkinson's disease with Dementia or Dementia with Lewy Bodies=11; age=69+6.9). Recordings were auto‐staged and technically reviewed, with 86% of the records having two‐night averages. Logistic regression and Mann‐Whitney U tests were used to characterize group differences based on age, conventional sleep metrics (i.e., sleep efficiency, sleep onset (SO), awakenings, percent of sleep time (%) in REM,N1, N2 and N3, and sleep spindles) and exploratory sleep measures [i.e., % supine, % Light N2 (L2=N2 epochs absent of spindles with K‐complexes and/or alpha or EMG (>40 Hz) intrusion), % NREM sleep with hypertonia (NRSH=>4 consecutive epochs with persistently elevated EMG power relative to delta and theta power) and % atypical N3 (AN3=epochs staged N3 with low theta and sigma power relative to delta, alpha, beta and EMG)]. Result: AD were older than both NC and α‐Syn patients (p<0.005). Both AD and α‐Syn had lower %REM and greater %supine than NC (p<0.005), and %NRSH was greater in α‐Syn than NC or AD (p<0.005). Based on logistic regression, AD was differentiated from NC based on age, %REM, %L2 (p<0.05) and %supine (p=0.06). α‐Syn was distinguished from NC using both conventional (%N3 and SO, p<0.05) and exploratory sleep metric (%AN3 and %NRSH, p<0.05; %supine, p=0.06). Age (p=0.05) and %NRSH (p<0.01) were the only metrics that differentiated α‐Syn from AD. Conclusion: Objective home sleep profiles hold promise for differentiating NDD patients from NC. The sleep metrics that provided the greatest distinction between NDD and NC were %REM, %supine and NRSH, while only NRSH distinguished AD from α‐Syn patients. Further confirmatory studies are underway. [ABSTRACT FROM AUTHOR]

Cigarette smoking has been associated repeatedly in observational studies with decreased risk of Parkinson's disease (PD), but its relationship to the risk of dementia or Alzheimer's disease (AD) is inconsistent. All of these studies have used clinical diagnoses of disease. We tested the hypothesis that lifetime cigarette use might be associated with reduced risk of neuropathologic changes of Lewy-related pathology (LRP) in multiple brain regions or with reduced risk of consensus neuropathologic changes of AD in a prospective community-based study of brain aging and dementia, the Adult Changes in Thought (ACT) study. We observed that heavy lifetime cigarette smoking (>50 pack years) was associated with significantly reduced relative risk (RR) for LRP, but not AD-type pathologic changes, after correcting for selection bias, and with significantly reduced frequency of LRP in the substantia nigra. These findings are the first of which we are aware to associate reduced LRP in human brain with any exposure, and substantiate observational studies that have associated cigarette smoking with reduced risk of PD. Although cigarette smoking is too toxic to suggest as a treatment, if confirmed, these findings may guide future therapeutic strategies that attempt to suppress LRP in human brain by other means. [ABSTRACT FROM AUTHOR]

Mutations in the leucine-rich repeat kinase 2 ( LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31-2.54; P = 3.3 × 10−4) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10-3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Lewy-related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (n = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (n = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia. [ABSTRACT FROM AUTHOR]

Lewy body (LB) inclusions are one of the pathological hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). One way to better understand the process leading to LB formation and associated pathogenesis responsible for neurodegeneration in PD and DLB is to examine the content of LB inclusions. Here, we performed a proteomic investigation of cortical LBs, obtained by laser capture microdissection from neurons in the temporal cortex of dementia patients with cortical LB disease. Analysis of over 2500 cortical LBs discovered 296 proteins; of those, 17 had been associated previously with brainstem and/or cortical LBs. We validated several proteins with immunohistochemical staining followed by confocal microscopy. The results demonstrated that heat shock cognate 71 kDa protein (also known as HSC70, HSP73, or HSPA10) was indeed not only colocalized with the majority of LBs in the temporal cortex but also colocalized to LBs in the frontal cortex of patients with diffuse LB disease. Our investigation represents the first extensive proteomic investigation of cortical LBs, and it is expected that characterization of the proteins in the cortical LBs may reveal novel mechanisms by which LB forms and pathways leading to neurodegeneration in DLB and/or advanced PD. Further investigation of these novel candidates is also necessary to ensure that the potential proteins in cortical LBs are not identified incorrectly because of incomplete current human protein database. [ABSTRACT FROM AUTHOR]

Background: Late‐onset Alzheimer's disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been complicated by both the genetic heterogeneity and the cost, until recently, of comprehensive DNA sequencing in ROIs. The known loci also leave much heritability unexplained. Method: We used the families in the AD Sequencing Project (ADSP) discovery family sample to identify variants of interest from whole genome sequences (WGS), and through the variants, genes implicated in risk. We used SNP‐based multipoint linkage analysis to identify ROIs with rare VOIs, carrying out analysis without trimming pedigrees. We pursued all ROIs with family‐specific lodmax scores >1.9, reducing the variants of interest by several filters. We carried out pedigree‐based genotype imputation from the available WGS data, followed by family‐based association analysis, filtered for low population minor allele frequency. We prioritized genes with a low false‐discovery rate for association of single‐cell transcription in brain with AD disease state (PMID:31209304), and genes with high expression in bulk brain (PMID: 24309898). Result: We obtained 46 distinct ROIs representing lodmax1.9‐3.5 per ROI in each of 26 of the 110 ADSP discovery families analyzed. 29 ROIs further investigated in 16 of the families yielded 59 prioritized genes, with 1‐11 genes/ROI. Only 4 out of 321 variants that passed all filters in these genes were in exons, with minimal overlap with genes identified in AD GWASs. Only one ROI occurred in two families, with evidence for a shared‐haplotype between these families, implicating FBXO2 and FBXO44. Both genes are implicated in ubiquitination, while FBXO2 interacts with BACE1. Multiple pathways, both known and new, are implicated, including the ubiquitin‐proteasome system, neural development and maintenance, and mitochondrial functions. Conclusion: This analysis underscores the evidence for extensive genetic heterogeneity and rare variants underlying AD risk, along with multiple potential mechanisms. The preponderance of prioritize non‐coding variants suggests alterations in gene regulation and/or expression as an aspect of AD genetic risk. [ABSTRACT FROM AUTHOR]

Background: The clinical syndrome of dementia with Lewy bodies (DLB) is well defined with good positive predictive value for the presence of Lewy body pathology at autopsy. However, the presence of Lewy body pathology in dementia is not always linked to the clinical syndrome of DLB, particularly early in the clinical course (e.g., prodromal and mild cognitive impairment), and co‐pathologies are quite frequent. This clinical and pathologic complexity leads to many challenges including early recognition and diagnosis, clinical management, and development of symptomatic and disease modifying therapies. To address these issues, a number of consortia have been established to longitudinally study DLB and related Lewy body diseases, including a US based Dementia with Lewy Bodies Consortium (DLBC). Method: The U.S.‐based DLBC is a multi‐centered, NIH funded, project to longitudinally and systematically study subjects with DLB and mild cognitive impairment/high likelihood DLB (MCI‐DLB). The primary goal of the DLBC is to generate biospecimens linked to clinical, imaging, and neuropathologic characterization in a longitudinally followed cohort across the participating DLBC sites. Biofluids, including blood and cerebrospinal fluid (CSF), and data generated by the DLBC will be ultimately be available to investigators through the NINDS‐funded Parkinson's Disease Biomarker Program. Result: To date, one hundred and thirteen subjects have been enrolled in the DLBC. Preliminary results from the first ninety‐two subjects note a male predominance in the sample (82 of 92, 89%). At baseline visit, mean age was 69.4 (SD 7.1 years), baseline UPDRS‐MDS Part III was 28.9 (15.7 SD) and MoCA 20.4 (SD 5.4). Neuropathologic data are limited, but suggest that an elevated CSF p‐tau may assist in clinically differentiating DLB with or without high levels of Alzheimer's disease pathology. Imaging results including volumetric MRI, amyloid imaging and DaTscan are pending. Conclusion: The development of DLB cohorts, such as the US based DLBC, is essential to understanding the complexity and pathobiologic significance of the clinical syndrome, biomarker characteristics and imaging findings in patients with underlying Lewy body disease. These results continue to emphasize the importance of further development of biomarkers in DLB and related neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

To investigate whether clinical and neuropathological differences exist between Alzheimer's disease (AD) cases with and without vascular lesions neuropathologically diagnosed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Descriptive observational study. A community-based registry that identified incident dementia cases. Of the 124 subjects with available clinical and neuropathological assessments, 30 had AD lesions alone, and 18 had AD with vascular lesions. Patients with other neuropathological findings were excluded. Dependent measures included demographic, clinical, and neuropathological characteristics. Neuropathological diagnoses were made using the CERAD criteria and Braak and Braak staging. Of the 124 autopsied cases, 85 cases were diagnosed with neuropathological AD. Of these, 30 had pathology consistent with “pure” AD, whereas 18 had AD pathology with significant vascular lesions (AD/V). There were no differences in age, sex, or education between groups. AD/V cases had higher baseline and final Mini-Mental State Examination (MMSE) scores than pure AD cases, but after adjusting for education, differences in MMSE scores were not statistically significant. The AD/V group had significantly lower Braak staging than the pure AD group, after adjusting for education and final MMSE scores. In this comparison study of AD cases with and without vascular lesions, AD/V cases had less severe AD pathology than those with AD alone, indicating that cerebrovascular disease likely contributes to the severity of cognitive impairment in those with AD. Controlling for vascular risk factors in patients with AD may have a significant effect on severity of dementia. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has swept across the world, causing a staggering number of deaths, particularly among older individuals. The most common symptoms of COVID‐19 are fever, dry cough, and shortness of breath, but delirium has been reported in older adults, including those with preexisting neurodegenerative disorders. Some research has suggested that the role of neuropsychiatric sequelae in COVID‐19, especially delirium, has been underreported and that the lack of fever and respiratory distress in this population may exacerbate underdiagnosis and subsequent mortality. Here, we discuss the variable course of COVID‐19 by detailing the course of illness in two individuals who are age 90+ with mild COVID‐19. Method: We conducted chart reviews and telephone interviews in two patients who were age 90+. Case 1 had an outpatient follow‐up visit via teleconferencing. Due to COVID‐19 protocols, in‐person research assessments were not completed. Both were on hospice due to underlying terminal medical conditions. Result: Both cases are age 90+ patients with dementia who receive hospice care for multiple underlying medical comorbidities. Case 1 presented at home with a low‐grade temperature that was below the CDC COVID‐19 guidelines for fever at that time; he experienced cough, confusion, and functional decline and was admitted to a COVID‐19 unit after testing positive for the disease. His workup also included a COVID‐19 laboratory panel, which was mostly abnormal (including extremely elevated brain natriuretic peptide) but had normal WBC. He did not experience further deterioration, and 22 days later, after testing COVID‐19 negative, he was discharged to a skilled nursing facility (SNF), followed by discharge to home 15 days later. Case 2 had metastatic carcinoma and a preexisting diagnosis of probable dementia with Lewy bodies. COVID‐19 was diagnosed through all‐resident screening at his SNF. He did not exhibit respiratory symptoms or fever at that time. While nursing staff reported confusion, agitation, and restlessness, these symptoms could not be differentiated from complications related to his underlying dementia. This patient was isolated within the SNF and was not hospitalized. Conclusion: These two cases demonstrate the variability of symptom manifestation in COVID‐19 in this high‐risk population. [ABSTRACT FROM AUTHOR]

Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P = 0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well., (Copyright © 2011 Wiley Periodicals, Inc.)