Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Novel RAB39B loss-of-function mutation in patient with typical early-onset Parkinson's disease.

RAB39B mutations have been identified in X-linked developmental delays. Recently, RAB39B mutations were identified in males with early-onset parkinsonism and intellectual disability. A novel loss-of-function RAB39B mutation was found in a female patient with typical early-onset Parkinson's disease (EOPD). RAB39B mutations may cause EOPD, potentially due to a-synuclein homeostasis disruption.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Genetics of Parkinson's Disease: state-of-the-art and role in clinical settings.

INTRODUCTION: Advances in sequencing technologies have enabled extensive genetic testing on an individual basis. Genome-wide association studies (GWAS) have provided insight into the pathophysiology of PD. Additionally, direct-to-consumer genetic testing has enabled the identification of genetic diseases and risk factors without genetic counselling. As genetics increasingly permeates clinical practice, this paper aims to summarise the most important information on genetics in PD forclinical practitioners. STATE-OF-THE-ART: LRRK2 mutations may be found in c.1% of all PD patients with an indistinguishable phenotype from sporadic PD. LRRK2-PD is more prevalent in patients with a positive family history (5-6%) and among certain populations (e.g. up to 41% in North Africans and Ashkenazi Jews). Other familial forms include PRKN (patients with early onset, EOPD), VPS35 (Western European ancestry), PINK1 (EOPD), DJ-1 (EOPD), and SNCA. GBA mutations are found in a large number of PD patients and are associated with faster progression and a poorer prognosis. GWAS have identified 90 genetic risk variants for developing PD and several genetic modifiers for the age at onset, disease progression, and response to treatment. CLINICAL IMPLICATIONS: Multigene panels using next-generation sequencing (NGS) are the first choice for genetic testing in clinical settings. Whole exome sequencing is increasingly being used, particularly as the second-tier testing in patients with negative results of multigene panels. NGS may not detect accurately copy number variants (CNV), meaning that additional analysis is warranted. In a case of a variant of unknown significance (VUS), we suggest firstly searching the up-to-date literature. Segregation studies and in silico predictions may shed more light on the character of the VUS; however, functional studies remain the gold standard. Several interventional clinical trials are active for carriers of LRRK2 and/or GBA mutations. FUTURE DIRECTIONS: Application of artificial intelligence and machine learning will enable high-throughput analysis of large sets of multimodal data. We speculate that, in the future, the treatment landscape for PD will be similar to that in oncological conditions, in which the presence of certain gene mutations or gene overexpression determines the prognosis and treatment decision-making.

Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with REM sleep behavior disorder: A substudy of the North American Prodromal Synucleinopathy Consortium.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g., Parkinson's disease (PD), Lewy Body Dementia (LBD), and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) - henceforth "neurotrauma" (NT) - increase the odds of RBD by ~2.5-fold and is associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight-polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy (NAPS) Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory and autonomic function were completed. This cross-sectional analysis compared cases (n=24; RBD+NT) to controls (n=96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD+NT reported earlier RBD symptom onset (37.5±11.9 vs. 52.2±15.1 years of age) and a more severe RBD phenotype. Similarly, RBD+NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSION: This cross-sectional, matched case:control study shows individuals with RBD+NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD+NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

Valosin-containing-protein pathogenic variant p.R487H in Parkinson's disease.

We describe a 66-year-old woman with Parkinson's disease, carrying a known pathogenic missense variant in the Valosin-containing-protein (VCP) gene. She responded excellently to L-dopa, had no cognitive or motoneuronal dysfunction. Laboratory analyses and MRI were unremarkable. Genetic testing revealed a heterozygous variant in VCP(NM_007126.5), chr9 (GRCh3 7):g.35060820C > T, c.1460G > A p.Arg487His (p.R487H).

Machine Learning Models of Polygenic Risk for Enhanced Prediction of Alzheimer Disease Endophenotypes.

Background and Objectives: Alzheimer disease (AD) has a polygenic architecture, for which genome-wide association studies (GWAS) have helped elucidate sequence variants (SVs) influencing susceptibility. Polygenic risk score (PRS) approaches show promise for generating summary measures of inherited risk for clinical AD based on the effects of APOE and other GWAS hits. However, existing PRS approaches, based on traditional regression models, explain only modest variation in AD dementia risk and AD-related endophenotypes. We hypothesized that machine learning (ML) models of polygenic risk (ML-PRS) could outperform standard regression-based PRS methods and therefore have the potential for greater clinical utility. Methods: We analyzed combined data from the Mayo Clinic Study of Aging (n = 1,791) and the Alzheimer's Disease Neuroimaging Initiative (n = 864). An AD PRS was computed for each participant using the top common SVs obtained from a large AD dementia GWAS. In parallel, ML models were trained using those SV genotypes, with amyloid PET burden as the primary outcome. Secondary outcomes included amyloid PET positivity and clinical diagnosis (cognitively unimpaired vs impaired). We compared performance between ML-PRS and standard PRS across 100 training sessions with different data splits. In each session, data were split into 80% training and 20% testing, and then five-fold cross-validation was used within the training set to ensure the best model was produced for testing. We also applied permutation importance techniques to assess which genetic factors contributed most to outcome prediction. Results: ML-PRS models outperformed the AD PRS (r2 = 0.28 vs r2 = 0.24 in test set) in explaining variation in amyloid PET burden. Among ML approaches, methods accounting for nonlinear genetic influences were superior to linear methods. ML-PRS models were also more accurate when predicting amyloid PET positivity (area under the curve [AUC] = 0.80 vs AUC = 0.63) and the presence of cognitive impairment (AUC = 0.75 vs AUC = 0.54) compared with the standard PRS. Discussion: We found that ML-PRS approaches improved upon standard PRS for prediction of AD endophenotypes, partly related to improved accounting for nonlinear effects of genetic susceptibility alleles. Further adaptations of the ML-PRS framework could help to close the gap of remaining unexplained heritability for AD and therefore facilitate more accurate presymptomatic and early-stage risk stratification for clinical decision-making.

miRNA family miR-29 inhibits PINK1-PRKN dependent mitophagy via ATG9A.

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.

Genetics of Parkinson's disease heterogeneity: A genome-wide association study of clinical subtypes.

INTRODUCTION: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes. METHODS: A total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data. RESULTS: We identified one genome-wide significant association (P < 5 × 10-8), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 × 10-8). Suggestive associations (P < 1 × 10-6) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 × 10-7), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 × 10-7), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 × 10-7), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 × 10-7), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 × 10-7). CONCLUSION: Our findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation.

Senile plaque-associated transactive response DNA-binding protein 43 in Alzheimer's disease: A case report spanning 16 years of memory loss.

Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming "apple-bite" or "flame-shaped" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.

Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy.

BACKGROUND: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. OBJECTIVE: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. METHODS: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. RESULTS: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. CONCLUSIONS: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.

Lysosomal Polygenic Burden Drives Cognitive Decline in Parkinson's Disease with Low Alzheimer Risk.

BACKGROUND: Genetics influence cognitive progression in Parkinson's disease, possibly through mechanisms related to Lewy and Alzheimer's disease pathology. Lysosomal polygenic burden has recently been linked to more severe Lewy pathology post mortem. OBJECTIVES: To assess the influence of lysosomal polygenic burden on cognitive progression in Parkinson's disease patients with low Alzheimer's disease risk. METHODS: Using Cox regression we assessed association between lysosomal polygenic scores and time to Montreal Cognitive Assessment score ≤ 21 in the Parkinson's Progression Markers Initiative cohort (n = 374), with replication in data from the Parkinson's Disease Biomarker Program (n = 777). Patients were stratified by Alzheimer's disease polygenic risk. RESULTS: The lysosomal polygenic score was associated with faster progression of cognitive decline in patients with low Alzheimer's disease risk in both datasets (P = 0.0032 and P = 0.0054, respectively). CONCLUSION: Our study supports complex interplay between genetics and neuropathology in Parkinson's disease-related cognitive impairment, emphasizing the role of lysosomal polygenic burden. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnosing multiple system atrophy: current clinical guidance and emerging molecular biomarkers.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder characterized by motor and autonomic dysfunction. Accurate and early diagnosis of MSA is challenging due to its clinical similarity with other neurodegenerative disorders, such as Parkinson's disease and atypical parkinsonian disorders. Currently, MSA diagnosis is based on clinical criteria drawing from the patient's symptoms, lack of response to levodopa therapy, neuroimaging studies, and exclusion of other diseases. However, these methods have limitations in sensitivity and specificity. Recent advances in molecular biomarker research, such as α-synuclein protein amplification assays (RT-QuIC) and other biomarkers in cerebrospinal fluid and blood, have shown promise in improving the diagnosis of MSA. Additionally, these biomarkers could also serve as targets for developing disease-modifying therapies and monitoring treatment response. In this review, we provide an overview of the clinical syndrome of MSA and discuss the current diagnostic criteria, limitations of current diagnostic methods, and emerging molecular biomarkers that offer hope for improving the accuracy and early detection of MSA.

Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives: To investigate the effects of genetic variants on risk and time to LID. Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID. Results: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile=1.27, 95% CI=1.03-1.56, p=0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile=1.38, 95% CI=1.07-1.79, p=0.0128; HRfourth_quartile=1.38, 95% CI=1.06-1.78, p=0.0147). Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.

Genome-wide association study identifies APOE and ZMIZ1 variants as mitophagy modifiers in Lewy body disease.

The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs). We identified a strong association with p-S65-Ub for APOE4 (rs429358; ß : 0.50, 95% CI: 0.41 to 0.69; p =8.67x10 -25 ) and a genome-wide significant association for ZMIZ1 (rs6480922; ß : -0.33, 95% CI: -0.45 to -0.22; p =1.42x10 -8 ). The increased p-S65-Ub levels in APOE4 -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly, ZMIZ1 rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain ( ZMIZ1 locus) and highlight a strong association of APOE4 with mitophagy alteration. With APOE4 being the strongest known risk factor for clinical Alzheimer's disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association.

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is neuropathologically classified into 3 corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed "minimal atrophy," was identified using structural MRI. The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype. METHODS: We applied 2 strategies in the Florida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak tangle stage IV (Braak IV) because of the relative paucity of neocortical tangle involvement compared with Braak >IV. Braak IV cases were compared with the 3 AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75th percentile) were defined as minimal atrophy. RESULTS: Braak IV cases (n = 37) differed from AD subtypes (limbic predominant [n = 174], typical [n = 986], and hippocampal sparing [n = 187] AD) in having the least years of education (median 12 years, group-wise p < 0.001) and the highest brain weight (median 1,140 g, p = 0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of APOE ε4 carriers (75%, p < 0.001), an amnestic syndrome (100%, p < 0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p < 0.001). Only 5% of Braak IV cases had amygdala-predominant Lewy bodies (the lowest frequency observed, p = 0.017), whereas 32% had coexisting pathology of Lewy body disease, which was greater than the other subtypes (p = 0.005). Nearly half (47%) of the Braak IV samples had coexisting limbic predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathologic change. Cases with a high brain weight (n = 201) were less likely to have amygdala-predominant Lewy bodies (14%, p = 0.006) and most likely to have Lewy body disease (31%, p = 0.042) compared with those with middle (n = 455) and low (n = 203) brain weight. DISCUSSION: The frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.

Diffuse argyrophilic grain disease with TDP-43 proteinopathy and neuronal intermediate filament inclusion disease: FTLD with mixed tau, TDP-43 and FUS pathologies.

Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins - tau, TDP-43 or FUS - forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer's disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called "cherry spots," that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer's type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases.