Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.

GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

BACKGROUND AND OBJECTIVES: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-ß-amyloid 1-42 (Aß42), phosphorylated tau 181 (p-tau181), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aß42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD ß-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Aß42 (A), p-tau181 (T), and serum NfL (N) and tested ATNPD prediction of longitudinal cognitive decline in PD. METHODS: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATNPD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected). RESULTS: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ2: p = 1). Patients with PD had overall lower CSF p-tau181 (ß = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (ß = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aß42 (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (ß = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aß42 (p = 0.18), p-tau181 (p = 1), or t-tau (p = 0.96). Using ATNPD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (ß = -73, 95% CI -110 to -37, p = 0.00077) than all other ATNPD statuses including A+ alone (A+T-N-; n = 75; 21%). DISCUSSION: In patients with early PD, CSF p-tau181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATNPD (incorporating CSF Aß42, CSF p-tau181, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

OBJECTIVE: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. METHODS: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. RESULTS: There were lower levels of tau pathology (ß = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 ß = 1.37, p < 0.001; MC1 ß = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (ß = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. INTERPRETATION: Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

Testing for Allele-specific Expression from Human Brain Samples.

Many single nucleotide polymorphisms (SNPs) identified by genome-wide association studies exert their effects on disease risk as expression quantitative trait loci (eQTL) via allele-specific expression (ASE). While databases for probing eQTLs in tissues from normal individuals exist, one may wish to ascertain eQTLs or ASE in specific tissues or disease-states not characterized in these databases. Here, we present a protocol to assess ASE of two possible target genes (GPNMB and KLHL7) of a known genome-wide association study (GWAS) Parkinson's disease (PD) risk locus in postmortem human brain tissue from PD and neurologically normal individuals. This was done using a sequence of RNA isolation, cDNA library generation, enrichment for transcripts of interest using customizable cDNA capture probes, paired-end RNA sequencing, and subsequent analysis. This method provides increased sensitivity relative to traditional bulk RNAseq-based and a blueprint that can be extended to the study of other genes, tissues, and disease states. Key features • Analysis of GPNMB allele-specific expression (ASE) in brain lysates from cognitively normal controls (NC) and Parkinson's disease (PD) individuals. • Builds on the ASE protocol of Mayba et al. (2014) and extends application from cells to human tissue. • Increased sensitivity by enrichment for desired transcript via RNA CaptureSeq (Mercer et al., 2014). • Optimized for human brain lysates from cingulate gyrus, caudate nucleus, and cerebellum.

Cognitive heterogeneity in Parkinson's disease: A mechanistic view.

Cognitive impairment occurs in most individuals with Parkinson's disease (PD), exacting a high toll on patients, their caregivers, and the healthcare system. In this review, we begin by summarizing the current clinical landscape surrounding cognition in PD. We then discuss how cognitive impairment and dementia may develop in PD based on the spread of the pathological protein alpha-synuclein (aSyn) from neurons in brainstem regions to those in the cortical regions of the brain responsible for higher cognitive functions, as first proposed in the Braak hypothesis. We appraise the Braak hypothesis from molecular (conformations of aSyn), cell biological (cell-to-cell spread of pathological aSyn), and organ-level (region-to-region spread of aSyn pathology at the whole brain level) viewpoints. Finally, we argue that individual host factors may be the most poorly understood aspect of this pathological process, accounting for substantial heterogeneity in the pattern and pace of cognitive decline in PD.

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.

Plasma phosphorylated tau181 predicts cognitive and functional decline.

OBJECTIVE: To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort. METHODS: Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform. RESULTS: Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia. INTERPRETATION: Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline.

Self- and Partner-Reported Subjective Memory Complaints: Association with Objective Cognitive Impairment and Risk of Decline.

Background: Episodic memory decline is a hallmark of Alzheimer's disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer's Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.

GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.

Many risk loci for Parkinson's disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to GPNMB through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene with potential for biomarker development and therapeutic targeting.

Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17). We find novel evidence for selective impairment of PIGD burden in LBD + AD vs LBD-AD (OR = 1.95, 95%CI = 1.02-3.70, p = 0.04) and a direct association of increasing CSF tau/Aß1-42 ratio with increasing PIGD disability in the total cohort (ß = 0.23, SE = 0.08, p = 0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD.

Genetic prediction of impulse control disorders in Parkinson's disease.

OBJECTIVE: To develop a clinico-genetic predictor of impulse control disorder (ICD) risk in Parkinson's disease (PD). METHODS: In 5770 individuals from three PD cohorts (the 23andMe, Inc.; the University of Pennsylvania [UPenn]; and the Parkinson's Progression Markers Initiative [PPMI]), we used a discovery-replication strategy to develop a clinico-genetic predictor for ICD risk. We first performed a Genomewide Association Study (GWAS) for ICDs anytime during PD in 5262 PD individuals from the 23andMe cohort. We then combined newly discovered ICD risk loci with 13 ICD risk loci previously reported in the literature to develop a model predicting ICD in a Training dataset (n = 339, from UPenn and PPMI cohorts). The model was tested in a non-overlapping Test dataset (n = 169, from UPenn and PPMI cohorts) and used to derive a continuous measure, the ICD-risk score (ICD-RS), enriching for PD individuals with ICD (ICD+ PD). RESULTS: By GWAS, we discovered four new loci associated with ICD at p-values of 4.9e-07 to 1.3e-06. Our best logistic regression model included seven clinical and two genetic variables, achieving an area under the receiver operating curve for ICD prediction of 0.75 in the Training and 0.72 in the Test dataset. The ICD-RS separated groups of PD individuals with ICD prevalence of nearly 40% (highest risk quartile) versus 7% (lowest risk quartile). INTERPRETATION: In this multi-cohort, international study, we developed an easily computed clinico-genetic tool, the ICD-RS, that substantially enriches for subgroups of PD at very high versus very low risk for ICD, enabling pharmacogenetic approaches to PD medication selection.

Plasma MIA, CRP, and Albumin Predict Cognitive Decline in Parkinson's Disease.

OBJECTIVE: Using a multi-cohort, discovery-replication-validation design, we sought new plasma biomarkers that predict which individuals with Parkinson's disease (PD) will experience cognitive decline. METHODS: In 108 discovery cohort PD individuals and 83 replication cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associated with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which patients with PD showed fast (> = 1 point drop/year on Montreal Cognitive Assessment [MoCA]) versus slow (< 1 point drop/year on MoCA) cognitive decline in the discovery cohort, testing it in the replication cohort. We developed alternate assays for the top 3 proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident mild cognitive impairment (MCI) or dementia - in a validation cohort of 118 individuals with PD. We investigated the top plasma biomarker for causal influence by Mendelian randomization (MR). RESULTS: A model with only 3 proteins (melanoma inhibitory activity protein [MIA], C-reactive protein [CRP], and albumin) separated fast versus slow cognitive decline subgroups with an area under the curve (AUC) of 0.80 in the validation cohort. The individuals with PD in the validation cohort in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA single nucleotide polymorphism (SNP) rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence. CONCLUSIONS: An easily obtained plasma-based predictor identifies individuals with PD at risk for cognitive decline. MIA may participate causally in development of cognitive decline. ANN NEUROL 2022;92:255-269.

Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease.

BACKGROUND: Neurofilament light chain protein (NfL) is a promising biomarker of neurodegeneration. OBJECTIVES: To determine whether plasma and CSF NfL (1) associate with motor or cognitive status in Parkinson's disease (PD) and (2) predict future motor or cognitive decline in PD. METHODS: Six hundred and fifteen participants with neurodegenerative diseases, including 152 PD and 200 healthy control participants, provided a plasma and/or cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the Kruskal-Wallis rank test. Within PD, cross-sectional associations between NfL and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Mattis Dementia Rating Scale (DRS-2) scores were assessed by linear regression; longitudinal analyses were performed using linear mixed-effects models and Cox regression. RESULTS: Plasma and CSF NfL levels correlated substantially (Spearman r = 0.64, P < 0.001); NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment (HR 5.34, P = 0.005). CONCLUSIONS: Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. © 2021 International Parkinson and Movement Disorder Society.

Of mice and men: What a mouse model of microglial C9ORF72 deficiency does-and does not-tell us about human neurodegenerative diseases.

Expansions in C9ORF72, which cause frontotemporal dementia and amyotrophic lateral sclerosis, result in formation of aberrant peptide and RNA species and decreased expression of the normal gene. In this issue of Neuron, Lall et al. (2021) report the consequences of microglial C9ORF72 deficiency in mouse models of aging and Alzheimer's disease.

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy.

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

L1CAM is not associated with extracellular vesicles in human cerebrospinal fluid or plasma.

L1CAM is a transmembrane protein expressed on neurons that was presumed to be found on neuron-derived extracellular vesicles (NDEVs) in human biofluids. We developed a panel of single-molecule array assays to evaluate the use of L1CAM for NDEV isolation. We demonstrate that L1CAM is not associated with extracellular vesicles in human plasma or cerebrospinal fluid and therefore recommend against its use as a marker in NDEV isolation protocols.