Neurology Genetics

INTRODUCTIONThe amyloid cascade hypothesis predicts that amyloid-beta (A{beta}) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A{beta}40 and A{beta}42 and total Tau (t-Tau) plasma biomarkers. METHODSPlasma A{beta}40, A{beta}42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between A{beta}s and t-Tau. RESULTSNo clear evidence that A{beta}40 or A{beta}42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the A{beta} biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSIONPlasma A{beta}40 or A{beta}42 do not appear to have a direct causal impact on t-Tau. In contrast, A{beta} aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

BackgroundParkinsons disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors. We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. MethodsWe performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. ResultsUsing exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. ConclusionsIntegrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

BackgroundLarge-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinsons disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser. MethodsWe performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimers Disease Sequencing Project. Clinical exome sequencing (CES) data from GP2 Release 8 was also included. ResultsThe integrated dataset includes 31,665 WGS and 9,559 CES samples, spanning eleven ancestries and over 300 million variants. ConclusionThe GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org, enabling broad access to PD genomic data and supporting global research efforts.

Background: PD GENEration (NCT04057794, NCT04994015), sponsored by the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson's disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson's community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson's disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration's implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.

The identification of Parkinsons Disease (PD) from post-mortem brain slices is time consuming for highly trained neuropathologists, often taking many hours per case. In this study, we demonstrate fully automatic PD detection, from single 1000um regions, from sections spanning from the dorsal motor nucleus of the vagus nerve to the frontal cortex. This is achieved via image processing and statistical methods, with improved accuracy demonstrated when using machine learning. Digitised stained brain sections were processed via a deep neural network to produce re-coloured, or synthetically stained, images which were then filtered and passed to a secondary network for classification. We demonstrate state-of-the-art PD detection (>90% accuracy on single 1000um regions), with the ability to perform binary classification on high resolution sections within minutes, in addition to demarcating regions of interest to the pathologist for manual visual verification. Executive SummaryThe identification of Parkinsons Disease (PD) from post-mortem brain slices is time consuming for highly trained neuropathologists, often taking many hours per case. Accurate classification and stratification of PD is critical for the confirmation that the brain donor suffered from PD and to maximise the potential usefulness of the brain in research studies to better understand the causes of PD and foster drug development. Parkinsons UK Brain Bank, at Imperial College London, has produced a dataset containing digitised images of brain sections immunostained for the protein alpha-synuclein (-syn), the pathological marker of PD; along with control cases from healthy donors. This dataset is much larger (over 400 cases), more consistent, and of higher quality (all have been stained with the same protocol and imaged within the same laboratory) than has been documented elsewhere in the literature; including those found in a meta-analysis study on detection of neurological disorders containing over 200 papers (Lima et al., 2022). The project team, consisting of neuroscientists and subject matter experts from: Imperial, NHS AI Lab Skunkworks, Parkinsons UK, and Polygeist have undertaken a 12 week project to examine the possibility of producing a Proof-of-Concept (PoC) tool to automatically load, enhance and ultimately classify those brain sections containing -syn. The initial focus of the project was to make a tool that could make a biomarker of PD, -syn, more visible to the pathologist; saving time in searching for the protein manually. This goal was quickly reached, producing a tool that could synthetically stain the -syn, marking regions of interest in a high-contrast bright green, making them quickly identifiable for the pathologist. Statistical analysis of the synthetically stained images showed that very few regions in the control group were stained compared to the PD group, raising the possibility that an automatic classifier could be developed, which became a stretch goal for the project. A bespoke neural network model was designed that processed the synthetically stained segments of each immunostained section and produced a binary judgement (whether a segment contains PD pathology or not). The model achieved >90% sensitivity for PD detection, much higher than is reported for neuropathologists (~60% sensitivity when searching for -syn patches across all stages, Signaevsky et al., 2022). While expert raters are still more precise (~6% better than the model), the model performed ~20% better than expert raters when considering precision and recall. The key output of the project is an open-source PoC tool that can automatically classify PD from digitised images of brain sections with accuracy that is approaching viability for real world applications. An MIT Licensed code repository has been released, containing all of the model development code, along with associated documentation, to allow others to build on the project teams work. This report summarises the scientific and engineering process undertaken through the development of the PoC tool.

BackgroundKnown pathogenic variants in Parkinsons disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale. ObjectivesThis study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries. MethodWe analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinsons Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality. ResultsGenes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified "good" (n=12), "medium" (n=4), and "bad" (n=9) variants. ConclusionOur results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.

BackgroundHuntington disease (HD) is a neurological disorder caused by an aberrant CAG expansion in the HTT gene, producing a mutant protein (mHTT). Although HD is classically characterized by adult-onset cortical and striatal degeneration, accumulating evidence suggests that altered cortical development may also contribute to disease pathogenesis. ObjectiveWe sought to investigate the impact of mHTT on neocortical patterning, which is a largely unexplored aspect of HD. MethodsUsing the HdhQ140 HD knock-in mouse model, we performed immunofluorescence and in situ hybridization to analyze the patterning of the cortex from embryonic day 10 to postnatal day 7. ResultsDuring embryogenesis, HTT expression exhibited a high medial-to-low lateral gradient in the neocortex, like that observed for key transcription factors involved in cortical patterning. Notably, HTT expression was absent from the cortical hem, a critical patterning center. In HD, the protein gradient remained unchanged whereas the expression in medial pallium seemed increased. During the early development of the cerebral hemispheres, the expression of morphogens and signaling pathways, including Shh, Fgf8, and Wnt/BMP genes, were disrupted in organizing centers, leading to altered expression of major neocortical transcription factors. At postnatal stages, the motor and somatosensory cortical areas were misplaced. These developmental alterations were associated with postnatal sensorimotor deficits relevant to HD. ConclusionsOur findings demonstrate that HD-related neurodevelopmental alterations arise as early as embryonic day 10 in mice. This supports previous work suggesting that defects in brain development contribute to HD pathogenesis prior to clinical onset.

BackgroundChitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimers disease (AD). Few studies have examined the spatial expression of chitinase expressing cells with respect to neuropathologic hallmarks of disease. MethodsRNA-sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterize the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD, and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP pathology. ResultsChit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of sALS and C9-ALS patients when compared to controls. Highest levels of Chit-1+ glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1+ glia were only significantly increased in sALS. Neither Chit-1+ nor CHI3L1+ glia were in close proximity to pTDP containing neurons in the motor cortex gray matter; however, there was a significant co-localization of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter. ConclusionsChit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter also contained phosphorylated TDP-43. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSPrior studies identified elevated levels of Chit-1 and CHI3L1 proteins in the CSF of various neurodegenerative conditions, though few studies examined levels of Chit-1 and CHI3L1 expressing cells both spatially and in relation to disease pathology. What this study addsWe performed an extensive spatial characterization of Chit-1 and CHI3L1 protein levels across multiple regions and neurodegenerative conditions. This study also correlates Chit-1 and CHI3L1 expression to TDP pathology and other clinical parameters of disease duration. How this study might affect research, practice or policyOur findings indicate that the majority of Chit-1 and CHI3L1 expressing glia are located in the cortical subpial layer and the white matter, suggesting a role for chitinases in modulating neuroinflammatory mechanisms or reparative/regenerative responses in the white matter of ALS and other neurodegenerative diseases. This study suggests new therapeutic opportunities for targeting chitinase expressing cells in neurodegenerative diseases.

Although adult Huntingtons disease (HD) studies have significantly advanced our understanding of the course of degeneration, they may underrepresent critical neurodevelopmental aspects of the disease. Significant gaps remain in understanding how mutant huntingtin affects early neurodevelopment, its long-term impact, as well as potential implications for treatment outcomes. The Childhood to Adult Neurodevelopment in Gene-Expanded Huntingtons Disease (ChANGE-HD; NCT01951588) study aims to evaluate brain structure and function in premanifest, at-risk children and young adults, and explore HDs developmental origins. Here, we introduce the ChANGE-HD study protocol, which will investigate and integrate the neurodevelopmental and neurodegenerative aspects of HD. The ChANGE-HD study is a prospective, multi-site observational trial with an accelerated longitudinal design. Four hundred participants aged 6-30 years who are at risk for HD will be recruited and asked to return for multiple visits (if possible). At each visit, cognitive, motor, behavioral, blood, and MRI data are collected. ChANGE-HD represents the first prospective multi-site study to systematically document brain structure and function during the premanifest phase of HD in children and young adults. Data collection is ongoing with first results anticipated in 2026-2027. The ChANGE-HD approach is likely to provide novel pathophysiological insights and guide the development of therapeutic strategies tailored to both the developmental and degenerative phases of the disease.

Background/AimsThe Parkinson Progression Markers Initiative (PPMI) is an international, longitudinal, observational study that acquires comprehensive clinical, imaging and genetic data, as well as cerebral spinal fluid (CSF) and blood biological samples from individuals in all stages of Parkinsons disease (PD) to develop biomarkers that accelerate therapeutic development. The effort to enroll a large population of prodromal individuals (participants with PD biomarkers and/or early symptoms) presents an opportunity to share insights for overcoming specific challenges unique to enrollment prior to the onset of typical symptoms. MethodsPaid and earned media, referral cohorts, and individual and community ambassadors were leveraged as recruitment strategies to attract and enroll a broad study population. The success of each strategy was measured as conversion to (i) informed consent, (ii) smell test completion, and (iii) identification of hyposmic individuals. Participants completed an eConsent and questionnaire online, followed by remote smell test screening for Parkinsons risk. Participants with hyposmia were invited to complete dopamine transporter (DAT) imaging. Those who continued to meet eligibility criteria were invited to enroll in the PPMI clinical study, for comprehensive longitudinal follow-up. ResultsOver 1.2 million visits to the smell test website were recorded and 79,837 participants consented to remote hyposmia screening. A smell test was sent to 57,754 participants and completed by 38,419; 6,649 were identified to be hyposmic (as defined by PPMI study cutoffs). DAT imaging was completed by 1,720, with 1,120 identified as eligible for longitudinal follow-up. The greatest number of participants who consented to smell testing came from paid media and social media ads, referral networks (commercial and study partners), and the MJFF community. Overall, 14.4% of participants who completed smell testing were confirmed to be hyposmic. The highest rates of conversion from completed UPSIT to confirmed case of hyposmia occurred with promoted online search results, earned press coverage, and radio ads. ConclusionPPMI provides a useful example of overcoming challenges to enrollment of participants with biomarkers and/or early symptoms (but without typical symptoms) of disease. Important lessons from these data for this study team, and other researchers alike, are to be agile in recruitment strategies, to utilize effective participant engagement approaches, and to prioritize centralized study teams/resources to offload site burden and streamline participant experience.

BackgroundReliable detection and accurate genotyping of structural variants (SVs) and insertion/deletions (indels) from whole-genome sequence (WGS) data is a significant challenge. We present a protocol for variant calling, quality control, call merging, sensitivity analysis, in silico genotyping, and laboratory validation protocols for generating a high-quality deletion call set from whole genome sequences as part of the Alzheimers Disease Sequencing Project (ADSP). This dataset contains 578 individuals from 111 families. MethodsWe applied two complementary pipelines (Scalpel and Parliament) for SV/indel calling, break-point refinement, genotyping, and local reassembly to produce a high-quality annotated call set. Sensitivity was measured in sample replicates (N=9) for all callers using in silico variant spike-in for a wide range of event sizes. We focused on deletions because these events were more reliably called. To evaluate caller specificity, we developed a novel metric called the D-score that leverages deletion sharing frequencies within and outside of families to rank recurring deletions. Assessment of overall quality across size bins was measured with the kinship coefficient. Individual callers were evaluated for computational cost, performance, sensitivity, and specificity. Quality of calls were evaluated by Sanger sequencing of predicted loss-of-function (LOF) variants, variants near AD candidate genes, and randomly selected genome-wide deletions ranging from 2 to 17,000 bp. ResultsWe generated a high-quality deletion call set across a wide range of event sizes consisting of 152,301 deletions with an average of 263 per genome. A total of 114 of 146 predicted deletions (78.1%) were validated by Sanger sequencing. Scalpel was more accurate in calling deletions [≤]100 bp, whereas for Parliament, sensitivity was improved for deletions > 900 bp. We validated 83.0% (88/106) and 72.5% (37/51) of calls made by Scalpel and Parliament, respectively. Eleven deletions called by both Parliament and Scalpel in the 101-900 bin were tested and all were confirmed by Sanger sequencing. ConclusionsWe developed a flexible protocol to assess the quality of deletion detection across a wide range of sizes. We also generated a truth set of Sanger sequencing validated deletions with precise breakpoints covering a wide spectrum of sizes between 1 and 17,000 bp.

CLN3 disease is an inherited neurodegenerative disease, typically with childhood onset, and characterized by vision loss, seizures, cognitive decline, and difficulties. The CLN3 Staging System (CLN3SS) characterizes disease progression. Our aim was to assess differences in cognitive test scores in relation to CLN3SS among individuals with CLN3 disease. We evaluated the relationship between cognitive test performance and the CLN3SS in individuals with genetically confirmed CLN3 disease. Participants completed tasks of verbal reasoning, vocabulary knowledge, attention, fund of information, and ability to recite the alphabet. One-way ANOVA testing assessed differences in mean cognitive test score among CLN3SS score groups, and Chi-square testing was used to compare the proportion in each CLN3SS group that could recite the alphabet. Data were evaluated from a sample of 85 individuals with a total 245 CLN3SS assessments conducted within 6 months of their cognitive testing, A significant decrease in test scores was found between CLN3SS Stages 1 (vision loss present) and 2 (vision loss and seizures present) for each of the cognitive tests. The proportion of participants able to recite the alphabet also decreased from Stage 1 to Stage 2 (X2=12.1, p<.01). Cognitive ability declines with advanced disease severity in CLN3 disease, though motor disability in Stage 3 likely contributes to difficulty participating in cognitive assessment at this later disease stage. Understanding the relationship between cognition and CLN3 disease stage may help guide decision making, i.e., determining who could or should undergo cognitive assessment for clinical care or for group stratification in disease modifying clinical trials.

BackgroundMen with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. MethodsThis study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. ResultsLongitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. ConclusionsThese findings suggest that executive function changes represent a prodrome of the later movement disorder.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimers disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

BackgroundHeterozygous variants in the GBA1 gene cause Parkinsons disease (PD) with variable penetrance and have been classified into severe, mild, and PD-specific risk variants based on their association with Gauchers disease (GD; mild and severe) or PD (risk variants). Polygenic risk scores (PRS) further modify PD susceptibility and may influence the age of onset in GBA1 variant carriers. Our study investigates the interaction between a genome wide PRS and pathogenic GBA1 variants (GBA1PVs), focusing on how established combined PD risk polymorphisms may influence GBA1-related PD risk across different levels of GBA1-mediated pathogenicity. MethodsGBA1 variants were identified from whole exome sequencing data in the UK Biobank (UKB) cohort and from GBA1-targeted PacBio sequencing in the Luxembourg Parkinsons Study (LuxPark). PRSs were calculated for all participants using established genome-wide significant SNPs, excluding variants within the GBA1 locus, and then categorized based on both PRS levels and GBA1PVs carrier status. Carriers of GBA1PVs were further divided into severe (Gaucher-related) +mild (PD-related) and risk groups. To evaluate the relationship between PRS, GBA1PVs carrier status or severity, and PD risk, logistic regression and Cox proportional hazards regression were conducted with disease presence as the dependent variable. ResultsWe identified GBA1PVs in 8.8% of PD patients in the UKB discovery cohort and 9.9% in the LuxPark replication cohort. GBA1PVs carriers had consistently higher PD risk compared to non-carriers across all PRS categories. In UKB, GBA1PVs carriers in the highest PRS category had a 2.3-fold increased risk of PD (OR: 2.34; 95% CI, 2.08-2.63) and cumulative incidence of 67% by the age of 75, while those in LuxPark had a 1.6-fold higher risk (OR: 1.64; 95% CI, 1.52-1.76), and cumulative incidence of 81% at the age of 75. Carriers of "severe+mild" GBA1 variants had nearly double the risk of PD compared to "risk" variant carriers, with ORs ranging from 2.05 to 3.69 in UKB and 1.73 to 1.98 in LuxPark. The interaction between the PRSs and GBA1PVs severity was similar in the two cohorts. ConclusionsOur findings demonstrate that GBA1PVs carrier status and severity significantly impact PD risk, with severe variants conferring higher risk than risk ones. Additionally, PRS consistently increases both PD risk and GBA1PVs penetrance in an additive manner across all variant types, defining a genetic background that influences PD penetrance in GBA1PVs carriers. The presence of additional PD-associated risk variants in GBA1 carriers defines new avenues to incorporate PRS and genetic risk data into future clinical trial design and genetic counselling in GBA1-associated PD.

BackgroundBarth syndrome is an inherited disorder that results from pathogenic mutations in TAZ, the gene responsible for encoding tafazzin, an enzyme that remodels the mitochondrial phospholipid cardiolipin. Barth syndrome is characterized by heart and skeletal muscle myopathy, growth delay, and neutropenia among other features. The TAZPOWER clinical trial investigated the effects of the mitochondria-targeting peptide elamipretide in patients with Barth syndrome. Methods and findingsTAZPOWER included a randomized, double-blind, crossover study of 12 weeks treatment with elamipretide or placebo in 12 patients with Barth syndrome. A broad spectrum of plasma and urine metabolites were measured using liquid chromatography-tandem mass spectrometry at baseline and after 12 weeks treatment with elamipretide or placebo. Of 51 "energy-linked" metabolites analyzed, we highlight here the effects of elamipretide on the plasma and urinary concentrations of several metabolites previously observed to be abnormal in patients with Barth syndrome. Elamipretide treatment was associated with significantly lowered medium- and short-chain acylcarnitines in plasma and urine, respectively (p < 0.05). Acetylcarnitine, 3-hydroxybutyrate, and 3-methylglutaconate trended to decrease after 12 weeks of elamipretide, but these trends did not reach statistical significance. After 12 weeks of treatment, elamipretide had no discernible effect on four amino acids previously characterized as having abnormal concentrations in patients with Barth syndrome. Lastly, elamipretide caused a significant rise in plasma taurine concentrations, an amino acid which has been observed to be decreased in patients with Barth syndrome. ConclusionsAs evidenced by reduced plasma and urinary content of acylcarnitines and trends for lowered ketone body 3-hydroxybutyrate, fat metabolism in Barth syndrome appears to be modified after 12 weeks of elamipretide treatment. Overall, these data are consistent with the improved mitochondrial function that may precede functional benefits with a longer duration of therapy with elamipretide in patients with Barth syndrome. Trial registrationClinicalTrials.gov NCT03098797. Summary pointsO_LIExploratory targeted metabolomic analyses of plasma and urine were performed after a double-blind, crossover trial in patients with Barth syndrome receiving elamipretide or placebo for 12 weeks. C_LIO_LIAmong 51 "energy-linked" metabolites analyzed in both plasma and urine, prominent changes were observed in metabolites associated with fat metabolism. C_LIO_LICollectively, plasma medium-chain (C6-C12) acylcarnitines were reduced after 12 weeks of elamipretide treatment in patients with Barth syndrome. C_LIO_LIUrinary acylcarnitine concentrations were also lowered with elamipretide in Barth syndrome patients, most prominently for shorter chain acylcarnitines. C_LIO_LIElamipretide for 12 weeks also trended to lower 3-methylglutaconate and the ketone body 3-hydroxybutyrate, although these decreases did not reach statistical significance. C_LIO_LIElamipretide also caused a significant rise in plasma taurine, which has been previously reported to be low in Barth syndrome patients. C_LIO_LIThese metabolite changes may be consistent with improved mitochondrial function that precedes the functional benefits observed in patients with Barth syndrome after longer-term therapy. C_LI

Parkinsons disease (PD) is a complex neurodegenerative disorder with environmental and genetic influences. Using genotyping array data of 661 South African PD cases and 737 controls, a polygenic risk score (PRS) analysis was conducted using PRSice-2. Summary statistics were used from two PD association studies as base datasets. The target dataset was split into training (70%; n=979) and validation (30%; n=419) cohorts. Various clumping window sizes, linkage disequilibrium thresholds, and p-value thresholds were tested to determine the optimal combination for risk prediction. Additionally, we investigated the variance explained by different combinations of covariates. Finally, top contributing variants were identified and cross-referenced with inferred local ancestry to assess ancestry-specific effects. Overall, modest predictive performance was observed (AUC: 0.6307-0.6311). Age at recruitment was the strongest individual predictor, while sex contributed the least. Local ancestry analysis indicated that the top contributing variants were not ancestry-specific risk variants. These findings provide the first evaluation of PRS performance for PD in a highly admixed South African cohort, underscoring the importance of including underrepresented populations in genetic risk prediction.

ImportanceThis study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimers disease (AD) and determines their relationship with disease status. ObjectiveA case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design, setting and participantsEyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measureRetinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. ResultsIncreased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR209-tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR209-tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and RelevanceThis study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.

BackgroundDNAJC13 was initially linked to autosomal dominant (AD) Parkinsons disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13s role in the disease. ObjectivesExplore the association between common and rare variants in DNAJC13 and Parkinsons disease. MethodsWe leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Disease (AMP-PD) and the diverse ancestry available through the Global Parkinsons Genetics Program (GP2), consisting of 2,471 patients and 3,098 controls, and 44,186 patients and 27,066 controls, respectively, to perform burden tests and association tests for rare and common variants, respectively. ResultsBurden analysis showed no association between rare variants in DNAJC13 and PD. However, association analysis within common non-synonymous variants nominated 5 variants within DNAJC13. Nevertheless, these associations require further validation since the analyses are still underpowered. DiscussionOur analysis did not find further evidence supporting DNAJC13 involvement in PD. However, studies of even larger cohorts and AD-PD families may bring definite answers about DNAJC13s role in PD.

INTRODUCTIONWidespread language complaints in the cognitively unimpaired (CU) may reflect Alzheimers Disease (AD) pathology and future objective impairments. METHODS138 CU, 45 mild cognitive impairment and 28 dementia participants from the TRIAD cohort underwent 18F-MK-6240 tau-PET and 18F-AZD-4694 amyloid-PET. Word-finding complaints, confrontation naming, semantic and phonemic fluency and word-knowledge were evaluated. Covariance, direct and stepwise discriminant, and voxel-wise regression analyses were conducted. RESULTSWord-finding complaints appeared in early tau stages (Braak 1-2), followed by naming difficulties (Braak 3-4), and widespread language impairments in later stages (Braak 5-6). Complaints over forgetting the names of objects, naming, and APOE significantly improved classification of early AD pathology. In CU, complaints over forgetting names of objects were linked to left fusiform and inferior temporal gyri tau accumulation. DISCUSSIONLanguage measures are useful in detecting and tracking AD-related pathophysiologies. Results encourage refinement of clinical tools for early detection and disease monitoring. HighlightsLanguage decline parallels tau buildup across PET-based Braak stages of AD. Subjective anomia marks earliest tau-related language symptom (Braak 1-2). Objective naming deficits emerge in the middle tau spread stages (Braak 3-4). Advanced tau spread reflects significant and widespread language impairments. Word-finding complaints correlate with left fusiform and inferior temporal tau. Research in contextSystematic review: The literature was reviewed using traditional sources. The core biological definition of Alzheimers disease (AD) has recently been linked to its defining cognitive clinical features of episodic memory impairments. Widespread subjective language complaints amongst cognitively unimpaired (CU) older adults and objective language impairments observed across the AD continuum suggests these measures and the further bridging of biological and clinical definitions of AD could play a critical, cost-effective role in disease detection and monitoring. Interpretation: Results extend to tau previous findings describing language changes in AD and related to amyloid status and grey-matter atrophy. They also establish the likely staging of language impairments across the biological AD continuum. Future directions: The manuscript contextualises the use of subjective word-finding complaints, alongside genetic risks to significantly enhance the prediction of underlying AD related pathology in CU. Languages measures used in clinical practice remain limited however and better test should be utilized and developed.