Citations

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Objectives Multiple system atrophy (MSA) is classified into parkinsonian (MSA‐P) and cerebellar (MSA‐C) phenotypes based on predominant motor features, with corresponding pathological classifications of striatonigral (SN) degeneration and olivopontocerebellar (OPC) atrophy; however, disease progression patterns remain poorly understood. We aimed to identify novel MSA subtypes based on neuronal loss patterns using unsupervised machine learning. Methods We applied the Subtype and Stage Inference (SuStaIn) algorithm to analyze neuronal loss patterns in 167 autopsy‐confirmed MSA. Neuronal loss was semi‐quantitatively assessed in 5 brain regions: putamen, substantia nigra, pontine nucleus, inferior olivary nucleus, and cerebellar Purkinje cells. Obtained subtypes were validated by clinicopathological information. Results Three distinct subtypes were identified: SN‐early subtype (54% [86/160]) with initial SN neuronal loss, OPC‐early subtype (28% [44/160]) with early OPC involvement, and SN‐OPC‐synchronous subtype (19% [30/160]) with concurrent early neuronal loss in both systems. These subtypes corresponded well with clinical phenotypes. The SN‐OPC‐synchronous subtype exhibited significantly shorter survival (median 6.2 years vs 6.9 and 7.4 years in SN‐early and OPC‐early subtypes; p = 0.0049), more frequent rapid progression (57% vs 24% and 41% in SN‐early and OPC‐early subtypes; p = 0.0048), and more frequent early falls (70% vs 36% and 50% in SN‐early and OPC‐early subtypes; p = 0.0039). Immunohistochemical validation confirmed extensive α‐synuclein pathology in both SN and OPC systems in the SN‐OPC‐synchronous subtype. Interpretation The SN‐OPC‐synchronous subtype provides insights into α‐synuclein propagation mechanisms, suggesting multiple initial seeding sites rather than unidirectional spread. This computational approach uncovered disease heterogeneity undetectable by conventional methods, potentially benefiting clinical trials through patient stratification. ANN NEUROL 2026;99:989–1000

Abstract Background An intense search is underway for tau PET tracers with enhanced capability to visualize tau aggregates. Research indicates that [18F] AV1451 and [18F]MK 6240 exhibit comparable binding properties in terms of spatial distribution and severity of tau aggregates, as observed both in‐vivo and in‐vitro. This study focused on head‐to‐head pathological comparison of both the tracers binding specificity to tangle maturity levels (pretangles, mature tangles and ghost tangles) of tau aggregates as seen on autoradiography as compared to CP‐13 (early tangle maturity marker) and PHF‐1(middling tangle maturity marker) immunohistochemical (IHC) stains in Alzheimer's disease (AD) and non‐AD tauopathies. Method Study participants included included those with AD and non‐AD tauopathies. Analyses were performed on serial 5um formalin fixed paraffin embedded postmortem human brain sections acquired from Mayo clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. IHC sections were incubated with antibodies CP‐13 (recognizing early tangle maturity) and PHF‐1 (recognizing middling tangle maturity). Result A total of 38 participants were examined. The participants included a spectrum from normal to AD, including mild cognitive impairment (MCI) and atypical AD. Participants with N279K (4R), P301L (4R), and R406W MAPT mutations (3R+4R) were included as well. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non‐AD tauopathies. Generally, early tangle maturity tau accumulation participants had more tau demonstrated with CP‐13 than PHF‐1 and both the tracers [18F]MK 6240 and [18F]AV 1451 binding are well correlated with the PHF‐1 staining suggesting the preference for middling tangle level and minimal to early tangles. Conclusion The emergence and validation of these new tau PET tracers have opened new opportunities for the development of more accurate diagnostic and management tools for AD. In our study on post‐mortem sections, [ 18 F]MK‐6240 and [ 18 F]Flortaucipir showed similar binding profiles with preference to middling tangle maturity levels.

Abstract Background Colony stimulating factor 1 receptor–related disorder (CSF1R‐RD) is a rare, rapidly progressive neurodegenerative disease with significant clinical heterogeneity. Apolipoprotein E (ApoE) polymorphism, known to modulate microglial function and influence neurodegeneration, may act as a genetic modifier in CSF1R‐RD. Objectives The objectives were to evaluate the distribution of ApoE alleles in CSF1R‐RD and assess their association with clinical and neuropathological features. Methods ApoE genotyping was performed in 55 individuals with CSF1R‐RD. Clinical data from 25 deceased patients were analyzed based on ApoE genotype. Neuropathological evaluation was conducted on brain tissue from 14 patients, with semiquantitative scoring of white matter pathology and microglial burden. Statistical comparisons were made between carriers and noncarriers of the ApoE4 allele. Results ApoE allele frequencies in CSF1R‐RD mirrored those of the general population (ε2: 7.3%, ε3: 79.1%, ε4: 13.6%). However, ApoE4 carriers exhibited significantly earlier symptom onset (median: 37.9 vs. 50.3 years, p = 0.0123) and death (median: 41.1 vs. 55.2 years, p = 0.0072). Neuropathological analysis revealed more severe white matter involvement and reduced microglial preservation in ApoE4 carriers ( p = 0.034). Conclusions Although ApoE allele distribution does not differ from the general population, the presence of the ApoE4 allele may influence the clinical trajectory and white matter pathology in CSF1R‐RD. These findings suggest that ApoE polymorphism is a potential modifier of disease course and should be considered in therapeutic planning and future research. © 2026 International Parkinson and Movement Disorder Society.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Background Immunohistochemically detected phosphorylated α‐synuclein (p‐α‐syn) in cutaneous nerves has been found in >95% of patients meeting consensus criteria for dementia with Lewy bodies (DLB); however, its performance in prodromal stages (mild cognitive impairment‐Lewy body [MCI‐LB]) and clinical practice is unknown. Objective We evaluated skin biopsy for p‐α‐syn in a convenience cohort of patients with suspected MCI‐LB or DLB in a tertiary care setting. Methods 53 patients underwent commercially available skin biopsy for skin nerve p‐α‐syn as part of a clinical evaluation for suspected MCI‐LB/DLB. Consensus MCI‐LB/DLB criteria blinded to skin biopsy result were applied through retrospective chart review; those not definitively meeting criteria were considered questionable synucleinopathy (QS). Results Median age at skin biopsy was 70 years (range, 43–87 years) with 81% men. 36 patients (68%) had positive skin biopsies. 32/43 (74%) patients meeting clinical consensus criteria for DLB/MCI‐LB had a positive skin biopsy, with higher frequency in MCI‐LB (87%) compared with DLB (60%). 4/10 (40%) QS had positive biopsies. One patient with a positive skin biopsy had no evidence of central nervous system (CNS) α‐syn on autopsy. Conclusions Positive skin biopsy for p‐α‐syn occurs across the spectrum of cognitive presentations of Lewy body disease including prodromal DLB, albeit at a lower frequency in this retrospective review of atypical cases compared with typical clinical presentations. A positive skin biopsy may not reflect CNS synucleinopathy as the etiology for a patient's symptoms in some cases. Longitudinal studies of skin biopsies for p‐α‐syn in suspected MCI‐LB/DLB with autopsy confirmation are needed. © 2025 International Parkinson and Movement Disorder Society.

Abstract Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.

Abstract Background Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder with rapid progression to death. Multiple efforts to develop a disease‐modifying therapy for PSP have yet to succeed. We previously reported the discovery of three potential therapeutic targets for PSP. These three genes, DDR2, KANK2, and STOM, are consistently upregulated in the brains of PSP patients and mouse models of tauopathy. Reducing their expression in a drosophila model significantly rescued the tau‐induced eye degeneration and tau seeding activity. To translate these targets into the clinic, we are developing antisense oligonucleotides (ASO) as potential therapies. Method We screened candidate ASOs in neuroglioma cell line H4. ASO hits were validated for their potency and safety. We also used iPSC‐derived neurons from PSP patients to test the potency and potential toxicity of our ASOs. To investigate target engagement, therapeutic efficacy and preliminary pharmacodynamic properties, we treated iPSC‐derived midbrain organoids with the ASO leads. Lastly, we will assess the off‐target effects of the ASOs by investigating the levels of mRNA transcripts that share similar sequences as our targets using RNAseq. Result Our in vitro screening identified ASO leads that significantly reduce the target gene expressions at mRNA and protein levels in a dose‐dependent manner. The ASO hits also exhibit low cellular toxicity in the H4 cell line. Upon treating iPSC neurons with ASO hits, we were able to validate the dose‐dependent reduction of target mRNAs. Cell viability analysis indicated low toxicity, suggesting that these ASOs are potent and safe. In midbrain organoid model, DDR2‐targeting ASO showed time‐dependent target engagement and were prioritized for further development. Conclusion We developed candidate therapeutics for PSP using ASOs that silence novel therapeutic targets discovered in our systems based cross‐species screening. We showed that our ASOs have low toxicity and confirmed target engagement at both mRNA and protein levels in vitro. The results suggest a favorable preclinical profile of our ASO leads that warrants additional investigations. Importantly, PSP shares congruent pathophysiological changes with other tauopathies, such as Alzheimer’s disease. These common perturbed pathways indicate that our ASOs can be potentially repurposed for multiple neurodegenerative tauopathies.

Abstract Background Brain cells secrete extracellular vesicles (EVs) containing signaling and pathological proteins related to Alzheimer's disease (AD) and related disorders. Recent studies demonstrate brain‐derived EVs (BDEVs) contain misfolded tau and are transmissible of tau pathology in the brain. However, the underlying mechanism regarding EV‐mediated tau pathology is still largely uncharacterized. Method We conducted the immuno‐affinity purification of tau in human brain‐derived EVs (BDEVs) isolated from age and sex‐matched 14 AD and 14 CTRL cases and performed tandem mass‐tag mass spectrometry to profile unbiased tau interactome in BDEVs. We used Nanotemper Monolith to validate the interaction of EV‐tau interactors with tau, and super‐resolution microscopy (Nanoimager) to detect their colocalization in a single‐EV level. We next designed siRNAs to silence EV‐tau interactors in SH‐SY5Y cells overexpressing human P301L tau (SH‐SY5Y‐P301Ltau) and assessed tau loading to EVs by Flow Nanoanalyzer. These EVs were tested for their uptake and tau seeding by human iPSC‐derived neurons (iNeurons). We finally tested the inhibitors of identified molecules on BDEV‐mediated tau propagation in vivo . Result A total of 764 proteins were identified in BDEV‐associated tau interactome from CTRL and AD patients. Sixty‐five proteins were significantly downregulated in AD BDEVs; whereas 5 proteins were significantly upregulated in AD BDEVs compared to CTRL BDEVs. The most enriched tau‐interacting proteins were significantly positively correlated with Braak stage. We confirmed the direct binding of candidate proteins to tau with micromolar binding affinities by Monolith, and their colocalization with tau in human BDEVs using Nanoimager. Silencing of candidate molecules in human SH‐SY5Y‐P301Ltau cells showed reduced loading of tau in EVs, their reduced uptake by iNeurons, and tau seeding activities. Finally, intracerebroventricular injection of neutralizing antibody against the most promising target results in reduction of tau pathology in PS19 mice expressing P301S human tau mutant. Conclusion Our study identified tau‐interacting molecules highly enriched in AD BDEVs compared to CTRL BDVs. Silencing of candidate molecule reduced tau loading to the EVs and their uptake by iNeurons and neutralizing antibody suppressed tau dissemination, highlighting them as promising therapeutic targets to halt tau pathology in AD and related tauopathy.