BACKGROUND:XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK. OBJECTIVE:The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. METHODS:We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls. RESULTS:In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N-acyl phosphatidylethanolamine was increased in the DLPFC. N-Acyl serine was reduced in all three regions. CONCLUSIONS:Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.

Neuropathologic features diagnostic of parkinsonian disorders infrequently occur in isolation; hyperphosphorylated tau (p-tau) and amyloid plaques are often observed in combination with α-synuclein deposition. Co-pathologies in neurodegenerative diseases are now recognized as the norm rather than an exception, but existing neuropathological assessment tools do not capture the complexity of concurrent co-pathologies. Characterization of this co-pathology is critical, as it has the potential to identify synergistic mechanisms. We developed a hierarchical cytoarchitectural classification system, which we applied to an autopsy series of military veterans with parkinsonism (n = 26), focusing on Lewy and neurofibrillary pathologies. We defined co-pathology as Type A (co-morbid), Type B (co-regional), Type C (co-cellular), or Type D (co-aggregate). The regional distributions of each co-pathology subtype were assessed using double-label immunohistochemistry in the frontal cortex, hippocampal formation, and midbrain. The frontal cortex demonstrated only subtypes A-C (no co-aggregates), whereas the midbrain and hippocampus showed all subtypes of copathology (A-D). In summary, we show marked differences in the prevalence and levels of mixed α-synuclein and tau pathology in this cohort. Our classification system has the potential to be applied broadly for the study of co-pathology in neurodegenerative disorders.

VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.

Foundation models have transformed computational pathology by providing generalizable representations from large-scale histology datasets. However, existing models are predominantly trained on surgical pathology data, which is enriched for non-nervous tissue and overrepresents neoplastic, inflammatory, metabolic, and other non-neurological diseases. Neuropathology represents a markedly different domain of histopathology, characterized by unique cell types (neurons, glia, etc.), distinct cytoarchitecture, and disease-specific pathological features including neurofibrillary tangles, amyloid plaques, Lewy bodies, and pattern-specific neurodegeneration. This domain mismatch may limit the ability of general-purpose foundation models to capture the morphological patterns critical for interpreting neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and cerebellar ataxias. To address this gap, we developed NeuroFM, a foundation model trained specifically on whole-slide images of brain tissue spanning diverse neurodegenerative pathologies. NeuroFM demonstrates superior performance compared to general-purpose models across multiple neuropathology-specific downstream tasks, including mixed dementia disease classification, hippocampal region segmentation, and neurodegenerative ataxia identification encompassing cerebellar essential tremor and spinocerebellar ataxia subtypes. This work establishes that domain-specialized foundation models trained on brain tissue can better capture neuropathology-specific features than models trained on general surgical pathology datasets. By tailoring foundation models to the unique morphological landscape of neurodegenerative diseases, NeuroFM enables more accurate and reliable AI-based analysis for brain disease diagnosis and research, setting a precedent for domain-specific model development in specialized areas of digital pathology.

The accumulation of abnormal tau protein in neurons and glia in the human brain is the defining feature of neurodegenerative diseases known as tauopathies. Progressive supranuclear palsy (PSP), the most common primary tauopathy, is typified by selective vulnerability of dopaminergic neurons and glia in the midbrain leading to an atypical parkinsonian movement disorder. To investigate candidate disease mechanisms underlying PSP, there is a critical need for model systems that more accurately recapitulate the cellular and molecular environment in the human brain. Human induced pluripotent stem cell (hiPSC)-derived organoid models have emerged as a powerful tool to address this gap. Skin biopsies were collected from living clinically diagnosed PSP patients or during autopsy. Fibroblasts were cultured and reprogrammed into hiPSCs using Sendai virus. HiPSCs were maintained with StemCultures FGF2 Discs to improve pluripotency and FACS was performed to confirm pluripotency marker expression. To generate midbrain organoids, hiPSCs were seeded into suspension spinner flasks, patterned using pharmacological directed differentiation, and grown for four months. Reliable patterning was confirmed with qRT-PCR, immunohistochemistry and immunoblot using a panel of cell-type specific markers. Astrocytes were extracted from mature organoids, cultured, and screened for astrocyte-specific markers. Fibroblasts have been banked from twenty-two PSP patients and seven reprogrammed into hiPSCs. Sporadic case status was determined by Sanger sequencing confirming the absence of a MAPT mutation. We found that hiPSCs grown with controlled-release FGF2 discs were 90-100% positive for pluripotency markers and negative for off-target genes. During patterning, organoids displayed morphological and cytoarchitectural patterns consistent with developing neuroectoderm and midbrain. Midbrain neural progenitor and dopaminergic markers such as FOXA2 , LMX1A , and TH were positive in a time-dependent manner, with mature dopaminergic neurons expressing NURR1 and GIRK2 detected by day 30. GFAP-positive astrocytes appeared around day 100. Astrocytes extracted from mature organoids were positive for multiple astrocyte markers. Sporadic PSP patient hiPSCs reliably differentiate into midbrain dopaminergic organoids and astrocytes, resulting in a sporadic tauopathy model containing key cell types affected in PSP. This cell collection is a valuable resource to investigate candidate mechanisms underlying tauopathy and could provide insight into cell-type specific disease drivers.

Progressive supranuclear palsy (PSP) is the most common primary tauopathy, with a constellation of pathological features including 4R-tau positive neurofibrillary tangles and tufted astrocytes. Most PSP cases are sporadic and associated with common structural variation in the 17q21.31 MAPT locus as well as other loci, including EIF2AK3 which is critical for the integrated stress response (ISR). Despite these known genetic risk associations, mechanisms underlying disease pathogenesis are unclear. To investigate candidate mechanisms, there is a critical need for model systems that better recapitulate the cellular complexity of the human brain. Induced pluripotent stem cell (iPSC) patient-derived organoid models are a powerful tool to study molecular and cellular changes in a disease-relevant genomic context. Single-nucleus RNA sequencing (snRNA-seq) was performed in the subthalamic nucleus region from autopsy PSP and control brains. Transcriptional differences were validated by immunohistochemistry (IHC) using antibodies for ISR activation markers and phosphorylated tau (p-tau). Fibroblasts grown from sporadic PSP patient skin were reprogrammed into iPSCs, and midbrain organoids were generated in spinner flasks through pharmacological directed differentiation. Total tau, tau isoform, p-tau, and ISR activation markers were assessed in PSP and control organoids. Differential gene expression and pathway analysis in PSP brain snRNA-seq data identified dysregulated EIF2 signaling, a target of the ISR, in vulnerable cell types. Histological validation in autopsy brain tissue showed PSP-vulnerable brain regions had the highest frequency of ISR activation, while no activation was detected in protected brain regions. ISR activation positively correlated with tau burden and was localized to p-tau + neurons and astrocytes. PSP organoids contained increased high molecular weight p-tau and 4R-tau, a higher ratio of p-tau:total tau, and different ISR activation levels compared to controls. SnRNA-seq and neurohistological data reveals ISR dysregulation in disease-affected cell types in PSP brain tissue. ISR activation positively associates with tau burden in vulnerable brain regions in PSP, providing a potential mechanistic link with EIF2AK3 genetic risk. PSP patient-derived organoids recapitulate key disease-relevant features, including elevation of toxic tau proteoforms and ISR dysregulation. This sporadic PSP organoid model will provide insight into cell-type specific drivers of neurodegeneration that underlie sporadic tauopathy.

INTRODUCTION:Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to many causes.METHODS:We reviewed the recent literature to identify newly-recognized causes of chorea, including auto-immune, metabolic, and genetic. We also focused upon developments in mechanisms relating to underlying pathophysiology of certain genetic choreas and advances in therapeutics.RESULTS:Novel autoantibodies continue to be identified as causes of chorea. Both COVID-19 infection and vaccination are reported to result rarely in chorea, although in some cases causality is not clearly established. Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders. Deep brain stimulation can be successful in certain circumstances.CONCLUSION:Our understanding of mechanisms underlying this movement disorder continues to advance, however much remains to be elucidated.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was the top activated pathway in vulnerable cell types. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

Progressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimer’s disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau (“tauopathies”) by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified six independent PSP susceptibility loci with genome-wide significant ( p < 5×10 -8 ) associations including five known ( MAPT , MOBP , STX6 , RUNX2 , SLCO1A2 ) and one novel locus ( C4A ). Integration with cell type-specific epigenomic annotations revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinson’s disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation in MOBP , STX6 , RUNX2 , SLCO1A2 , and C4A in the pathogenesis of PSP.

IntroductionThe unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.MethodsA comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson’s disease patients (n = 6), Huntington’s disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients’ characteristics.ResultsStatistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).DiscussionThis study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.

XK disease is a very rare, multi-system disease, which can present with a wide spectrum of symptoms. This disorder can also be identified pre-symptomatically with the incidental detection of serological abnormalities when typing erythrocytes in peripheral blood, or on other routine laboratory testing. Increasing awareness of this disorder and improved access to genetic testing are resulting in increasing identification of affected patients and families. Here we provide updates to some previously-reported families and patients and provide additional clinical details. We also report four new cases with a variety of presentations, one of whom had a novel mutation.

Movement Disorders Clinical PracticeVolume 10, Issue 2 p. 346-347 LETTERS: NEW OBSERVATION Amantadine Treatment for Hyperkinetic Movements in Chorea-Acanthocytosis Correction(s) for this article Erratum Volume 10Issue 7Movement Disorders Clinical Practice pages: 1166-1166 First Published online: June 21, 2023 Luis E. Zayas MD, PT,, Corresponding Author Luis E. Zayas MD, PT, [email protected] Department of Neurology, University of Tennessee Medical Center, Knoxville, Tennessee, USA Correspondence to: Dr. Luis E. Zayas, Department of Neurology, University of Tennessee Medical Center, 1975 Town Center Blvd, Knoxville, TN 37922, USA; E-mail: [email protected]Search for more papers by this authorRuth H. Walker MB, ChB, PhD, Ruth H. Walker MB, ChB, PhD Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA Department of Neurology, Mount Sinai School of Medicine, New York, New York, USASearch for more papers by this author Luis E. Zayas MD, PT,, Corresponding Author Luis E. Zayas MD, PT, [email protected] Department of Neurology, University of Tennessee Medical Center, Knoxville, Tennessee, USA Correspondence to: Dr. Luis E. Zayas, Department of Neurology, University of Tennessee Medical Center, 1975 Town Center Blvd, Knoxville, TN 37922, USA; E-mail: [email protected]Search for more papers by this authorRuth H. Walker MB, ChB, PhD, Ruth H. Walker MB, ChB, PhD Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA Department of Neurology, Mount Sinai School of Medicine, New York, New York, USASearch for more papers by this author First published: 14 November 2022 https://doi.org/10.1002/mdc3.13623Citations: 1 Relevant disclosures and conflicts of interest are listed at the end of this article. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Arrango GJ, Tenorio M, Marulanda E, et al. Neuroacanthocytosis:clínico-pathological study of a family with different phenotypes. Mov Disord 2002; 17: S223–S237. 2Connolly BS, Hazraiti LN, Lang AE. Neuropathological findings in chorea-acanthocytosis: new insights into mechanisms underlying parkinsonism and seizures. Acta Neuropathol 2014; 127: 163–615. 3Schwab RS, England AC Jr. Amantadine HCL (Symmetrel) and its relations to Levo-Dopa in the treatment of Parkinson's disease. Trans Am Neurol Assoc 1969; 94: 85–90. 4Rascol O, Fabbri M, Poewe W. Amantadine in the treatment of Parkinson's disease and other movement disorders. Lancet Neurol 2021; 20: 1048–1056. 5Cera N, Bifolchetti S, Martinotti G, et al. Amantadine and cognitive pathological gambling and other impulse control disorders. Neurophychiatr Dis Treat 2014; 10: 1093–1101. Citing Literature Volume10, Issue2February 2023Pages 346-347 ReferencesRelatedInformation

BACKGROUND Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Chorea‐acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites.

There is a paucity of genetic characterization in people with Parkinson’s disease (PD) of Latino and Afro-Caribbean descent. Screening LRRK2 and GBA variants in 32 New Yorkers of Puerto Rican ethnicity with PD and in 119 non-Hispanic-non-Jewish European PD cases revealed that Puerto Rican participants were more likely to harbor the LRRK2-p.G2019S variant (15.6% vs. 4.2%, respectively). Additionally, whole exome sequencing of twelve Puerto Rican and Dominican PD participants was performed as an exploratory study.