Advancing cell therapy for neurodegenerative diseases

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 512 - 529

Published: April 20, 2023

Language: Английский

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Analysis of inflammatory markers and tau deposits in an autopsy series of nine patients with anti-IgLON5 disease

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(4), P. 631 - 645

Published: Aug. 30, 2023

Abstract Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with specific tauopathy. Only few post-mortem neuropathological studies have been reported so far. Little known about the pathogenic mechanisms that result neurodegeneration. We investigated neuropathology of anti-IgLON5 and characterized cellular humoral inflammation. included nine (six them previously published). Median age patients was 71 years (53–82 years), median duration 6 (0.5–13 female to male ratio 5:4. Six 9 presented prominent Five had classical anti-IgLON5-related brainstem tauopathy another neuronal glial 4-repeat tauopathy, consistent progressive supranuclear palsy (PSP). Three short (median 1.25 years) only showed primary age-related neurofibrillary pathology. Inflammatory infiltrates T B cells were mild moderate did not significantly differ between or without In contrast, we found an extensive neuropil deposition IgG4 tegmentum brainstem, olivary nucleus, cerebellar cortex most two typical IgLON5-related The deposits particularly these regions accompanied by IgG1 deposits. Activated complement (C9neo) absent. Our study indicates tau pathology occurs later stages may also present PSP-phenotype exclusively at predilection sites for suggests antibodies precede Early start immunotherapy might prevent irreversible damage progression disease, least subgroup patients.

Language: Английский

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Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Aug. 16, 2024

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, inadequate analysis variants as well larger mutations, such small insertions/deletions (indels) structural (SVs). Method In this study, we performed whole genome sequencing (WGS) conducted single nucleotide (SNVs), indels, SVs, cohort 1,718 cases 2,944 controls European ancestry. Of individuals, 1,441 autopsy-confirmed 277 clinically diagnosed. Results Our common SNVs indels confirmed known genetic loci at MAPT , MOBP S TX6 SLCO1A2 DUSP10 SP1 further uncovered novel signals APOE FCHO1/MAP1S, KIF13A, TRIM24, TNXB, ELOVL1 . Notably, contrast to Alzheimer’s (AD), observed ε2 allele be risk PSP. Analysis identified significant ZNF592 gene network module neuronal genes dysregulated Moreover, seven SVs associated with H1/H2 haplotype region (17q21.31) other loci, including IGH PCMT1 CYP2A13 SMCP region, there burden deletions duplications ( P = 6.73 × 10 –3 ) Conclusions Through WGS, significantly enhanced our understanding basis PSP, providing new targets exploring mechanisms therapeutic interventions.

Language: Английский

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Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery

Annals of Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Objective Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP challenging due to the lack models reproducing its key pathological features. This study aimed model sporadic PSP‐Richardson's syndrome (PSP‐RS) using multi‐donor midbrain organoids (MOs). Methods The MOs were generated pooling induced pluripotent stem cells (iPSCs) from 4 patients with probable PSP‐RS compared them 3 healthy control (HC) subjects. We performed comprehensive analyses over 120 days assess neuronal death, reactive gliosis, accumulation 4R‐tau forms (pThr231, pSer396, pThr181, pSer202/pThr205 [AT8]) immunofluorescence microscopy Western blot. On day 90, immunohistochemical analysis pSer396 AT8 antibodies was conducted pathology. Results PSP‐derived showed progressive size reduction HC‐derived MOs, linked upregulated apoptosis‐related mRNA markers. Dopaminergic neuron degeneration marked decreased tyrosine hydroxylase (TH) increased neurofilament light chain (NfL). Immunofluorescence blot revealed all investigated peak at 90 days, along significant rise in GFAP‐positive MOs. Immunochemistry confirmed typical histological alterations, such as neurofibrillary tufted‐shaped astrocytes, absent organoids. Interpretation developed robust vitro molecular histologic features disease. result holds promise advancing basic clinical research PSP, paving way diagnosis identification novel therapeutic targets. ANN NEUROL 2025

Language: Английский

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Annual percentage change of MR Parkinsonism index in progressive supranuclear palsy: a feasibility study

European Radiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Language: Английский

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Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(3), P. 395 - 414

Published: June 24, 2023

Abstract Microtubule-associated protein tau ( MAPT ) aggregates in neurons, astrocytes and oligodendrocytes a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is target therapy the strategy includes either elimination pathological or reducing expression, thus amount made to prevent its aggregation. Disease-associated affects brain regions sequential manner that cell-to-cell spreading. Involvement glial cells show interpreted as taking up misfolded assuming do not express enough . Although studies have evaluated expression human tissue homogenates, it clear whether compromised accumulating tau. To address these perplexing aspects disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), single-nuclear(sn) RNAseq systematically map quantify dynamics across different cell types controls n = 3) cytopathology PSP 3). transcripts were detected oligodendrocytes, varied between within each type, preserved all PSP. These results propose complex scenario types, where, addition ingested tau, cellular provides pool for local production can (1) be phosphorylated aggregated, (2) feed seeding by providing physiological both accentuating process. Since does compromise gene PSP, complete loss an early pathogenic component less likely. observations provide rationale dual approach decreasing targeting removal

Language: Английский

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Clinicoradiologic and Neuropathologic Evaluation of Corticobasal Syndrome

Neurology, Journal Year: 2023, Volume and Issue: 101(3)

Published: June 2, 2023

Corticobasal syndrome (CBS) is a clinical phenotype characterized by asymmetric parkinsonism, rigidity, myoclonus, and apraxia. Originally believed secondary to corticobasal degeneration (CBD), mounting clinicopathologic studies have revealed heterogenous neuropathologies. The objectives of this study were determine the pathologic heterogeneity CBS, clinicoradiologic findings associated with different underlying pathologies causing positive predictive value (PPV) current diagnostic criteria for CBD among patients CBS.

Language: Английский

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Unusual combinations of neurodegenerative pathologies with chronic traumatic encephalopathy (CTE) complicates clinical prediction of CTE

European Journal of Neurology, Journal Year: 2024, Volume and Issue: 31(6)

Published: Feb. 25, 2024

Abstract Background and purpose Chronic traumatic encephalopathy (CTE) has gained widespread attention due to its association with multiple concussions contact sports. However, CTE remains a postmortem diagnosis, the link between clinical symptoms pathology is poorly understood. This study aimed investigate presence of copathologies their impact on in former sports athletes. Methods was retrospective case series design 12 consecutive cases athletes referred for autopsy. Analyses are descriptive include history as well pathological findings autopsied brains. Results All participants had concussions, all but one documented progressive cognitive, psychiatric, and/or motor symptoms. The results showed that 11 evidence brain, also other copathologies, including different combinations tauopathies, rare entities. Conclusions heterogeneity after repetitive head injuries diverse accompanying complicate prediction practice. It prudent consider possibility when clinically assessing patients injuries, especially they age, attributing neurological or cognitive solely presumptive elderly should be discouraged.

Language: Английский

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Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Feb. 26, 2024

Language: Английский

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