Pure argyrophilic grain disease revisited: independent effects on limbic, neocortical, and striato-pallido-nigral degeneration and the development of dementia in a series with a low to moderate Braak stage

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Июль 31, 2024

Abstract Agyrophilic grains (AGs) are age-related limbic-predominant lesions in which four-repeat tau is selectively accumulated. Because previous methodologically heterogeneous studies have demonstrated inconsistent findings on the relationship between AGs and dementia, whether affect cognitive function remains unclear. To address this question, we first comprehensively evaluated distribution quantity of Gallyas-positive severity neuronal loss limbic, neocortical, subcortical regions 30 cases pure argyrophilic grain disease (pAGD) Braak stages I–IV without other degenerative diseases, 34 control that had only neurofibrillary tangles with no or minimal Aβ deposits. Then, examined independent effects dementia by employing multivariate ordered logistic regression binomial regression. Of pAGD cases, three were classified diffuse form pAGD, evident not limbic region but also neocortex nuclei. In all developed amygdala, followed temporo-frontal cortex, hippocampal CA1, substantia nigra, finally, striatum globus pallidus progression Saito AG stage. analyses stage affected striatum, pallidus, nigra age, stage, TDP-43 encephalopathy (LATE-NC) 23 28 lacked two more lacunae and/or one large infarctions, 100 per × 400 visual field amygdala (OR 10.02, 95% CI 1.12–89.43) CA1 12.22, 1.70–87.81), presence inferior temporal cortex 8.18, 1.03–65.13) moderate (III–IV), LATE-NC. Given these findings, high density increase gyrus may contribute to occurrence through loss, at least a low

Язык: Английский

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Post-mortem neuropathology of idiopathic rapid eye movement sleep behaviour disorder: a case series

The Lancet Neurology, Год журнала: 2024, Номер 23(12), С. 1238 - 1251

Опубликована: Ноя. 20, 2024

Язык: Английский

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Low clinical sensitivity and unexpectedly high incidence for neuropathologically diagnosed progressive supranuclear palsy

Journal of Neuropathology & Experimental Neurology, Год журнала: 2023, Номер 82(5), С. 438 - 451

Опубликована: Апрель 11, 2023

Abstract The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological using Rainwater criteria define neuropathological PSP. Of 954 autopsy cases, 101 met neuropathologic diagnosis these, 87 were termed PSP as they also had either dementia or parkinsonism both. prevalence clinicopathologically defined subjects in entire dataset 9.1%, while incidence rate estimated at 780 per 100 000 persons year, roughly 50-fold greater than most previous clinically determined estimates. A 99.6% specific but only 9.2% sensitive based on first examination, 99.3% 20.7% final exam. 35/87 (∼40%) no form assessment, decreased 18/83 (21.7%) assessment. Our confirms high specificity low sensitivity is likely primarily responsible underestimates population rate.

Язык: Английский

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Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Annals of Neurology, Год журнала: 2023, Номер 95(2), С. 314 - 324

Опубликована: Ноя. 3, 2023

Objective Exposure to repetitive head impacts (RHI) is associated with later‐life cognitive symptoms and neuropathologies, including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts often due multiple pathologies; however, the frequency contributions of these pathologies impairment people exposed RHI are unknown. Here, we examined relative 13 neuropathologies dementia RHI‐exposed brain donors. Methods Neuropathologists tissue from 571 donors assessed for presence CTE, Alzheimer disease (AD), Lewy body (LBD), transactive response DNA‐binding protein 43 (TDP‐43) inclusions. status was by dementia, Functional Activities Questionnaire, Difficulties Scale. Spearman rho calculated assess intercorrelation pathologies. Additionally, frequencies pathological co‐occurrence were compared a simulated distribution assuming no intercorrelation. Logistic linear regressions tested associations between scale scores. Results The sample age range 18–97 years (median = 65.0, interquartile 46.0–76.0). Of donors, 77.2% had at least one moderate–severe neurodegenerative or cerebrovascular pathology. Stage III–IV CTE most common (43.1%), followed TDP‐43 pathology, AD, hippocampal sclerosis. Neuropathologies intercorrelated, there fewer unique combinations than expected if independent ( p < 0.001). greatest contributors neocortical LBD, sclerosis, cerebral amyloid angiopathy, CTE. Interpretation In this wide‐ranging ages, correlated. Mixed underlie contact sport athletes. ANN NEUROL 2024;95:314–324

Язык: Английский

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Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(14), С. 11596 - 11596

Опубликована: Июль 18, 2023

Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) sporadic Alzheimer's disease (sAD). We assessed Aβ severity temporal lobe cerebellum ten DS sAD cases. Immunohistochemistry was performed using antibodies against eight different epitopes (6F/3D, Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate at third glutamic acid (AβNp3E), phosphorylated- (p-)Aβ 8th serine (AβpSer8)), six pathological (p-Ser202/Thr205, p-Thr231, p-Ser396, Alz50, MC1, GT38). Findings were evaluated semi-quantitatively quantitatively digital pathology. cases had significantly higher neocortical parenchymal (Aβ38, AβpSer8), cerebellar (Aβ40, AβNp3E, AβpSer8) than Furthermore, a larger mean plaque size AβNp3E) lobe, greater cerebral Aβ42 quantitative analysis. Western blotting corroborated these findings. Regarding pathology, more severe cases, especially white matter MC1). Greater total Alz50) confirmed by Our suggest that signatures are distinct from those sAD.

Язык: Английский

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Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 2, 2023

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes human PSP brains, although their cell-specificity unknown. Further, systematic data integration experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets are currently lacking. In this study, we combine bulk tissue (n = 408) single nucleus RNAseq 34) from control brains with mouse tauopathy validations Drosophila models for discovery of high-confidence expression potential. We discover, replicate, annotate thousands differentially expressed genes PSP, many which reside glia-enriched co-expression modules cells. DDR2, STOM, KANK2 promising striking cross-species validations. share our findings via interactive application tool Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our reveal robust glial provide systems biology approach, target discoveries potential other diseases.

Язык: Английский

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Neuronal and glial vulnerability of the suprachiasmatic nucleus in tauopathies: evidence from human studies and animal models

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 10, 2024

Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm disorders. The rhythm, recurring 24-hour cycle governing human biological activity, is regulated by the hypothalamic suprachiasmatic nucleus (SCN) endogenous transcriptional-translational feedback loops. Surprisingly, little attention has been given investigating tauopathy-driven neuropathology SCN repercussions gene dysfunction brain affected tauopathies. This review aims provide an overview current literature on vulnerability tauopathies humans. Emphasis placed elucidating neuronal glial changes contributing widespread disruption molecular clock. Furthermore, this identifies areas knowledge requiring further investigation.

Язык: Английский

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Substantia Nigra Pathology, Contact Sports Play, and Parkinsonism in Chronic Traumatic Encephalopathy

JAMA Neurology, Год журнала: 2024, Номер 81(9), С. 916 - 916

Опубликована: Июль 15, 2024

Parkinsonism is associated with traumatic brain injury and chronic encephalopathy (CTE), a neurodegenerative disease repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals CTE are yet to be defined.

Язык: Английский

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Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Авг. 14, 2024

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well astrocytes and oligodendrocytes. While astrocytic deposits are rarely observed normal aging (so-called aging-related astrogliopathy, ARTAG) Alzheimer's (AD), the form of tufted pathognomonic hallmark PSP. Classical biochemical experiments emphasized synthesis central nervous system, suggesting that inclusions might be derived from uptake extracellular neuronal-derived tau. However, recent single-nucleus RNAseq highlight fact MAPT, gene encoding tau, also expressed astrocytes, albeit lower amounts. We, therefore, revisited question whether astrocyte-driven expression contribute to aggregates PSP performing fluorescent situ hybridization/immunohistochemical co-localization human postmortem brain specimens individuals with AD ARTAG controls. We find that, but not AD, tau-immunoreactive have higher levels MAPT mRNA compared do aggregates. These results suggest responses unique this tauopathy support possibility fundamental changes astrocyte-endogenous biology increased protein underlies formation characteristic

Язык: Английский

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MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Авг. 17, 2024

Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in brain. Biochemically, inclusions PSP are enriched for proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative pre-mRNA splicing. While preferential aggregation reduced degradation 4R thought to play role inclusion formation toxicity, hypothesis altered expression mRNA isoforms plays causal role. This stems observation associated common variation gene (MAPT) at 17q21.31 locus which contains low copy number flanking large recurrent genomic inversion. The complex structural changes give rise two dominant haplotypes, termed H1 H2, have potential markedly influence expression. Here, we explored haplotype-dependent differences using bulk RNA-seq dataset derived human post-mortem brain tissue (n = 84) controls 77) rigorous computational pipeline, including We found 3579 differentially expressed genes temporal cortex 10,011 cerebellum. also 7214 differential splicing events 18,802 In cerebellum, total levels proportion transcripts encoding were significantly increased compared controls. cortex, reads was cases haplotype cortex. Further, observed marked difference KANSL1 strongly both regions. These findings support sporadic increases might this disorder.

Язык: Английский

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