Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity DOI Creative Commons

Tiffany G. Lam,

Sophie K. Ross,

Benjamin Ciener

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract In recent years, multiple groups have shown that what is currently thought of as "Alzheimer’s Disease" (AD) may be usefully viewed several related disease subtypes. As these efforts continued, a issue how common co-pathologies and ethnicity intersect with AD The goal this study was to use dataset constituting 153 pathologic variables recorded on 666 brain autopsies better define relate established Pathologic clustering suggests 8 subtypes within cohort, further analysis reveals the previously described continuum from hippocampal predominant sparing well represented in our data. Small vessel overall highest cluster low hippocampal/cortical tau ratio, across all clusters small segregates separately Lewy body disease. Two are identified extensive bodies outside amygdala (one high ratio one ratio), we find an inverse relationship between cortical pathology two clusters. Finally, brains persons Hispanic descent significantly more neuroanatomic areas. We not uniformly distributed clusters, particularly pronounced significant pathology, where donors only found ratio. summary, data decades banked new relationships patterns AD-related proteinopathy, co-pathology, ethnicity, highlights utility subtyping classify pathology. Abbreviated summary Multiple Here, utilize cases demonstrate co-pathology most widely used methods subtyping.

Language: Английский

Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease DOI Creative Commons

Miyah R. Davis,

Edward Robinson,

Yosef Koronyo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 21, 2024

Abstract Accumulation of pathological tau isoforms, especially hyperphosphorylated at serine 396 (pS396-tau) and oligomers, has been demonstrated in the retinas patients with mild cognitive impairment (MCI) Alzheimer’s disease (AD). Previous studies have noted a decrease retinal ganglion cells (RGCs) AD patients, but presence impact isoforms RGCs RGC integrity, particularly early stages, not explored. To investigate this, we examined superior temporal cross-sections from 25 MCI (due to AD) or dementia 16 cognitively normal (CN) controls, matched for age gender. We utilized marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining assess neuronal density cell layer (GCL). Our study found that hypertrophic containing pS396-tau T22-positive oligomers were more frequently observed compared CN subjects. Quantitative analyses indicated decline 46-55% 55-56% reductions RBPMS + (P<0.01) GCL neurons (P<0.01-0.001), respectively, patients. This count was accompanied by increases necroptotic-like morphology cleaved caspase-3 apoptotic Furthermore, there 2.1 3.1-fold increase (P<0.05-0.0001) pS396-tau-laden greater abundance individuals higher Braak stages (V-VI), severe clinical ratings (CDR=3), lower mini-mental state examination (MMSE) scores. Strong correlations between total amount RGCs, counts correlating significantly brain neurofibrillary tangle scores ( r = 0.71, P= 0.0001), stage 0.65, 0.0009), MMSE -0.76, 0.0004). These findings suggest tauopathy, characterized oligomeric is associated may contribute degeneration AD. Future research should validate these larger cohorts explore noninvasive imaging techniques target pathology improve detection monitor progression.

Language: Английский

Citations

3
Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer's Disease Neuroimaging Initiative Study DOI
Duygu Tosun,

Zachary Hausle,

Pamela Thropp

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 16, 2024

CSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD.

Language: Английский

Citations

2
Ultrastructural diversity of alpha-Synuclein pathology in the post-mortem brain of Parkinson patients: implications for Lewy Body formation DOI Creative Commons
Amanda J. Lewis, Lukas van den Heuvel, Marta Di Fabrizio

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

Abstract Lewy bodies, the major pathological hallmark of Parkinson’s disease, are intraneuronal inclusions rich in aggregated alpha-synuclein (aSyn). To understand cellular mechanisms behind formation bodies and aggregation aSyn, we used correlative light electron microscopy detailed ultrastructural analysis postmortem brain tissue samples Parkinson patients. We found that somal aSyn dopaminergic neurons were exclusively fibrillar, while membranous-type located outside cell soma likely compact neuritic aggregates. These displayed phenotypic heterogeneity, ranging from predominantly membranous to mixed membranous/fibrillar ultrastructures. Our data suggest fibrillar form via distinct mechanisms, with providing environment for initial nucleation fibrils, which could then spread a prion-like mechanism bodies. This study provides important insight into body highlights importance membrane interactions future therapeutic intervention.

Language: Английский

Citations

2
Introduction to Alzheimer's Disease, Biomarkers, and the AI Revolution DOI
Bancha Yingngam

Advances in medical technologies and clinical practice book series, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 23

Published: June 28, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative that results in steady decline cognitive ability and memory function. As society ages, the need for an optimum AD management strategy becomes more important. This chapter analyzes stage-construction etiology escalating symptoms of discovered throughout this review, as well identification barrier to precise diagnosis. The artificial intelligence achieve quicker detection through machine learning, data analytics, predictive modeling also being considered. Therefore, employing AI AD-related studies novel approach enhancing patient outcomes. Proper diagnosis parallel increased probability many parameters one most difficult moments identify. However, use evaluation sensor network technologies big analysis has advanced, preventive instruments can be used. Thus, technology gives humanity hope stop or, at very least, slow down tragedy.

Language: Английский

Citations

1
Identification of isoAsp7-Aβ as a major Aβ variant in Alzheimer’s disease, dementia with Lewy bodies and vascular dementia DOI Creative Commons

Sarah Schrempel,

Anna Katharina Kottwitz,

Anke Piechotta

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Dec. 3, 2024

Abstract The formation of amyloid-β (Aβ) aggregates in brain is a neuropathological hallmark Alzheimer’s disease (AD). However, there mounting evidence that Aβ also plays pathogenic role other types dementia and specific post-translational modifications contribute to its profile. objective this study was test the hypothesis distinct are characterized by patterns post-translationally modified variants. We conducted comparative analysis quantified as well with pyroglutamate (pGlu3-Aβ pGlu11-Aβ), N-truncation (Aβ(4-X)), isoaspartate racemization (isoAsp7-Aβ isoAsp27-Aβ), phosphorylation (pSer8-Aβ pSer26-Aβ) or nitration (3NTyr10-Aβ) modification post mortem human tissue from non-demented control subjects comparison classified pre-symptomatic AD (Pre-AD), AD, Lewy bodies vascular dementia. modification-specific immunohistochemical labelings sections posterior superior temporal gyrus were examined machine learning-based segmentation protocols immunoassay analyses after sequential extraction carried out. Our findings revealed cases displayed highest concentrations all variants followed bodies, Pre-AD, controls. With both analytical methods, we identified isoAsp7-Aβ variant highly abundant form clinical conditions, Aβ(4-X), pGlu3-Aβ, pGlu11-Aβ pSer8-Aβ. These detected plaque compact, coarse-grained, cored diffuse morphologies and, varying frequencies, cerebral blood vessels. 3NTyr10-Aβ, pSer26-Aβ isoAsp27-Aβ not found be present plaques but intraneuronally. There strong positive correlation between Thal phase moderate negative performance on Mini Mental State Examination. Furthermore, abundance APOE 3/4 carriers. In aggregation assays, isoAsp7-Aβ, pGlu3-Aβ showed instant fibril without lag phase, whereas did fibrils. conclude targeting modifications, particular variant, might considered for diagnostic therapeutic approaches different Hence, our have implications current antibody-based therapies AD.

Language: Английский

Citations

1
Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health DOI Open Access
Valerie Uytterhoeven, Patrik Verstreken, Eliana Nachman

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 224(2)

Published: Dec. 24, 2024

Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's (PD), occurring before widespread protein aggregation, neuronal loss, cognitive decline. While field has focused on aggregation Tau α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even their aggregation. Therefore, understanding mechanisms by which α-Syn affect terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses potentially halting neurodegeneration. This review focuses molecular converge caused α-Syn. Both have physiological roles synapses. However, during disease, they acquire abnormal functions due to aberrant interactions mislocalization. We provide overview current research different essential pathways influenced Finally, we highlight promising therapeutic targets maintaining synaptic function both tauopathies synucleinopathies.

Language: Английский

Citations

1
Bradykinesia and postural instability in a model of prodromal Synucleinopathy with alpha-Synuclein aggregation in the gigantocellular nuclei. DOI Creative Commons
Vasileios Theologidis, Sara A. Ferreira, Nanna Møller Jensen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 9, 2024

ABSTRACT α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in brainstem, including gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during prodromal phase Parkinson disease (PD). Accordingly, there burgeoning interest animal model development for understanding pathological significance synucleinopathy, relation to motor and/or non-motor symptomatology PD. Here, we report an experimental paradigm induction aSyn aggregation with stereotaxic delivery pre-formed fibrillar (PFF) pontine GRN transgenic mice expressing mutant human Ala53Thr (M83 line). Our data show that PFF aSyn-induced aggregate pathology leads progressive decline spontaneous locomotion and early phenotype postural instability. This bradykinesia was followed by moribund stage, characterized worsening performance impaired survival substantial several brain regions beyond GRN. Collectively, our observations suggest framework studying features movement disability With further refinements, anticipate this holds promise as test-bed translational research PD related disorders.

Language: Английский

Citations

0
Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity DOI Creative Commons

Tiffany G. Lam,

Sophie K. Ross,

Benjamin Ciener

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract In recent years, multiple groups have shown that what is currently thought of as "Alzheimer’s Disease" (AD) may be usefully viewed several related disease subtypes. As these efforts continued, a issue how common co-pathologies and ethnicity intersect with AD The goal this study was to use dataset constituting 153 pathologic variables recorded on 666 brain autopsies better define relate established Pathologic clustering suggests 8 subtypes within cohort, further analysis reveals the previously described continuum from hippocampal predominant sparing well represented in our data. Small vessel overall highest cluster low hippocampal/cortical tau ratio, across all clusters small segregates separately Lewy body disease. Two are identified extensive bodies outside amygdala (one high ratio one ratio), we find an inverse relationship between cortical pathology two clusters. Finally, brains persons Hispanic descent significantly more neuroanatomic areas. We not uniformly distributed clusters, particularly pronounced significant pathology, where donors only found ratio. summary, data decades banked new relationships patterns AD-related proteinopathy, co-pathology, ethnicity, highlights utility subtyping classify pathology. Abbreviated summary Multiple Here, utilize cases demonstrate co-pathology most widely used methods subtyping.

Language: Английский

Citations

0