Clinical and diagnostic implications of Alzheimer’s disease copathology in Lewy body disease

Brain, Journal Year: 2024, Volume and Issue: 147(10), P. 3325 - 3343

Published: July 11, 2024

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body (LBD), occurring approximately half all cases. Evidence shows that LBD patients with AD copathology show an accelerated course, greater risk cognitive decline and overall poorer prognosis. However, LBD-AD cases may heterogeneous motor non-motor phenotypes higher dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize current understanding by discussing synergistic effects neuropathological changes their clinical relevance. Furthermore, provide extensive overview neuroimaging fluid biomarkers under assessment for use possible diagnostic prognostic values. can predicted vivo means CSF, MRI PET markers, whereas most promising technique to date identifying different biological tissues α-synuclein seed amplification assay. Pathological imaging CSF are associated likelihood but do always mirror severity as pure AD. Implementing blood-based might allow faster screening copathology, thus improving sensitivity LBD-AD. Finally, discuss literature on novel candidate being exploited investigate other aspects neurodegeneration, such neuroaxonal injury, glial activation synaptic dysfunction. The thorough characterization should taken into account when considering differential diagnoses syndromes, evaluation individual level, guide symptomatic disease-modifying therapies.

Language: Английский

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Physiological roles of α-synuclein serine-129 phosphorylation – not an oxymoron

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(7), P. 480 - 490

Published: June 12, 2024

Language: Английский

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In vivo detection of Alzheimer's and Lewy body disease concurrence: Clinical implications and future perspectives

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5757 - 5770

Published: June 21, 2024

Abstract INTRODUCTION The recent introduction of seed amplification assays (SAAs) detecting misfolded α‐synuclein, a pathology‐specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization patients with co‐occurring Alzheimer's (AD) LBD since early clinical or even preclinical stage. METHODS We reviewed studies an biomarker‐based diagnosis AD‐LBD copathology. RESULTS Studies large cohorts cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect coexistence AD LB pathology approximately 20%–25% them, independently primary diagnosis. Compared to those pure AD, showed worse global cognition, especially attentive/executive visuospatial functions, motor functions. In unimpaired individuals, concurrent pathologies predicted longitudinal cognitive progression faster worsening memory, DISCUSSION Future research aiming better precision medicine approach should develop SAAs further reach quantitative evaluation staging each underlying using single biofluid sample. Highlights α‐Synuclein provide specific (LBD). allow (AD). coexist 20‐25% elderly ∼8% asymptomatic. causes is associated attentive/executive,

Language: Английский

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Association of CSF α‐synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 20, 2024

Abstract INTRODUCTION Cerebrospinal fluid (CSF) α‐synuclein (α‐syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co‐pathology in Alzheimer's disease. METHODS A total of 1637 cross‐sectional 407 longitudinal CSF samples from the Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined dynamics amyloid beta (Aβ), α‐syn seeds, phosphorylated tau181 (p‐tau181), along global domain‐specific cognition stable SAA+, SAA−, those who converted to SAA+ SAA−. RESULTS individuals had faster cognitive decline than notably mild impairment, presented earlier symptom onset. conversion was associated Aβ42 positivity but did not impact progression either or p‐tau181 status. Aβ42, p‐tau181, SAA all strong predictors clinical progression, particularly Aβ42. In vitro, kinetic parameters participant demographics, profiles, decline. DISCUSSION These results highlight interplay between their association disease progression. HIGHLIGHTS Seed greater Thirty‐four progressed SAA− that is, ≈ 5% conversion. (Aβ) pathology status biomarkers. Change diagnosis both biomarkers features

Language: Английский

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Parkinson’s Disease: Biomarkers for Diagnosis and Disease Progression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12379 - 12379

Published: Nov. 18, 2024

Parkinson's disease (PD) is a progressive neurological that causes both motor and nonmotor symptoms. While our understanding of putative mechanisms has advanced significantly, it remains challenging to verify biomarkers with sufficient evidence for regular clinical use. Clinical symptoms are the primary basis diagnosing disease, which can be mild in early stages overlap other disorders. As result, testing medical records mostly relied upon diagnosis, posing substantial challenges during initial diagnosis continuous monitoring. Recent biochemical, neuroimaging, genetic have helped us understand pathophysiology disease. This comprehensive study focuses on these biomarkers, were chosen based their relevance, methodological excellence, contribution field. Biochemical including α-synuclein glial fibrillary acidic protein (GFAP), predict severity progression. The dopaminergic system widely used as neuroimaging biomarker diagnose PD. Numerous genes genome wide association (GWAS) sites been related development research SNCA gene leucine-rich repeat kinase 2 (LRRK2) shown promising results. By evaluating current studies, this review intends uncover gaps validation use, while also highlighting improvements. It emphasizes need dependable reproducible indicators improving PD prognosis. These may open up new avenues progression tracking, personalized treatment programs.

Language: Английский

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Neuropathological stages of neuronal, astrocytic and oligodendrocytic alpha-synuclein pathology in Parkinson’s disease

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 11, 2025

Abstract Alpha-synucleinopathies are neurodegenerative diseases characterized by the spread of alpha-synuclein (α-syn) aggregates throughout central nervous system in a stereotypical manner. These include Lewy body disease (LBD), which encompass Dementia with bodies (DLB), Parkinson’s Disease (PD), and (PDD), Multiple System Atrophy (MSA). LBD MSA chiefly contain α-syn neurons oligodendrocytes, respectively, although glial pathology is increasingly being recognized. Semi-quantitative machine learning-based quantifications neuronal, oligodendrocytic astrocytic were implemented on cohort post-mortem tissue samples. The neuroanatomical distribution each cell-type specific was evaluated using conditional probability matrices Subtype Stage Inference (SuStaIn) algorithm. We revealed extensive LBD, emphasizing disease- region-specific profile pathology, absent minimal substantia nigra LBD. Furthermore, we have described distinct morphologies found to correlate density inclusions. Astrocytic mainly centered amygdala exhibited unique progression whilst oligodendrocytes displayed akin established neuronal pattern. SuStaIn modeling further used test for heterogeneity spatiotemporal progression, revealing that subset cases might follow an alternative Based these findings, introduce novel multimodal framework integrates, first time, temporal spatial alongside PD, providing information regarding role glia pathogenesis.

Language: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer’s disease

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 15, 2025

Abstract Pathological tau isoforms, including hyperphosphorylated at serine 396 (pS396-tau) and oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) AD dementia. These exhibit significant retinal ganglion cell (RGC) loss, however presence isoforms RGCs their impact on RGC integrity, particularly early AD, have not been studied. Here, we analyzed superior temporal cross-sections from 25 MCI or 16 age- sex-matched cognitively normal controls. Using marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining, found a 46–56% reduction RBPMS + neurons layer (GCL) ( P < 0.05–0.001). loss was accompanied by soma hypertrophy (10–50% enlargement, 0.05–0.0001), nuclear displacement, apoptosis (30–50% increase, 0.05–0.01), prominent expression granulovacuolar degeneration (GVD) bodies GVD-necroptotic markers. Both pS396-tau Oligo-tau were identified RGCs, hypertrophic cells. PS396-tau counts significantly increased 2.1–3.5-fold versus control 0.05–0.0001). Tauopathy-laden strongly inter-correlated r =0.85, 0.0001) tauopathy associated =-0.40–(-0.64), 0.05–0.01). Their abundance correlated brain pathology deficits, higher tauopathy-laden Braak stages (V–VI), clinical dementia ratings (CDR = 3), mini-mental state examination (MMSE ≤ 26) scores. central mid-periphery showed closest associations status, while exhibited strongest correlations (NFTs, stages, ABC scores; S =0.78–0.81, 0.001–0.0001) decline (MMSE; =-0.79, 0.0019). Overall, these findings identify link between pathogenic involving apoptotic death pathways. Future research should validate results larger more diverse cohorts develop as potential noninvasive biomarker for detection monitoring progression.

Language: Английский

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Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 17, 2025

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 and distinct subcortical system leads progressive decline home cage activity, which was accompanied by postural instability impaired coordination. The brainstem neurons lumbar spinal cord heralded onset moribund stage, culminated survival. 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

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Overlapping presence of β-amyloid, tau, p-tau, and α-synuclein in skin nerve fibers in Alzheimer's disease

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(3)

Published: March 1, 2025

Skin nerve fiber deposition of proteins can be strongly associated with neurodegenerative diseases, such as phosphorylated α-synuclein (p-SN) in synucleinopathies. Little is known about other proteins, tau or β-amyloid, skin fibers patients Alzheimer's disease (AD) and their link to underlying neurodegeneration. We therefore aimed for describing the presence distribution these AD non-AD controls. biopsies were taken from 45 (n = 23) controls 22). Nerve identified using antibodies against protein gene product 9.5 (PGP9.5), deposits evaluated double-immunostaining β-amyloid 1-42 (Aβ1-42), p-SN, tau, phospho-tau (p-tau). Aβ1-42 was present 7/23 (30.4%) 7/22 (31.8%) p-tau detected 12/23 (52.2%) 9/22 (40.9%) Tau 19/23 (82.6%) 16/22 (72.7%) p-SN 8/22 (36.4%) Frequencies not significantly different between groups frequency did correlate severity cognitive impairment. Deposits 1-42, both patient groups; however, qualitative assessment discriminate at this sample size. Future analyses spreading peripheral nerves may give new insights into pathophysiology but require quantitative detection.

Language: Английский

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Distinct neuronal vulnerability and metabolic dysfunctions are characteristic features of fast-progressing Alzheimer's patients with Lewy bodies

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108396 - 108396

Published: March 1, 2025

Language: Английский

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