Retinal pathological features and proteome signatures of Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 145(4), P. 409 - 438

Published: Feb. 11, 2023

Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly early stages of functional impairment, how they relate to progression brain remain largely unknown. To better understand pathological features AD retina, we conducted an extensive histopathological biochemical investigation postmortem retina tissues from 86 human donors. Quantitative examination superior inferior temporal retinas mild cognitive impairment (MCI) patients compared those with normal cognition (NC) revealed significant increases amyloid β-protein (Aβ

Language: Английский

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Alzheimer's disease pathophysiology in the Retina

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 101, P. 101273 - 101273

Published: May 15, 2024

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks AD, including amyloid β-protein (Aβ) deposits abnormal tau protein isoforms, in retinas AD patients animal models. Moreover, structural functional vascular abnormalities such as reduced blood flow, Aβ deposition, blood-retinal barrier damage, along with inflammation neurodegeneration, been described mild cognitive impairment dementia. Histological, biochemical, clinical studies demonstrated that nature severity pathologies brain correspond. Proteomics analysis revealed a similar pattern dysregulated proteins biological pathways patients, enhanced inflammatory neurodegenerative processes, impaired oxidative-phosphorylation, mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific deposits, well vasculopathy neurodegeneration living suggesting alterations at different stages links to pathology. Current exploratory ophthalmic modalities, optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, hyperspectral imaging, may offer promise assessment AD. However, further research needed deepen our understanding AD's impact on its progression. To advance this field, future require replication larger diverse cohorts confirmed biomarkers standardized retinal techniques. This will validate aiding early screening monitoring.

Language: Английский

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Retina pathology as a target for biomarkers for Alzheimer's disease: Current status, ophthalmopathological background, challenges, and future directions

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(1), P. 728 - 740

Published: Nov. 2, 2023

Abstract There is emerging evidence that amyloid beta protein (Aβ) and tau‐related lesions in the retina are associated with Alzheimer's disease (AD). Aβ hyperphosphorylated (p)‐tau deposits have been described were small spots visualized by vivo imaging techniques as well degeneration of retina. These changes correlate brain deposition determined histological quantification, positron emission tomography (PET) or clinical diagnosis AD. However, literature not coherent on these histopathological findings. One important reason for this variability methods interpretation findings across different studies. In perspective, we indicate critical methodological deviations among groups suggest a roadmap moving forward how to harmonize (i) histopathologic examination retinal tissue; (ii) methods, devices, algorithms; (iii) inclusion/exclusion criteria studies aiming at biomarker validation.

Language: Английский

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Retinal arterial Aβ₄₀ deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(11), P. 5185 - 5197

Published: May 11, 2023

Abstract INTRODUCTION Vascular amyloid beta (Aβ) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that retinal vascular tight junctions (TJs) compromised linked to status. METHODS TJ components Aβ expression capillaries larger blood vessels determined post mortem from 34 MCI or AD patients 27 normal controls correlated with neuropathology. RESULTS Severe decreases zonula occludens‐1 (ZO‐1) claudin‐5 correlating abundant arteriolar 40 deposition identified Retinal deficiency was closely associated cerebral angiopathy, whereas ZO‐1 defects pathology cognitive deficits. DISCUSSION uncovered deficiencies blood–retinal barrier markers for potential imaging targets screening monitoring. Intense suggests a common pathogenic mechanism failed clearance via intramural periarterial drainage.

Language: Английский

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Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

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

Published: July 9, 2024

Abstract This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection status. Retinal cross-sections from predefined superior-temporal inferior-temporal subregions corresponding brains neuropathologically confirmed AD patients a clinical diagnosis either mild cognitive impairment (MCI) or dementia ( n = 45) were compared retinas age- sex-matched normal cognition 30) non-AD 4). isoforms, including tangles, paired helical filament (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), citrullinated-tau (Cit-tau), stereologically analyzed by immunohistochemistry Nanostring GeoMx digital spatial profiling, correlated neuropathological outcomes. Our data indicated significant increases AD-related pretangle especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR -tau; 4.1-fold), Oligo-tau (T22 + , 9.2-fold), as well mature tangle forms like MC-1-positive (1.8-fold) PHF-tau (2.3-fold), to control retinas. MCI also exhibited substantial (5.2-fold), CitR -tau (3.5-fold), pS396-tau (2.2-fold). analysis elevated retinal epitopes: Ser214 Ser396 (2.6-fold), Ser404 (2.4-fold), Thr231 (1.8-fold), particularly patients. Strong associations found between versus brain pathology status: a) vs. Braak stage, neurofibrillary tangles (NFTs), CDR scores ρ 0.63–0.71), b) neuropil threads (NTs) ABC 0.69–0.71), c) NTs, NFTs, 0.67–0.74). Notably, strongly Aβ 42 arterial 40 r 0.76–0.86). Overall, this identifies quantifies diverse patients, underscoring link cognition. These findings advocate for further exploration tauopathy biomarkers facilitate detection monitoring via noninvasive imaging.

Language: Английский

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Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 14, 2025

Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of amyloid-β peptide (Aβ) and intraneuronal accumulation abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied other co-pathologies in brain that may contribute to cognitive impairment, such as vascular lesions, transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate extent AD patients, several biomarkers have been developed. Specific tracers target visualize Aβ plaques, p-τ αSyn pathology or inflammation positron emission tomography. In addition imaging biomarkers, cerebrospinal fluid, blood-based biomarker assays reflecting AD-specific non-specific processes either already clinical use development. this review, we will introduce pathological brain, related discuss what respective determined at post-mortem histopathological analysis. It became evident initial stages plaque not detected with currently available biomarkers. Interestingly, precedes deposition, especially beginning when unable detect it. Later, takes lead accelerates pathology, fitting well known evolution measures over time. Some still lack clinically established today, TDP-43 cortical microinfarcts. summary, specific for AD-related pathologies allow accurate diagnosis based on pathobiological parameters. Although current excellent pathologies, they fail which analysis required. Accordingly, neuropathological studies remain essential understand development early stages. Moreover, there an urgent need co-pathologies, limbic predominant, age-related encephalopathy-related modify interacting p-τ. Novel approaches vesicle-based cryptic RNA/peptides help better future.

Language: Английский

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Hyperspectral retinal imaging biomarkers of ocular and systemic diseases

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

Published: May 22, 2024

Abstract Hyperspectral imaging is a frontier in the field of medical technology. It enables simultaneous collection spectroscopic and spatial data. Structural physiological information encoded these data can be used to identify localise typically elusive biomarkers. Studies retinal hyperspectral have provided novel insights into disease pathophysiology new ways non-invasive diagnosis monitoring systemic diseases. This review provides concise overview recent advances imaging.

Language: Английский

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Clearance of interstitial fluid (ISF) and CSF (CLIC) group‐part of Vascular Professional Interest Area (PIA), updates in 2022‐2023. Cerebrovascular disease and the failure of elimination of Amyloid‐β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(2), P. 1421 - 1435

Published: Oct. 28, 2023

Abstract This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal (CLIC) group, within Vascular Professional Interest Area (PIA) Alzheimer's Association International Society to Advance Research Treatment (ISTAART). The overarching objectives CLIC group are to: (1) understand age‐related physiology changes that underlie impaired clearance interstitial fluid (ISF) cerebrospinal (CSF) (CLIC); (2) cellular molecular mechanisms underlying intramural periarterial drainage (IPAD) in brain; (3) establish novel diagnostic tests for disease (AD), cerebral amyloid angiopathy (CAA), retinal vasculopathy, amyloid‐related imaging abnormalities (ARIA) spontaneous iatrogenic CAA‐related inflammation (CAA‐ri), vasomotion; (4) therapies facilitate IPAD eliminate β (Aβ) aging brain retina, prevent or reduce AD CAA pathology ARIA side events associated with immunotherapy.

Language: Английский

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mHealth hyperspectral learning for instantaneous spatiospectral imaging of hemodynamics

PNAS Nexus, Journal Year: 2023, Volume and Issue: 2(4)

Published: March 29, 2023

Abstract Hyperspectral imaging acquires data in both the spatial and frequency domains to offer abundant physical or biological information. However, conventional hyperspectral has intrinsic limitations of bulky instruments, slow acquisition rate, spatiospectral trade-off. Here we introduce learning for snapshot which sampled a small subarea are incorporated into algorithm recover hypercube. exploits idea that photograph is more than merely picture contains detailed spectral A sampling enables spectrally informed hypercube from red–green–blue (RGB) image without complete measurements. capable recovering full spectroscopic resolution hypercube, comparable high resolutions scientific spectrometers. also ultrafast dynamic imaging, leveraging ultraslow video recording an off-the-shelf smartphone, given comprises time series multiple RGB images. To demonstrate its versatility, experimental model vascular development used extract hemodynamic parameters via statistical deep approaches. Subsequently, hemodynamics peripheral microcirculation assessed at temporal up millisecond, using smartphone camera. This method analogous compressed sensing; however, it further allows reliable recovery key feature extractions with transparent algorithm. learning-powered yields eliminates trade-off, offering simple hardware requirements potential applications various machine techniques.

Language: Английский

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Retinal and Optic Nerve Lesions Correspond to Amyloid in Autosomal Dominant Alzheimer's Disease

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Autosomal dominant Alzheimer’s disease (ADAD) is a rare form of (AD) in which the biology can be explored during presymptomatic phase illness. The retina an outgrowth central nervous system and therefore provides opportunity for direct observation neural tissue its vasculature life. Retinal thinning measured vivo has been previously described persons carrying ADAD mutations through fundoscopy but pathologic correlates have not reported. We describe retinal lesions detected using patient homozygous A431E mutation PSEN1 pathological correlates. seen with life corresponded to intraretinal prelaminar optic nerve head amyloid β 42 -protein that were surrounded by perivascular anti-11A50-B10-Aβ 40 gliosis. then performed cross-sectional, observational study forty-one Latinos three cohorts consisting (1) causing mutations, (2) at 50% risk for, testing negative (3) elderly subjects at-risk ADAD. Clinical exam demonstrated novel, yellow, Cohort 1 absence drusen. Fifty-six percent had >10 compared 0% 25% Cohorts 2 3, respectively ( P < 0.04). There some controversy as detectability Aβ AD our findings verify presence intraretinal, prelaminar, amyloidosis detectable subset patients.

Language: Английский

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