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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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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Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases

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

Published: Aug. 19, 2024

The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown presence specific hallmark proteins Alzheimer's disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy post-mortem cohort with different diseases pathology retina. eyes were collected collaboration Netherlands Brain Bank from donors disease (n = 17), tauopathies 8), 27), degeneration mixed 11), other 6), cognitively normal controls 25). Multiple cross sections optic nerve immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 p62-lck ligand (p62) assessed inclusions. was observed diffuse signal neuropathological changes. Amyloid-beta vessel wall cytoplasmic granular deposits all groups. Alpha-synuclein Lewy neurites associated oligodendroglial inclusions multiple system atrophy. Anti-pTDP-43 generally showed typical inclusion bodies cases TDP-43 also later stages limbic-associated encephalopathy. P62 similar those seen anti-pTDP-43. Furthermore, significantly increasing Braak neurofibrillary tangles bodies, respectively. Mixed this consisted 6) high LB (> 4) low or moderate AD pathology, 1, NFT 6, Thal phase 5) combination low/moderate scores brain 4). There no advanced co-pathologies. In seven ≥ 4, retina, while tau group 11) not observed. From study, we conclude that reflects major Although levels copathology found brains most cases, primarily manifested main disease. These findings indicate appropriate imaging techniques, become highly accurate indicators diagnosing brain.

Language: Английский

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Transport of β-amyloid from brain to eye causes retinal degeneration in Alzheimer’s disease

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(11)

Published: Sept. 24, 2024

The eye is closely connected to the brain, providing a unique window detect pathological changes in brain. In this study, we discovered β-amyloid (Aβ) deposits along ocular glymphatic system patients with Alzheimer’s disease (AD) and 5×FAD transgenic mouse model. Interestingly, Aβ from brain can flow into eyes optic nerve through cerebrospinal fluid (CSF), causing retinal degeneration. mainly observed sheath, neural axon, perivascular space, which might represent critical steps of transportation eyes. Aquaporin-4 facilitates influx brain–eye transport out-excretion retina, its absence or loss polarity exacerbates brain-derived induced damage visual impairment. These results revealed brain-to-eye as major contributor AD retinopathy, highlighting new therapeutic avenue neurodegenerative disease.

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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Choroidal and retinal vascular changes in adults with Down syndrome: Insights into the Alzheimer's disease continuum

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION Retinal and choroidal vascular changes have been proposed as a non‐invasive central nervous system (CNS) proxy for clinical trials in Alzheimer's disease (AD). However, their role Down syndrome (DS), the largest genetically predisposed group AD, remains unclear. METHODS We conducted ultra‐widefield optical coherence tomography imaging on 24 individuals with DS 17 controls extracted various parameters. Data were analyzed using logistic linear regression models. RESULTS The retinae exhibited supernumerary vessels that wider thinned more rapidly along paths ( p = 0.01). There was complex retinal 0.047) less peripheral tree 0.001), increased numbers of microvascular abnormalities 0.038) reduced choroid vascularity index < 0.001). DISCUSSION found are present adults before onset AD might become early surrogates cerebral abnormalities. Highlights Eye showed seen AD. Far microaneurysms hemorrhages associated to DS. Wider faster thinning Reduced complexity retina linked Lower

Language: Английский

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Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer’s Disease and Vascular Dementia

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

The blood-brain barrier (BBB) plays a critical role in maintaining ion and fluid homeostasis, essential for brain metabolism neuronal function. Regulation of nutrient, water, transport across the BBB is tightly controlled by specialized transporters channels located within its unique cellular components. These dynamic processes not only influence BBB’s structure but also impact vital signaling mechanisms, optimal Disruption ion, pH, balance at associated with pathology has been implicated various neurological conditions, including stroke, epilepsy, trauma, neurodegenerative diseases such as Alzheimer’s disease (AD). However, knowledge gaps exist regarding dysregulation on function dementias. Several factors contribute to this gap: complex nature these historical research focus mechanisms technical challenges studying in vivo models lack efficient vitro dementia models. This review provides an overview current roles poses specific questions: 1) How are expression activity key altered AD vascular (VaD); 2) Do changes dysfunction progression; 3) Can restoring mitigate improve clinical outcomes. Addressing will provide greater insight into disorders.

Language: Английский

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Multimorbidity, cognitive phenotypes, and Alzheimer's disease plasma biomarkers in older adults: A population‐based study

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(3), P. 1550 - 1561

Published: Dec. 2, 2023

Abstract INTRODUCTION To examine the burden and clusters of multimorbidity in association with mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD)‐related plasma biomarkers among older adults. METHODS This population‐based study included 5432 participants (age ≥60 years); these, amyloid beta (Aβ), total tau, neurofilament light chain (NfL) were measured a subsample ( n = 1412). We used hierarchical clustering to generate five from 23 chronic diseases. diagnosed dementia MCI following international criteria. Data analyzed using logistic linear regression models. RESULTS The number diseases was associated (multivariable‐adjusted odds ratio 1.22; 95% confidence interval [CI] 1.11 1.33), AD (1.13; 1.01 1.26), vascular (VaD) (1.44; 1.25 1.64), non‐amnestic (1.25; 1.13 1.37). Metabolic cluster VaD MCI, whereas degenerative ocular p < 0.05). increased Aβ NfL DISCUSSION Multimorbidity are differentially subtypes AD‐related Highlights multimorbidity. presence load impairment. biomarkers.

Language: Английский

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Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: June 28, 2024

The relationship between amyloidosis and vasculature in cognitive impairment Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative topographic assessment of retinal perivascular amyloid plaque (AP) distribution individuals with both normal impaired cognition. Using retrospective dataset scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects varying states, we developed novel image processing method to examine peri-arteriolar peri-venular curcumin-positive AP burden. further correlated neuroimaging measures neurocognitive scores. Our study unveiled that counts surpassed throughout the entire cohort (P < 0.0001), irrespective primary, secondary, or tertiary vascular branch location, notable increase among cognitively individuals. Moreover, secondary count was elevated 0.01). Significantly, count, particularly venules, exhibited strong correlation clinical dementia rating, Montreal score, hippocampal volume, white matter hyperintensity count. In conclusion, our exploratory analysis detected greater versus marked elevation deposition regions subjects. These findings underscore potential feasibility imaging predicting decline AD progression. Larger longitudinal studies encompassing diverse populations AD-biomarker confirmation are warranted delineate temporal-spatial dynamics continuum.

Language: Английский

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