Alzheimer's disease pathophysiology in the Retina

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101273 - 101273

Опубликована: Май 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.

Язык: Английский

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Clinical-radiological presentation and natural history of iatrogenic cerebral amyloid angiopathy

Journal of Neurology Neurosurgery & Psychiatry, Год журнала: 2025, Номер unknown, С. jnnp - 335164

Опубликована: Фев. 12, 2025

Background We aimed to describe neuroimaging features, clinical profiles and long-term outcomes in patients with iatrogenic cerebral amyloid angiopathy (iCAA). Methods performed a systematic literature search for case series of iCAA included individual their longitudinal data this pooled cohort study. Patients meeting modified version the Queen Square criteria were included. Baseline follow-up MRIs centrally analysed markers CAA using validated rating scales. Results 51 (68.6% male, median age at presentation 48 years), 51.0% probable 49.0% possible iCAA. evaluated 219 acquired over time 3.7 years (IQR 1.8–6.4). There 43 symptomatic intracerebral haemorrhages (ICH) 24 during follow-up, rate 16.7 per 100 patient-years. previous supratentorial brain surgery had an ipsilateral-dominant distribution spread haemorrhagic on MRI. 14/51 (27.5%) transient inflammatory changes (cortical or parenchymal oedema, sulcal hyperintensities). Haemorrhagic progressed follow-up. In addition ICH, 36 asymptomatic ICH (mostly smaller intragyral haemorrhages) detected scans. Besides numerous lobar microbleeds (median 16 baseline, 53 last follow-up), deep present 19.6% baseline 44.4% Severe perivascular spaces centrum semiovale common (64.7%) (95.6%). Conclusions appear have distinctive MRI characteristics, which might differentiate from other subtypes provide new insights into underlying disease mechanisms.

Язык: Английский

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Intramural hematomas and astrocytic infiltration precede perivascular inflammation in a rat model of repetitive low-level blast injury

Journal of Neuropathology & Experimental Neurology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Abstract In modern war theaters, exposures to blast overpressures are one of the most common causes brain injury. These pervasive events result in acute and chronic cerebrovascular degenerative processes. Using a rat model blast-induced mild traumatic injury, we identified intramural periarterial hematomas as early primary lesions induced by exposures. resulted intravascular cell death, layer reorganization, plasma leakage into intraperiarterial basal membranes that constitute drainage system (IPAD). Plasma metalloproteases, including MMP-9, IPAD may degrade extracellular matrix components compromising normal cerebral interstitial fluid drainage, arterial structure function leading vascular Related subacute effects exposure included increased MMP-9 expression perivascular reactive astrocytes extension astrocytic processes through layers affected vessels. results, combination with levels proinflammatory cytokines absence MHC II-expressing microglia, suggest an role clearing provide further mechanistic evidence precede onset neurovascular inflammation.

Язык: 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, Год журнала: 2023, Номер 20(2), С. 1421 - 1435

Опубликована: Окт. 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.

Язык: Английский

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Pathogenesis, manifestations, diagnosis, and management of CNS complications in hereditary ATTR amyloidosis

Amyloid, Год журнала: 2024, Номер unknown, С. 1 - 12

Опубликована: Дек. 3, 2024

The clinical efficacy of transthyretin (TTR) tetramer stabilisers and TTR gene silencers in addition to liver transplantation has been established for hereditary ATTR (ATTRv) amyloidosis. Accordingly, non-central nervous system (CNS) systemic amyloidosis manifestations, such as peripheral neuropathy cardiomyopathy, are now being overcome. However, emerging disease-modifying therapeutics have limited effects on CNS since they target the blood-circulating produced liver, not cerebral spinal fluid (CSF) synthesised choroid plexus. involvement is therefore becoming most common severe complication patients with ATTRv amyloidosis, including transient focal neurologic episodes, haemorrhagic ischaemic stroke, cognitive decline, cranial nerve dysfunction. Pathologically, extensive amyloid depositions observable leptomeninges leptomeningeal vessels, which direct contact CSF. Amyloid positron emission tomography a useful biomarker early detection treatment evaluation early-onset V30M (p.V30M) variant. Treatment-wise, blood-brain barrier-permeable stabilisers, intrathecal injection silencers, monoclonal antibodies against misfolded and/or may potentially ameliorate development novel imaging/CSF biomarkers therapies greatest unmet medical need require further trials.

Язык: Английский

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Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(3)

Опубликована: Март 1, 2025

Abstract INTRODUCTION The presence of tau aggregates in and around the brain vasculature Alzheimer's disease (AD) tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs). METHODS We used an vitro model blood–brain barrier (BBB) understand mechanisms fibrillar tau–mediated EC BBB pathology, confirming our findings 3‐month‐old P301S mice brains extracted microvessels. RESULTS Protofibrillar species induce permeability through increase glycolysis, which activates ECs toward a pro‐inflammatory phenotype, inducing loss junction protein expression localization. Warburg‐like metabolic shift glycolysis increased vascular pathological phenotypes are also present young mice. DISCUSSION In sum, work reveals that species, by enhancing glycolytic metabolism, promote inflammatory function, highlighting importance addressing targeting early tau‐mediated neurovascular damage AD tauopathies. Highlights improve understanding pathology Fibrillar mediates changes, inflammation, dysfunction. These events replicated at stages tauopathy mouse model. Inhibiting altered reduces activation.

Язык: Английский

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Updated imaging markers in cerebral amyloid angiopathy: What radiologists need to know

Japanese Journal of Radiology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 28, 2024

Abstract Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease pathologically characterized by the progressive accumulation of amyloid-beta (Aβ) peptide in cerebrovascular walls, affecting both cortical and leptomeningeal vessels. Amyloid deposition results fragile vessels, which may lead to lobar intracerebral hemorrhage (ICH) cognitive impairment. To evaluate probability severity CAA, imaging markers depicted on CT MRI techniques are crucial, as brain pathological examination highly invasive. Although Boston criteria have established diagnostic value been updated version 2.0, due aging population, patients with CAA should also be assessed for their risk future ICH or Furthermore, increased awareness essential when introducing anticoagulants infarct elderly anti-amyloid antibodies Alzheimer’s disease, these worsen CAA-related hemorrhagic lesions. However, radiological literature has not comprehensively updated. Here, we review clinical significance. We discuss characteristics inflammation, amyloid-related abnormalities, iatrogenic-CAA.

Язык: Английский

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Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors

Cells, Год журнала: 2023, Номер 12(24), С. 2840 - 2840

Опубликована: Дек. 14, 2023

Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer’s disease (AD), which triggers loss vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering blood flow, waste clearance, and promoting cognitive impairment. We have previously shown that, endothelial (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 DR5 mitochondria-mediated while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent EC vitro vivo. In this study, we analyzed Aβ-induced extrinsic intrinsic (DR- mitochondria-mediated) apoptotic pathways BVSMC, aiming to unveil new therapeutic targets BVSMC stress death. show that both are activated BVSMCs by oligomeric Aβ42 Aβ40-Q22 (AβQ22) mitochondrial respiration severely impaired. Importantly, CAIs methazolamide (MTZ) acetazolamide (ATZ) pro-apoptotic effects BVSMCs, reducing caspase 3 activation arterial walls TgSwDI animals, a murine model amyloid angiopathy (CAA). This study reveals molecular promising strategy against dysfunction AD, CAA, ARIA (amyloid-related imaging abnormalities) complications recently anti-Aβ antibodies.

Язык: Английский

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Neuroimmunology of Cardiovascular Disease

Current Hypertension Reports, Год журнала: 2024, Номер 26(7), С. 339 - 347

Опубликована: Апрель 13, 2024

Abstract Purpose of Review Cardiovascular disease (CVD) is a leading cause death and chronic disability worldwide. Yet, despite extensive intervention strategies the number persons affected by CVD continues to rise. Thus, there great interest in unveiling novel mechanisms that may lead new treatments. Considering this dilemma, recent focus has turned neuroimmune involved pathology deeper understanding brain’s involvement pathology. This review provides an overview salient findings regarding contribute CVD. Recent Findings The brain contains niches comprised glia parenchyma immune cells at borders, strong evidence these are important both health disease. Mechanistic studies suggest activation modulates progression hypertension heart failure contributes inevitable end-organ damage brain. Summary supporting role progression. However, additional research needed understand effects prolonged on function.

Язык: Английский

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Severe cerebral amyloid angiopathy related inflammation (CAA-ri) associated with vaccination: Case report and literature review

Journal of Neuroimmunology, Год журнала: 2024, Номер 394, С. 578406 - 578406

Опубликована: Июль 23, 2024

Язык: Английский

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