Alzheimer's disease pathophysiology in the Retina
Gaire BP, Koronyo Y, Fuchs DT, Shi H, Rentsendorj A, Danziger R, Vit JP, Mirzaei N, Doustar J, Sheyn J, Hampel H, Vergallo A, Davis MR, Jallow O, Baldacci F, Verdooner SR, Barron E, Mirzaei M, Gupta VK, Graham SL, Tayebi M, Carare RO, Sadun AA, Miller CA, Dumitrascu OM, Lahiri S, Gao L, Black KL and Koronyo-Hamaoui M
Alzheimer's disease pathophysiology in the Retina
Gaire BP, Koronyo Y, Fuchs DT, Shi H, Rentsendorj A, Danziger R, Vit JP, Mirzaei N, Doustar J, Sheyn J, Hampel H, Vergallo A, Davis MR, Jallow O, Baldacci F, Verdooner SR, Barron E, Mirzaei M, Gupta VK, Graham SL, Tayebi M, Carare RO, Sadun AA, Miller CA, Dumitrascu OM, Lahiri S, Gao L, Black KL and Koronyo-Hamaoui M
The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid β-protein (Aβ) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aβ deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.
Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.
Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies
van Veluw SJ, Benveniste H, Bakker ENTP, Carare RO, Greenberg SM, Iliff JJ, Lorthois S, Van Nostrand WE, Petzold GC, Shih AY and van Osch MJP
Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies
van Veluw SJ, Benveniste H, Bakker ENTP, Carare RO, Greenberg SM, Iliff JJ, Lorthois S, Van Nostrand WE, Petzold GC, Shih AY and van Osch MJP
The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid β-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.
[1-C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects
Mehta NH, Wang X, Keil SA, Xi K, Zhou L, Lee K, Tan W, Spector E, Goldan A, Kelly J, Karakatsanis NA, Mozley PD, Nehmeh S, Chazen JL, Morin S, Babich J, Ivanidze J, Pahlajani S, Tanzi EB, Saint-Louis L, Butler T, Chen K, Rusinek H, Carare RO, Li Y, Chiang GC and de Leon MJ
[1-C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects
Mehta NH, Wang X, Keil SA, Xi K, Zhou L, Lee K, Tan W, Spector E, Goldan A, Kelly J, Karakatsanis NA, Mozley PD, Nehmeh S, Chazen JL, Morin S, Babich J, Ivanidze J, Pahlajani S, Tanzi EB, Saint-Louis L, Butler T, Chen K, Rusinek H, Carare RO, Li Y, Chiang GC and de Leon MJ
Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid.
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
Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N and Carare RO
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
Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N and Carare RO
This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.
Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition.
A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging
Digpal R, Arkill KP, Doherty R, Yates J, Milne LK, Broomes N, Katsamenis OL, Macdonald J, Ditchfield A, Narata AP, Darekar A, Carare RO, Fabian M, Galea I and Bulters D
A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging
Digpal R, Arkill KP, Doherty R, Yates J, Milne LK, Broomes N, Katsamenis OL, Macdonald J, Ditchfield A, Narata AP, Darekar A, Carare RO, Fabian M, Galea I and Bulters D
Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, = 0.001 and = 0.002), endothelial cell markers (CD34 and CD31, = 0.007 and = 0.003), glycans (Alcian blue, = 0.003) and wall thickness ( = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors
Anzovino A, Canepa E, Alves M, Lemon NL, Carare RO and Fossati S
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors
Anzovino A, Canepa E, Alves M, Lemon NL, Carare RO and Fossati S
Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death. We show that both apoptotic pathways are activated in BVSMCs by oligomeric Aβ42 and and mitochondrial respiration is severely impaired. Importantly, the CAIs methazolamide (MTZ) and acetazolamide (ATZ) prevent the pro-apoptotic effects in BVSMCs, while reducing caspase 3 activation and Aβ deposition in the arterial walls of TgSwDI animals, a murine model of cerebral amyloid angiopathy (CAA). This study reveals new molecular targets and a promising therapeutic strategy against BVSMC dysfunction in AD, CAA, and ARIA (amyloid-related imaging abnormalities) complications of recently FDA-approved anti-Aβ antibodies.
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
One of the most complex and challenging developments at the beginning of the third millennium is the alarming increase in demographic aging, mainly-but not exclusively-affecting developed countries. This reality results in one of the harsh medical, social, and economic consequences: the continuously increasing number of people with dementia, including Alzheimer's disease (AD), which accounts for up to 80% of all such types of pathology. Its large and progressive disabling potential, which eventually leads to death, therefore represents an important public health matter, especially because there is no known cure for this disease. Consequently, periodic reappraisals of different therapeutic possibilities are necessary. For this purpose, we conducted this systematic literature review investigating nonpharmacological interventions for AD, including their currently known cellular and molecular action bases. This endeavor was based on the PRISMA method, by which we selected 116 eligible articles published during the last year. Because of the unfortunate lack of effective treatments for AD, it is necessary to enhance efforts toward identifying and improving various therapeutic and rehabilitative approaches, as well as related prophylactic measures.
Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease
Kelly L, Sharp MM, Thomas I, Brown C, Schrag M, Antunes LV, Solopova E, Martinez-Gonzalez J, Rodríguez C and Carare RO
Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease
Kelly L, Sharp MM, Thomas I, Brown C, Schrag M, Antunes LV, Solopova E, Martinez-Gonzalez J, Rodríguez C and Carare RO
Alzheimer's disease is the commonest form of dementia. It is likely that a lack of clearance of amyloid beta (Aβ) results in its accumulation in the parenchyma as Aβ oligomers and insoluble plaques, and within the walls of blood vessels as cerebral amyloid angiopathy (CAA). The drainage of Aβ along the basement membranes of blood vessels as intramural periarterial drainage (IPAD), could be improved if the driving force behind IPAD could be augmented, therefore reducing Aβ accumulation. There are alterations in the composition of the vascular basement membrane in Alzheimer's disease. Lysyl oxidase (LOX) is an enzyme involved in the remodelling of the extracellular matrix and its expression and function is altered in various disease states. The expression of LOX is increased in Alzheimer's disease, but it is unclear whether this is a contributory factor in the impairment of IPAD in Alzheimer's disease. The pharmacological inhibition of LOX may be a strategy to improve IPAD and reduce the accumulation of Aβ in the parenchyma and within the walls of blood vessels.