Carare, Roxana Octavia

Abstract Background The interplay between vascular dysfunction and brain amyloidosis in driving Alzheimer's disease (AD) pathogenesis and cognitive decline is increasingly recognized. The retina, sharing an embryonic origin with the brain, offers an accessible CNS organ for high‐resolution, noninvasive imaging of AD‐related vascular pathology. However, the exact nature of retinal vascular damage in AD—especially in early disease stages—and its relationship with cerebral amyloid angiopathy (CAA) and cognitive impairment remain understudied. Method We examined vascular abnormalities in retinas of MCI and AD via histopathology and in‐vivo imaging studies. Postmortem retinas from 53–62 individuals (CN: 22; MCI/AD: 31–40) underwent immunohistochemistry for pericyte integrity, vascular Aβ42/40, and endothelial TJ proteins, with dysregulated proteins quantified by mass spectrometry in 12 additional AD/CN cases. Retinal curcumin‐amyloid imaging by scanning‐laser ophthalmoscope in 28–34 live participants (CN[MOCA>26]: 8–15; MCI/AD[MOCA≤26]: 13–19) assessed peri‐arteriolar/venular amyloid plaques (APs). Perivascular AP burden was correlated with MRI measures (hippocampal volume, WMH lesions) and cognitive/neuropsychiatric parameters. Result Retinal pericyte loss, reflected by PDGFRβ deficiency and apoptosis, was evident in MCI and AD patients and correlated with vascular Aβ42/40 accumulation and CAA severity (r=0.68–0.84; p <0.01–0.0001). Retinal endothelial ZO‐1 and claudin‐5 levels were significantly reduced, correlating with arteriolar Aβ40 deposition, suggesting impaired retinal Aβ clearance. Retinal capillary claudin‐5 and arteriolar Aβ40 strongly associated with CAA (r=0.75–0.77, p <0.0001), while ZO‐1 moderately correlated with brain amyloidosis/tauopathy, CAA, and cognitive decline (r=0.43–0.57, p <0.01–0.001). Both histological and in‐vivo imaging studies revealed greater Aβ deposition in retinal arterioles, particularly in secondary and tertiary branches, compared to venules or capillaries ( p <0.01–0.0001). Retinal perivascular APs in secondary/tertiary branches imaged in living patients correlated with cognitive impairment (global CDR, MOCA), hippocampal atrophy, and WMH lesions (r=0.51–0.66, p <0.05–0.001). Perivascular APs in the secondary (β=0.397, p = 0.033) and tertiary (β=0.756, p = 0.017) arteriolar branches showed significant interactions with hippocampal volumetry for visual memory. Conclusion Retinal arteriolar Aβ accumulation, pericyte loss, and TJ dysfunction contribute to early AD vascular pathology. If validated in larger cohorts, these findings support retinal vascular biomarkers as tools for predicting cognitive decline, monitoring AD progression, and assessing CAA severity.

AbstractBackgroundScanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals.Method34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined.ResultWe analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count.ConclusionRetinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Significance Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.