Koronyo‐Hamaoui, Maya

Abstract Background Sensitive, accessible biomarkers of the pathologies underlying Alzheimer's disease and related dementias (ADRD) are critical for accurate diagnosis, deeper understanding of disease mechanisms, and development of new therapies with validated target engagement. The retina is connected to the brain via the optic nerve, which may facilitate the transmission and spread of amyloid beta (Aβ) and tau species. In postmortem studies, retinal Aβ deposits have been associated with neuritic Aβ‐plaque and neurofibrillary tangle burden, particularly in the entorhinal and temporal cortices. The goal of the current study was to evaluate associations between retinal perivascular amyloid and cognition, as well as to explore effect modification by hippocampal volumetry. Method Participants, aged ≥40 years, underwent retinal imaging, brain MRI, FDG‐PET, and a comprehensive neuropsychological assessment. Retinal amyloid imaging was conducted following curcumin ingestion and pupil dilation using a confocal scanning laser ophthalmoscope. Perivascular Aβ plaque counts were quantified in the superotemporal peripheral region following manual identification and tracking of retinal arteries and veins. Associations between retinal perivascular Aβ plaque counts with cognitive domains were evaluated using linear regression models adjusted for age, sex, and estimated premorbid functioning. Where significant associations were detected ( p ‐value<0.05), effect modification by hippocampal volumetry was examined with additional adjustment for intracranial volume. Result The sample included 26 participants (mean age 65±7 years, 50% female). Higher amyloid plaque counts in the perivascular secondary small and tertiary branches and in the periarteriolar tertiary branch were associated with poorer verbal and visual memory (Table 1). Significant interactions were observed between amyloid plaque count in the perivascular secondary small branch (β(95% Confidence Interval) = 0.397(0.037‐0.756), p = 0.033) and periarteriolar tertiary branch (β(95% Confidence Interval) = 0.756(0.165–1.346), p = 0.017) with hippocampal volumetry for visual memory. Conclusion Our pilot study provides preliminary evidence that perivascular Aβ accumulation in smaller vessels of the superotemporal retina may be a marker of memory impairment that may interact synergistically with hippocampal atrophy. Longitudinal studies consisting of multimodal ophthalmic assessments, brain imaging, ADRD biofluid markers, and cognitive testing will be necessary to capture the temporal sequence of retinal pathological changes and their associations with those in the brain.

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.

AbstractINTRODUCTIONGiven the close interactions between the retina and the brain, retinal amyloid imaging may serve as a diagnostic and prognostic tool for Alzheimer's disease and related dementias. This retrospective study investigated multivariable associations between retinal perivascular amyloid and cognitive domains.METHODSIntegrated analysis of retinal perivascular amyloid imaging, neuropsychological assessment, and brain magnetic resonance imaging in adults with and without cognitive impairment (N = 26; mean age: 65 ± 7 years; 50% female). Correlations between perivascular amyloid plaque burden and cognitive domains were evaluated with linear regression and interactions with hippocampal volumetry were explored.RESULTSHigher perivascular and periarteriolar amyloid plaque count in the secondary small and tertiary branches were associated with poorer verbal and visual memory in this cohort (p = 0.005–0.009). Higher perivascular amyloid burden interacted with hippocampal atrophy to worsen visual memory (p = 0.033).DISCUSSIONRetinal perivascular amyloid may serve as a non‐invasive marker for cognitive impairment and may shed insight into pathological changes in the brain.Highlights In vivo retinal perivascular amyloid plaque counts are associated with poorer memory. Retinal perivascular amyloid interacted with hippocampal atrophy to worsen memory. Retinal amyloid imaging is a potential biomarker for neurodegenerative diseases.

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.

Introduction: The vascular contribution to Alzheimer’s disease (AD) and AD-related dementias is increasingly recognized. Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina, vascular changes and amyloid plaque deposition. The relationship between retinal vascular changes and peri-vascular amyloid deposition in the continuum of neurodegeneration is imperfectly understood. In this exploratory topographic analysis of a cohort of subjects with normal and impaired cognition that underwent SLO, we investigated the retinal vascular-adjacent (para-vascular) amyloid plaque distribution and its correlation with cognitive measures. Methods: 34 subjects with cognitive decline underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal para-arteriolar and para-venular curcumin positive amyloid plaques were quantified in the supero-temporal retinal quadrant, in the first-, second- and third-order retinal vascular branches. The para-venous and para-arteriolar amyloid count were compared between patients with normal and impaired cognition, and their correlation with brain volumes and white matter hyperintensities was determined. Results: We analyzed retinal para-venous and para-arteriolar amyloid and vascular-structural parameters derived from 29 subjects, mean (SD) age 65(7), 48% female. Para-arteriolar plaque was higher than para-venular plaque in the entire cohort (p<0.0001). Secondary branch para-venular amyloid plaque count was higher in patients with impaired cognition, CDR ≥1 and MOCA ≤26. The para-arterial plaque count in the secondary branches significantly correlated with hippocampal volume and white matter hyperintensities scores. Conclusion: Our topographic analysis of the amyloid plaque distribution in retinal para-vascular regions shows higher amyloid accumulation in the para-arteriolar regions overall, and specifically in the secondary para-venular branches in patients with impaired cognition. Larger longitudinal studies are needed to study the temporal and spatial relationship between vascular dysfunction and para-vascular amyloid deposition in AD.

Introduction: Retinal imaging is a non-invasive tool to study both retinal vasculature and neurodegeneration. In this exploratory retinal curcumin-fluorescence imaging (RFI) study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status. Methods: We used quantitative RFI in a cohort of patients with cognitive impairment to automatically compute retinal amyloid burden. Retinal blood vessels were segmented, and the vessel tortuosity index (VTI), inflection index, and branching angle were quantified. We assessed the correlations between retinal vascular and amyloid parameters, and cognitive domain Z-scores using linear regression models. Results: Thirty-four subjects were enrolled and twenty-nine (55% female, mean age 64 ± 6 years) were included in the combined retinal amyloid and vascular analysis. Eleven subjects had normal cognition and 18 had impaired cognition. Retinal VTI was discriminated among cognitive scores. The combined proximal mid-periphery amyloid count and venous VTI index exhibited significant differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs. 0.91 ± 1.4, p = 0.006), and correlated with both the Wechsler Memory Scale-IV and SF-36 mental component score Z-scores (p < 0.05). Conclusion: This pilot study showed that retinal venular VTI combined with the proximal mid-periphery amyloid count could predict verbal memory loss. Future research is needed to finesse the clinical application of this retinal imaging-based technology.

Abstract INTRODUCTION: Retinal imaging is a non-invasive tool to study retinal vasculature and neurodegeneration. Patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD)-related cognitive disorder exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid beta-protein (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification, holding promise as an early-stage pathological biomarker of AD. In this exploratory study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status.METHODS: We used scanning laser ophthalmoscopy to assess quantitative CRFI in a cohort of patients with cognitive impairment that underwent standard neuropsychological testing. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index, vessel inflection index and branching angle was quantified. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole, proximal mid-periphery, and distal mid-periphery. Investigators performing quantifications were blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters and cognitive domain Z-scores.RESULTS: In this pilot study, 34 subjects underwent automated retinal amyloid imaging and 29 subjects (55% female, mean age 64±6 years) had the combined retinal amyloid and peripapillary vascular analysis. Eleven subjects had normal cognition, 15 MCI, 2 probable AD and 1 non-AD dementia. CRFI was increased in individuals with impaired versus normal cognitive function (p 0.0012). Venous VTI was the most significant vascular parameter that differ across levels of CDR. Branching angle correlated with amyloid count in the distal mid-periphery (p=0.03), whereas vessel inflexion index correlated with posterior pole amyloid count (p=0.02). The combined proximal mid-periphery amyloid count – venous tortuosity index was found to exhibit highly significant group differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs 0.91 ± 1.4, p=0.006). The combined proximal mid-periphery amyloid-venous tortuosity index also correlated with verbal memory (Wechsler Memory Scale-IV; p=0.001) and cognitive-related quality of life (SF-36 mental component score Z-scores; p=0.039).CONCLUSION: Retinal venular tortuosity discriminates across cognitive scores and in combination with proximal mid-periphery amyloid count predicts verbal memory and cognitive-related quality-of-life. Future research is needed to confirm the clinical utility of this integrated retinal imaging-based methodology.

Introduction: Retinal vascular features predict cognitive performance and retinal imaging is a non-invasive tool to study brain health. Patients with Alzheimer’s disease (AD)-related cognitive disorders exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid-beta (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification. In this study, we sought to determine whether and which retinal arterial and venous parameters are predictive of retinal Aβ burden and cognitive Z-scores. Methods: We used scanning laser ophthalmoscopy with RetiaTM (Centervue, Inc) to obtain CRFI in a cohort of patients with cognitive decline. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index (VTI), vessel inflection index (VII), and branching angle (VBA) were quantified, independently for arteries and veins. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole (PP), proximal mid-periphery (PMP), and distal mid-periphery (DMP). All quantifications were done blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters. Results: 29 subjects (55% female, mean age 64±6 years) were included in the analysis: 11 had normal cognition, 16 mild cognitive impairment and 2 probable AD. Venous VTI was the only vascular parameter significantly different across levels of Clinical Dementia Rate scores and between cognitively normal and impaired. Venous VBA was a significant predictor of DMP amyloid count (p=0.03). Arterial VII significantly predicted PP amyloid count (p=0.02). VBA predicted Wechsler Adult Intelligence Scale Z-score (p=0.08). The combined VTI-PMP amyloid index significantly predicted Wechsler Memory Scale, California Verbal Learning Test and SF-36 mental component score Z-scores (p<0.05). Conclusion: Retinal venous tortuosity discriminates across cognitive scores and in combination with PMP amyloid count may predict verbal memory and related quality-of-life scores.