Dataset Information

Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease.

ABSTRACT:

Introduction

This study characterizes retinal capillary blood flow in subjects with autosomal dominant Alzheimer's disease (ADAD)-causing mutations.

Methods

Carriers of PSEN1 or APP mutations were prospectively recruited and split into early-stage (ES) and late-stage (LS) groups. Controls were normal subjects and non-carriers from the at-risk group. Capillary blood flow was quantified using an optical coherence tomography angiography-based measure of erythrocyte flux through capillary segments. Statistical analyses were adjusted for correlation between two eyes of the same subject.

Results

ES carriers had significantly greater capillary blood flow than controls and LS carriers. ES and LS carriers had significantly greater capillary blood flow heterogeneity than controls. There was no difference between capillary blood flow of LS carriers and controls.

Discussion

ES ADAD carriers demonstrate increased retinal capillary blood flow and flow heterogeneity compared to controls. These findings support the hypothesis that increased perfusion is a pathophysiologic feature of presymptomatic stages of ADAD.

SUBMITTER: Singer MB

PROVIDER: S-EPMC7931411 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease.

Singer Maxwell B MB Ringman John M JM Chu Zhongdi Z Zhou Xiao X Jiang Xuejuan X Shahidzadeh Anoush A Wang Ruikang K RK Kashani Amir H AH

Alzheimer's & dementia (Amsterdam, Netherlands) 20210304 1

<h4>Introduction</h4>This study characterizes retinal capillary blood flow in subjects with autosomal dominant Alzheimer's disease (ADAD)-causing mutations.<h4>Methods</h4>Carriers of <i>PSEN1</i> or <i>APP</i> mutations were prospectively recruited and split into early-stage (ES) and late-stage (LS) groups. Controls were normal subjects and non-carriers from the at-risk group. Capillary blood flow was quantified using an optical coherence tomography angiography-based measure of erythrocyte flux ...[more]

PMID: 33728371

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Project description:Extensive effort has been made studying retinal pathology in Alzheimer's disease (AD) to improve early noninvasive diagnosis and treatment. Particularly relevant are vascular changes, which appear prominent in early brain pathogenesis and could predict cognitive decline. Recently, we identified platelet-derived growth factor receptor beta (PDGFRβ) deficiency and pericyte loss associated with vascular Aβ deposition in the neurosensory retina of mild cognitively impaired (MCI) and AD patients. However, the pathological mechanisms of retinal vascular changes and their possible relationships with vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) integrity remain unknown. Here, we evaluated the retinas of transgenic APPSWE/PS1ΔE9 mouse models of AD (ADtg mice) and wild-type mice at different ages for capillary degeneration, PDGFRβ expression, vascular amyloidosis, permeability and inner BRB tight-junction molecules. Using a retinal vascular isolation technique followed by periodic acid-Schiff or immunofluorescent staining, we discovered significant retinal capillary degeneration in ADtg mice compared to age- and sex-matched wild-type mice (P < 0.0001). This small vessel degeneration reached significance in 8-month-old mice (P = 0.0035), with males more susceptible than females. Degeneration of retinal capillaries also progressively increased with age in healthy mice (P = 0.0145); however, the phenomenon was significantly worse during AD-like progression (P = 0.0001). A substantial vascular PDGFRβ deficiency (~ 50% reduction, P = 0.0017) along with prominent vascular Aβ deposition was further detected in the retina of ADtg mice, which inversely correlated with the extent of degenerated capillaries (Pearson's r = - 0.8, P = 0.0016). Importantly, tight-junction alterations such as claudin-1 downregulation and increased BRB permeability, demonstrated in vivo by retinal fluorescein imaging and ex vivo following injection of FITC-dextran (2000 kD) and Texas Red-dextran (3 kD), were found in ADtg mice. Overall, the identification of age- and Alzheimer's-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages in ADtg mice could contribute to the development of novel targets for AD diagnosis and therapy.

Project description:Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Dataset Information

Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease.

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