Capillary function progressively deteriorates in prodromal Alzheimer's disease: A longitudinal MRI perfusion study.

Cardiovascular risk factors are associated with the development of Alzheimer's disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively impaired (MCI) patients with prodromal AD compared to 12 MCI patients without evidence of AD and 10 cognitively intact age-matched controls. The pAD-MCI patients displayed widespread deterioration in microvascular cerebral perfusion associated with capillary dysfunction. No such changes were observed in the other two groups, suggesting that the dysfunction in capillary perfusion is linked to the AD pathophysiology. The observed capillary dysfunction may limit local oxygenation in AD leading to downstream ß-amyloid aggregation, tau hyperphosphorylation, neuroinflammation and neuronal dysfunction. The findings are in agreement with the capillary dysfunction hypothesis of AD, suggesting that increasing heterogeneity of capillary blood flow is a primary pathological event in AD.

Impaired perfusion and capillary dysfunction in prodromal Alzheimer's disease.

INTRODUCTION: Cardiovascular disease increases the risk of developing Alzheimer's disease (AD), and growing evidence suggests an involvement of cerebrovascular pathology in AD. Capillary dysfunction, a condition in which capillary flow disturbances rather than arterial blood supply limit brain oxygen extraction, could represent an overlooked vascular contributor to neurodegeneration. We examined whether cortical capillary transit-time heterogeneity (CTH), an index of capillary dysfunction, is elevated in amyloid-positive patients with mild cognitive impairment (prodromal AD [pAD]). METHODS: We performed structural and perfusion weighted MRI in 22 pAD patients and 21 healthy controls. RESULTS: We found hypoperfusion, reduced blood volume, and elevated CTH in the parietal and frontal cortices of pAD-patients compared to controls, while only the precuneus showed focal cortical atrophy. DISCUSSION: We propose that microvascular flow disturbances antedate cortical atrophy and may limit local tissue oxygenation in pAD. We speculate that capillary dysfunction contributes to the development of neurodegeneration in AD.

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease.

INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aß in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.