Chronic Hypoperfusion Due to Intracranial Large Artery Stenosis Is Not Associated with Cerebral β-Amyloid Deposition and Brain Atrophy

Chronic Hypoperfusion Due to Intracranial Large Artery Stenosis Is Not Associated with Cerebral β-Amyloid Deposition and Brain Atrophy

Alzheimer’s disease (AD) is the most common form of aging-related dementia, imposing a significant burden on patients and society. β-amyloid (Aβ) deposition is considered a key event in AD pathogenesis, yet the underlying causes remain unclear. Cerebral blood flow (CBF) reduction and insufficient perfusion are observed in AD patients, even in those with mild cognitive impairment (MCI). Vascular risk factors (VRFs) such as hypertension, diabetes mellitus, cardiovascular diseases, and hypercholesterolemia are associated with an increased risk of AD, cognitive decline, and neurodegeneration, potentially due to chronic cerebral hypoperfusion. However, the direct causal relationship between hypoperfusion and AD pathology remains uncertain. This study investigates the impact of chronic cerebral hypoperfusion on Aβ deposition and brain atrophy in cognitively normal patients with unilateral intracranial large artery stenosis.

The study enrolled cognitively normal patients with unilateral chronic cerebral hypoperfusion, defined as reduced perfusion in one cerebral hemisphere detected by computed tomography perfusion (CTP) with or without severe middle cerebral artery (MCA) or internal carotid artery (ICA) stenosis. The contralateral hemisphere served as the control. Participants underwent clinical assessments, including medical history, physical examination, laboratory tests, apolipoprotein E genotyping, and neuropsychological tests. Imaging studies included non-enhanced CT (NECT), CT angiography (CTA), CTP, and 11C-Pittsburgh compound-positron emission tomography (PiB-PET). Brain atrophy indices were calculated from CT images, and Aβ burden was assessed using standardized uptake ratios (SUVRs).

The study included 10 participants (4 males, 6 females) with a median age of 64 years (range: 47–76 years). All patients exhibited reduced perfusion in one hemisphere without clinical manifestations of acute stroke or cognitive impairment. Six patients had ICA or MCA occlusions, three had severe stenosis, and one had patchy hypoperfusion without significant large vessel stenosis. The Aβ deposition, measured by cortical SUVRs, showed no significant differences between hypoperfused and normally perfused regions. In the volume of interest (VOI), the median cortical SUVR was 1.11 (interquartile range [IQR]: 1.02–1.11) in hypoperfused regions compared to 1.10 (IQR: 1.02–1.13) in controls (P = 0.721). Similarly, in the region of interest (ROI), the median cortical SUVR was 1.11 (IQR: 1.09–1.12) in hypoperfused regions versus 1.10 (IQR: 1.09–1.13) in controls (P = 0.241). One subject exhibited bilateral abnormal PiB uptake (SUVR >1.42), but this did not alter the overall findings. The gray/white matter (GM/WM) retention ratio also showed no significant differences between hypoperfused and control regions in VOIs (0.77 vs. 0.78, P = 0.333) or ROIs (0.84 vs. 0.84, P = 0.445).

Brain atrophy indices, including the Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular indices, were measured to assess neurodegeneration. No significant differences were observed between hypoperfused and control hemispheres. For example, the Bicaudate index was 0.11 (IQR: 0.10–0.13) in hypoperfused regions versus 0.13 (IQR: 0.11–0.14) in controls (P = 0.060). Similarly, the Bifrontal index was 0.32 (IQR: 0.30–0.34) in hypoperfused regions compared to 0.31 (IQR: 0.31–0.34) in controls (P = 0.707). Other indices, including Evans, Cella, Cella media, and Ventricular, also showed no significant differences (P > 0.05).

The findings suggest that chronic hypoperfusion due to intracranial large artery stenosis does not directly induce cerebral Aβ deposition or neurodegeneration in humans. This contrasts with animal studies, where chronic hypoperfusion increased Aβ deposition and neurodegeneration. However, human studies, including this one, have consistently shown no direct correlation between hypoperfusion and Aβ burden. The lack of association may be due to differences in the duration or severity of hypoperfusion or compensatory mechanisms in humans. Additionally, the study excluded patients with small vessel diseases or microvascular changes, which may independently contribute to AD pathology.

The study has several strengths, including the use of unilateral hypoperfusion to control for individual heterogeneity and the exclusion of major stroke patients to minimize confounding factors. The relatively older age of participants also aligns with the typical onset of AD-related pathological changes. However, the small sample size and unknown duration of hypoperfusion limit the generalizability of the findings. Future studies with larger cohorts and longer follow-up periods are needed to confirm these results and explore the potential role of small vessel diseases in AD pathogenesis.

In conclusion, chronic cerebral hypoperfusion due to large vessel stenosis is not associated with increased Aβ deposition or brain atrophy in cognitively normal patients. These findings suggest that hypoperfusion may not directly induce AD-related pathological changes in humans, highlighting the need for further research into the complex interplay between vascular and neurodegenerative processes in AD.

doi.org/10.1097/CM9.0000000000001918

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