Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum

Abstract

Background and Objectives:To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer’s disease (AD) continuum.Methods:We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben positron emission tomography scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVS into the EPVS+ (> 10 EPVSs) and EPVS– (0–10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than seven EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the inter-group differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores.Results:Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (β = −0.58, SE = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS– groups in the rate of longitudinal decreases in MMSE scores.Discussion:Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline β-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.

The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis

“…In fact, it has been suggested by DTI-ALPS (diffusion tensor image analysis along the perivascular space), an MRI-based approach ( Taoka et al, 2017 ), that CAA is indeed associated with lower MVPVS diffusivity ( Xu et al, 2022 ). However, by employing 11C-Pittsburgh B compound (PIB) PET ( Banerjee et al, 2017 ) or florbetaben/florbetapir PET ( Sepehrband et al, 2021 ; Wang et al, 2021 ; Jeong et al, 2022 ), the association between MVPVS and CAA has not been confirmed in the Alzheimer’s disease continuum, which commonly co-occurs with cerebral amyloid angiopathy. In addition, two studies found an association of MVPVS with tau by employing flortaucipir PET ( Sepehrband et al, 2021 ; Wang et al, 2021 ) or CSF analysis ( Wang et al, 2022 ).…”

Role of the glymphatic system and perivascular spaces as a potential biomarker for post‐stroke epilepsy

“…This is illustrated by studies, described in detail above, investigating ePVS in patients with focal epilepsy that indicate that PVS asymmetry is correlated to the SOZ. 62,66,67 As in generalized epilepsy and neurodegenerative and neuroinflammatory diseases, 28,29,31,32,49,103 it is thus hypothesized that in PSE and other focal epilepsy conditions, it is relative ePVS asymmetry rather than absolute ePVS number and volume, which is associated with pathology and epileptogenesis. 62,66,67 3.…”

“…103,106 While ePVS may have limited use in the differential diagnosis of dementias, studies in AD have shown relationships with cognitive decline and studies in MS associations with disease severity. 29,31 Therefore, ePVS may be a marker of disease severity and sequelae.…”

“…In many neurological and neurodegenerative conditions, it is increased PVS volume and numbers, which are positively correlated with pathology and disease 28–32 . In Alzheimer's disease, Parkinson's disease, vascular dementia, cerebral amyloid angiopathy, and multiple sclerosis (MS), enlarged PVSs (ePVSs) are associated with length of disease and disease burden 28–32 .…”

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

“…While the aforementioned evidence and deductions are compelling, some studies did not find clear associations of AD diagnosis or pathology with PVS burden (30,31), casting doubt on the involvement of PVS alterations in AD and the validity of the clearance hypothesis. Longitudinal studies that could establish specific factors that mechanistically drive PVS enlargement are scarce due to the persistent methodological challenges to quantify PVS reliably and computationally using repeated measures (32).…”