Jul 2026· Annals of Neurology· Vol 100, pp. 695-708· 0 citations· 20 references
Medicine
TL;DR
Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis and suggest that PVS-BG may identify individuals at increased risk of progressive SVD.
Abstract
Objective
Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally.
Methods
We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [11C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation.
RESULT
Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA.
Interpretation
Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.
ABSTRACT Objective Peak‐width of skeletonized mean diffusivity (PSMD) and diffusion tensor imaging–analysis along the perivascular space (DTI‐ALPS), reflecting white matter integrity and glymphatic function, are altered in Alzheimer's disease (AD). We evaluated whether these biomarkers differ between AD participants with and without concomitant cerebral amyloid angiopathy (CAA). Methods The study included 50 AD participants with mild cognitive impairment/mild dementia, and intermediate to high AD neuropathologic change at autopsy. AD was categorized as AD with CAA and AD without CAA based on CAA neuropathology. We evaluated global and regional (frontal, parietal, temporal and occipital) PSMD; left, right and mean DTI‐ALPS indices and their association with clinical measures [Clinical dementia rating sum‐of‐boxes (CDR‐SB) from CDR Dementia Staging Instrument, mini mental state examination (MMSE), cognitive composites: memory, processing speed, executive function, and language]. Results AD participants with CAA (n = 17) had higher global [4.02 ± 1.44 (mean ± SD × 10−4 mm2/s) vs. 3.12 ± 0.91, β = −0.80, 95% CI (−1.42, −0.18), p = 0.012] and occipital PSMD [4.02 ± 1.10 vs. 3.00 ± 1.08, β = −0.88, 95% CI (−1.51, −0.26), p = 0.026] than those without CAA. No PSMD metric was associated with any clinical measure. However, imaging‐by‐group interactions showed global PSMD associated with language [β = −0.89, 95% CI (−1.53, −0.26), p = 0.027] and parietal PSMD with language [β = −1.05, 95% CI (−1.74, −0.36), p = 0.014] and memory [β = −0.83, 95% CI (−1.38, −0.28), p = 0.015]. DTI‐ALPS indices did not differ by group. Higher mean and right DTI‐ALPS indices were associated with preserved language function [mean: β = 9.33, 95% CI (2.05, 16.62), p = 0.036; right: β = 7.75, 95% CI (1.54, 13.95), p = 0.043] without imaging‐by‐group interactions. Interpretation Global and occipital PSMD may help identify AD participants with concomitant CAA.
Debina Laishram, G. Du, Sangam Kanekar et al.· Annals of Clinical and Trans...· 0 citations
RATIONALE AND OBJECTIVES
The perivascular spaces (PVS) serve as primary conduits for brain waste clearance. PVS enlargement (EPVS) is commonly observed in aging and neurodegenerative conditions. However, it remains unclear whether EPVS influences the β-amyloid (Aβ) deposition in Alzheimer's disease (AD).
MATERIALS AND METHODS
We included 524 participants from the ADNI database, all of whom had at least one follow-up 18F-florbetapir (FBP) PET scan. Using a deep-learning segmentation method, we calculated the PVS volume fraction (PVSVF) in the basal ganglia (BG) and white matter (WM) regions for each participant. Participants were then categorized into high- and low-EPVS-burden groups based on the median PVSVF. Linear mixed-effects models were employed to investigate the relationship between PVSVF and the annual rate of change in FBP PET standardized uptake value ratio (SUVR), incorporating both the linear and quadratic terms of baseline FBP SUVR. Analyses were performed for the entire cohort and within AD subgroups. For WM EPVS, additional analyses were conducted after excluding participants with severe white matter hyperintensity.
RESULTS
We confirmed that the annual rate of change in FBP SUVR follows an inverted U-shaped relationship with baseline FBP SUVR. Regarding BG EPVS, a significant interaction was identified between PVSVF and the squared baseline FBP SUVR in predicting the annual rate of change in FBP SUVR (FBP SUVR² × BG PVSVF: β = 8.350, P = 0.001). The high BG EPVS burden group showed sustained Aβ accumulation at the late disease period. In contrast, WM PVSVF showed no association with the annual rate of change in FBP SUVR. Similar results were observed within the AD continuum groups.
CONCLUSION
Higher baseline BG-EPVS burden was associated with a more sustained rate of amyloid-β accumulation among participants with high baseline amyloid burden.
Ling-Yun Liu, Qing-Ze Zeng, Xiao Luo et al.· Academic Radiology· 0 citations
BACKGROUND
Amyloid abnormality is a defining component of Alzheimer disease (AD) biology but does not fully account for variation in executive-function decline, which may also reflect white matter and periventricular injury.
PURPOSE
To compare periventricular diffusivity (PVeD), diffusion tensor image analysis along the perivascular space (ALPS), and G-Along Perivascular Space (G-ALPS), an algebraic variation of ALPS, as diffusion MRI measures in relation to amyloid abnormality and longitudinal executive-function decline.
STUDY TYPE
Retrospective.
POPULATION
The imaging-baseline cohort included 1190 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (70.6 ± 7.5 years; 666 female, 524 male). The primary analytic sample included 302 participants (70.6 ± 6.1 years; 168 female, 134 male).
FIELD STRENGTH/SEQUENCE
3 T/diffusion-weighted spin-echo echo-planar imaging and 3D T1-weighted inversion-prepared gradient-echo imaging.
ASSESSMENT
PVeD, ALPS, and G-ALPS were evaluated in relation to cerebrospinal fluid Aβ42, amyloid positron emission tomography (PET) Centiloid, structural MRI measures, white matter hyperintensity (WMH), and longitudinal Alzheimer's Disease Neuroimaging Initiative Executive Function composite (ADNI-EF).
STATISTICAL TESTS
Group comparisons, regression, longitudinal models, and bootstrap indirect-effect analyses with Benjamini-Hochberg correction were performed.
RESULTS
All three diffusion MRI measures differed across diagnostic groups, with mean values of PVeD, ALPS, and G-ALPS showing lower levels in dementia than cognitively normal participants (PVeD: 0.456 ± 0.048 vs. 0.430 ± 0.047; ALPS: 1.291 ± 0.188 vs. 1.163 ± 0.186; G-ALPS: 1.757 ± 0.512 vs. 1.393 ± 0.467). G-ALPS showed the most consistent association with ADNI-EF trajectory (β = 0.031, 95% CI: 0.003-0.059). Exploratory models identified statistical indirect effects involving inverted CSF Aβ42, ADNI-EF decline, and PVeD (-0.0518), ALPS (-0.0407), or G-ALPS (-0.0460); all survived Benjamini-Hochberg correction, with a corresponding G-ALPS effect for amyloid PET Centiloid (-0.0169).
DATA CONCLUSION
Periventricular and perivascular-space diffusion MRI measures were associated with amyloid abnormality and executive-function decline, mainly in cognitively normal and mild cognitive impairment participants.
EVIDENCE LEVEL
3.
TECHNICAL EFFICACY
Stage 2.
Cheng Chen, Jia-Long Gu, Qi-Li Hu et al.· Journal of Magnetic Resonanc...· 0 citations
White matter hyperintensities (WMHs), a hallmark of cerebral small vessel disease, frequently coexist with Alzheimer's disease (AD) and facilitate cognitive deterioration. Juxtaventricular WMH (JVWMH) is hypothesized to reflect pathological processes at the cerebrospinal fluid (CSF)-parenchyma interface and hold particular clinical significance. Therefore, this study specifically investigated associations between JVWMH burden and cognitive performance, CSF volume (CSFV), and amyloid-β (Aβ) pathology. Automated WMH segmentation was applied in two cohorts: 295 from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and 82 from a memory clinic. All participants underwent 3-T magnetic resonance imaging, amyloid-positron emission tomography, and cognitive assessment. Analyses evaluated JVWMH associations with Aβ, its discriminative value for cognitive impairment (CI) versus cognitively normal (CN), prediction of longitudinal decline, and mediation of CSFV-cognition relationships. JVWMH volume significantly discriminated CI from CN participants in both cohorts and predicted cognitive decline in longitudinal AIBL data. JVWMH volume showed strong correlations with CSFV in both cohorts. Notably, JVWMH partially mediated the associations between CSFV and cognition in the AIBL cohort. Non-juxtaventricular WMHs and Fazekas scores demonstrated no significant diagnostic or predictive power. JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD. Its correlation with CSFV implicates CSF-parenchyma interface processes, though causality remains unproven. These findings highlight the importance of incorporating spatially stratified WMH metrics in AD research to better capture disease-relevant white matter pathology. Question: JVWMH volume provides diagnostic and prognostic value beyond conventional WMH metrics in AD. Findings: JVWMH volume discriminated CI from normal cognition, predicted longitudinal decline, correlated with CSF volume, and partially mediated CSF volume–cognition associations. Relevance statement: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD, highlighting the value of spatially stratified WMH analysis in AD research to better capture disease-relevant white matter pathology. Question: JVWMH volume provides diagnostic and prognostic value beyond conventional WMH metrics in AD. Findings: JVWMH volume discriminated CI from normal cognition, predicted longitudinal decline, correlated with CSF volume, and partially mediated CSF volume–cognition associations. Relevance statement: JVWMH volume provides diagnostic and prognostic information beyond conventional WMH metrics in AD, highlighting the value of spatially stratified WMH analysis in AD research to better capture disease-relevant white matter pathology.
Yi-Wen Bao, Ya-Qing Ji, Li-Na Wang et al.· European Radiology Experimen...· 0 citations
From a neuropathological perspective, the most well-known pathological change in Alzheimer's disease (AD) to date is primarily tau protein hyperphosphorylation, which leads to the formation of intracellular neurofibrillary tangles (NFTs) and amyloid protein deposition-namely, the accumulation of amyloid protein (Aβ) and other protein aggregates outside cells, resulting in neurofibrillary tangles. The glymphatic system, driven by arterial pulsation, clears waste, including amyloid-β, via perivascular spaces (PVS). In AD, vascular dysfunction and slow-wave sleep speculation have been separately observed, and both are hypothesized to impair glymphatic clearance. However, causal links among these factors remain unproven, and the proposed self‑reinforcing cycle-where vascular failure may aggravate protein deposition and further vascular damage-is speculative. This study utilized two-dimensional cine phase-contrast MRI (PC-MRI) and four-dimensional flow MRI (4D-Flow) to quantify hydrodynamic parameters, including cerebrospinal fluid (CSF) flow in the cerebral aqueduct (CA) and blood flow in the internal carotid artery (ICA). Altered CSF-vascular association was observed in AD, suggesting possible glymphatic involvement. The integration of CSF and vascular flow metrics provides a promising biomarker framework for early AD detection and monitoring. PC-MRI and 4D-Flow reveal altered CSF-vascular association in Alzheimer's disease, reflecting potential glymphatic alteration and offering a non-invasive, quantitative method for potential adjunctive biomarker and disease monitoring.
Meng-Ying Lu, Yu-Shan Zheng, Ting-Ting Chen et al.· Journal of Visualized Experi...· 0 citations
Background/Objectives: Perivascular spaces (PVS) are MRI-visible compartments surrounding cerebral vessels and are increasingly interpreted as markers of cerebral small-vessel disease and glymphatic-system dysfunction. PVS burden is multifactorial, with possible contributions from vascular risk, atrophy, white matter disease, sleep, inflammation, diabetes, pathological protein deposition, genetic susceptibility, and venous drainage anatomy. This study evaluated whether apolipoprotein E (APOE) ε4 carrier status and venous sinus volumes are associated with quantitative PVS burden in patients across the cognitive spectrum. Methods: In this cross-sectional observational MRI study, 110 participants with normal cognition or varying cognitive impairment underwent 3T brain MRI and cognitive assessment. PVS lesion count and total PVS volume were quantified from T2-weighted (T2W) imaging using an automated deep learning segmentation approach. Venous sinus volumes were derived for the transverse, straight, and superior sagittal sinus segments and reported in mm3. APOE genotype was analyzed as ε4 carrier status. Non-parametric correlations, ordered cognitive-stage trend tests, APOE group comparisons, and adjusted partial Spearman analyses were performed. Results: Dorsal superior sagittal sinus (SSS-D) volume was associated with PVS count (ρ = 0.353, p < 0.001) and total PVS volume (ρ = 0.285, p = 0.009). These associations persisted after adjustment for age, sex, medial temporal atrophy (MTA), Fazekas score, and estimated intracranial volume (eTIV). APOE ε4 carrier status was not associated with PVS volume or count. PVS burden tended to decrease with greater cognitive-stage severity, while MTA increased across cognitive stages. Conclusions: In this cohort, SSS-D volume was associated with automated 3T T2W MRI-detectable PVS burden, whereas APOE ε4 carrier status was not a dominant predictor. These findings support further study of venous sinus morphology as a potential contributor to MRI-visible PVS burden, while longitudinal and flow-sensitive studies are needed to clarify causality and glymphatic clearance mechanisms.
Gvido Kārlis Skuburs, Kristīne Šneidere-Pītersa, A. Platkājis et al.· Diagnostics· 0 citations
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