Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Abstract

Background Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer’s disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer’s continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer’s continuum.

Enlarged perivascular spaces and white matter hyperintensities in patients with frontotemporal lobar degeneration syndromes

“…Several studies have found associations between EPVS and neurodegenerative diseases, including Alzheimer's disease (Banerjee et al, 2017), Parkinson's disease (Li et al, 2020;Donahue et al, 2021;Shen et al, 2021), Fabry disease (Lyndon et al, 2021), and Huntington's disease (Chan et al, 2021). A previous study even found an association between EPVS and brain tau deposition in normal older population (Wang et al, 2021) and early AD continuum (Vilor-Tejedor et al, 2021). To the best of our knowledge, no specific study has investigated the distribution characteristics and clinical value of EPVS across the FTLD syndromes.…”

Perivascular spaces as a potential biomarker of Alzheimer’s disease

“…Many believe that tau is cleared through intracellular degradation (Tarasoff-Conway et al, 2015); however, upon being released into the interstitium (by AD-related neuronal death), it can then be cleared by the glymphatic system (Iliff et al, 2014). Vilor-Tejedor et al (2021) used 322 CN individuals diagnosed with AD-like pathology demonstrating that ePVS in the centrum semi-ovale was associated with elevated CSF p-tau and t-tau (Vilor-Tejedor et al, 2021). Another study determined that NFT pathology was a good correlate for ePVS burden in patients with AD and vascular lesion AD compared to controls (Boespflug et al, 2018).…”

Biomarkers involved in the pathogenesis of cerebral small-vessel disease

“…Higher levels of P-Tau, T-Tau, and neurogranin in Aβ-positive individuals were significantly associated with EPVS in centrum semiovale ( 79 ). And CRP was strongly associated with EPVS in CSVD patients with higher Aβ1-42 ( 47 ).…”