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.

Keywords: Alzheimer’s disease; CSF biomarkers; MRI; Perivascular spaces; Tau pathophysiology; Virchow-Robin spaces.

Fig. 1

Flow chart that shows the selection of the participants of the study. ALFA study, ALzheimer and FAmilies; PVS, perivascular spaces; CSF, cerebrospinal fluid; BG, basal ganglia; CS, centrum semiovale; N, sample

Fig. 2

Perivascular spaces rating. A Score of 1 in basal ganglia (non-severe). B Score of 4 in basal ganglia (severe). C Score of 1 (non-severe) in centrum semiovale. D Score of 4 (severe) in centrum semiovale. Circle: an enlarged Perivascular Space

Fig. 3

Distribution of Perivascular Spaces by degree of severity. Legend: BG, Basal Ganglia; CS, centrum semiovale. Model 1 shows associations correcting by age, sex and cardiovascular risk factors. Model 2 shows associations correcting by age, sex, cardiovascular risk factors and Aβ40. Blue color intensities indicate the magnitude of the associations (higher levels of biomarkers). Abbreviations: AD, Alzheimer’s disease; PVS, perivascular spaces; BG, basal ganglia; CS, centrum semiovale; CSF, cerebrospinal fluid; Aβ40, amyloid-β 40; Aβ42, amyloid-β 42; GFAP, glial fibrillary acidic protein; IL6, interleukin-6; NfL, neurofilament light; p-tau, phosphorylated tau; sTREM2, soluble triggering receptor expressed on myeloid cells 2 (TREM2); t-tau, total tau