Abstract
BackgroundPerivascular 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.ObjectiveWe 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.MethodsThe 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).ResultsThe 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.ConclusionsOur 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.
Highlights
Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain
Our results support that enlargement of PVS (ePVS) in the centrum semiovale (CS) are associated with tau pathophysiology, neurode‐ generation, and synaptic dysfunction in asymptomatic stages of the Alzheimer’s continuum
Characteristics of the Cerebrospinal fluid (CSF) biomarker sample according to ePVS degree are shown in Table 2, and characteristics of the sample stratified by Amyloid-β 42 (Aβ42)/40 status are shown in Supplemental Table 1
Summary
Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. Enlargement of PVS (ePVS) may result in impaired ISF drainage and has been shown to be associated with cerebral amyloid angiopathy in cognitively impaired patients [8, 9], and with peripheral neuroinflammatory biomarkers in the elderly [10, 11]. The impairment of this biological mechanism might contribute to the development of AD pathophysiology, characterized by Aβ plaques and tau tangles. The term “Alzheimer’s pathologic change” is used when there is evidence of Aβ pathology but not tau, whereas the term “Alzheimer’s disease” is applied whenever there is evidence of both Aβ and tau pathology, regardless of the clinical manifestations
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