Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer’s Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer’s Disease

Article type: Research Article

Authors: Boespflug, Erin L.^{a; *} | Simon, Matthew J.^b | Leonard, Emmalyn^b | Grafe, Marjorie^c | Woltjer, Randall^{a; c} | Silbert, Lisa C.^a | Kaye, Jeffrey A.^a | Iliff, Jeffrey J.^{b; d}

Affiliations: [a] Layton Aging & Alzheimer’s Disease Center, Oregon Health & Science University, Portland, OR, USA | [b] Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA | [c] Pathology Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA | [d] Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA

Correspondence: [*] Correspondence to: Erin L. Boespflug, Department of Neurology, Oregon Health and Science University, Layton Aging and Alzheimer’s Disease Center, Hatfield Research Center, CR131, 3251 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Tel.: +1 503 494 1266; E-mail: boespfle@ohsu.edu.

Abstract: Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer’s disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

Keywords: Amyloid, aquaporin-4, astrocytes, cerebrovascular disease, glymphatic, perivascular space, virchow-robin space

DOI: 10.3233/JAD-180367

Journal: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1587-1597, 2018