White matter hyperintensities and the surrounding normal appearing white matter are associated with water channel disruption in the oldest old

• Published in: Alzheimer's & dementia Vol. 20; no. 6; pp. 3839 - 3851
• Main Authors: Silbert, Lisa C., Roese, Natalie E., Krajbich, Victoria, Hurworth, Justin, Lahna, David, Schwartz, Daniel L., Dodge, Hiroko H., Woltjer, Randall L.
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01.06.2024
• Subjects: Aged; Aged, 80 and over; Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; aquaporin; Aquaporins - metabolism; Astrocytes - metabolism; Astrocytes - pathology; Autopsy; Brain - pathology; Female; Humans; Magnetic Resonance Imaging; Male; oldest old; pathology; White Matter - diagnostic imaging; White Matter - pathology; white matter hyperintensity; magnetic resonance imaging; pathology; aquaporin; oldest old; white matter hyperintensity
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13816

INTRODUCTION Age‐related magnetic resonance imaging (MRI) T2 white matter hyperintensities (WMHs) are common and associated with neurological decline. We investigated the histopathological underpinnings of MRI WMH and surrounding normal appearing white matter (NAWM), with a focus on astroglial phenotypes. METHODS Brain samples from 51 oldest old Oregon Alzheimer's Disease Research Center participants who came to autopsy underwent post mortem (PM) 7 tesla MRI with targeted histopathological sampling of WMHs and NAWM. Stained slides were digitized and quantified. Mixed‐effects models determined differences in molecular characteristics between WMHs and the NAWM and across NAWM. RESULTS PM MRI‐targeted WMHs are characterized by demyelination, microglial activation, and prominent astrocytic alterations, including disrupted aquaporin (AQP) expression. Similar changes occur within the surrounding NAWM in a pattern of decreasing severity with increased distance from WMHs. DISCUSSION Decreased AQP expression within WMH and proximal NAWM suggest an overwhelmed system wherein water homeostasis is no longer maintained, contributing to WM damage in older individuals. Highlights Post mortem magnetic resonance imaging (MRI) was used to characterize the pathology of white matter hyperintensities (WMHs) and surrounding normal appearing white matter (NAWM). Stained immunohistochemical (IHC) slides from targeted WMH and NAWM samples were digitized and quantified. WMHs and NAWM were associated with inflammation, demyelination, and gliosis. WMHs and NAWM astrocytic changes included decreased AQP1 and AQP4 expression. Abnormal NAWM pathology diminished in severity with increasing distance from WMH.