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Evidence for an ischaemic origin of deep white matter lesions in the ageing brain
Author(s) -
Ince P. G.,
Fernando M.
Publication year - 2002
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1046/j.1365-2990.2002.39286_8.x
Subject(s) - pathology , hyperintensity , microglia , medicine , immunohistochemistry , white matter , pathophysiology , pathological , pathogenesis , ischemia , magnetic resonance imaging , cardiology , inflammation , radiology
The pathogenesis of white matter lesions (WMLs) is not established. Evidence from clinical,. pathological and pathophysiological studies favours a vascular mechanism for subcortical WMLs (DWML) and a nonischaemic origin for periventricular (PV) hyperintensities. Small vessel degeneration giving rise to ischaemia is the hypothetical origin for subcortical WMLs. Methods: PV lesions (PVL) and deep subcortical lesions (DWML) demonstrated in MRI scans of fixed coronal brain slices, from elderly postmortem brain donors to the MRC CFAS(N) cohort, were sampled together with nonlesional WM from the same brains. Immunohistochemistry was performed to detect activated microglia (CD68), endothelial activation (ICAM‐1), capillary basement membrane (Collagen IV), and hypoxia‐inducible factor‐1α (HIF‐1α) expression. Quantitative analysis of microvasculature was performed with digital images using Image Pro Plus software. The sample consisted of 18 PV (seven nonlesional) and 23 DWML (11 nonlesional) regions from 15 subjects. Statistical analysis was performed using SPSS software. Results: Vascular changes in arterioles were related to ML and not to dementia. DWML arterioles had thicker walls ( P < 0.001; 95%CI = 5.6–8.4), bigger external diameters ( P < 0.001; 95%CI = 7.7–17.8) and larger perivascular spaces ( P < 0.05; 95%CI = 13.3–19.4) than nonlesional areas. Vascular lumen diameters remained the same. The ICAM‐1/Collagen 4 ratio was significantly elevated in lesional DWML ( P = 0.001) but not in the periventricular regions ( P = 0.85) reflecting capillary endothelial activation. HIF‐1α expression ( P = 0.004) and presence of activated microglia ( P = 0.001) were more frequent in DWML. The prevalence (χ 2 = 0.053; P = 0.82) and absolute counts ( P = 0.07) of HIF‐1α expression, and the presence of activated microglia ( P = 0.95) in PVL were not increased over control WM. Discussion: DWML show vascular degenerative changes in arterioles, reactive changes in capillaries and persistent HIF expression, all consistent with chronic ischaemia. The study raises the possibility that an age‐related impairment of the neovascular response to ischaemia results in WM lesions.