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P4–166: Age–associated periventricular white matter rarefaction does not correlate with clinical or pathologic evidence of vascular disease
Author(s) -
Murray Melissa,
Jack Clifford R.,
Dickson Dennis W.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1905
Subject(s) - medicine , pathology , white matter , hyperintensity , leukoaraiosis , fluid attenuated inversion recovery , magnetic resonance imaging , cardiology , radiology
subcortical infarcts and leukoencephalopathy) is a genetic form of vascular dementia. Mean age of presentation is 45 years; mean age of death is 65. Symptoms include migraine, transient ischemic attacks, strokes, mood disorders, and dementia. CADASIL is associated with mutations in the Notch3 gene on chromosome 19. The Notch transmembrane receptor family mediates signaling related to cell fate determination during development. It is not known how the Notch3 mutation leads to vascular degeneration and why disease onset occurs relatively late in life. Insulin and insulin-like growth factor-1 and -2 (IGF-1&2) signaling mediate Notch and AAH (aspartyl asparaginyl beta hydroxylase), which influence cell motility. We hypothesize that decreased cell motility disrupts assembly of the cytoskeleton and functioning of actin in smooth muscle contraction and constriction, causing damage to arterial smooth muscle and endothelial cells. Objective(s): To measure gene expression, in parenchyma and vessels of brain cortex and white matter (WM), of molecules involved in the insulin/IGF-1&2 and Notch/AAH signaling pathways. Methods: Postmortem brain tissue was taken from 3 CADASIL patients and 9 aged controls. For parenchymal tissue analysis, 3 cortex samples and 3 WM samples were taken from the temporal lobe of each subject. For vessel analysis, samples were taken from the cortex and WM. Microvessel RNA was isolated using a Dextran gradient cushion. RNA was extracted and reverse transcribed, and mRNA levels were measured by real time quantitative RT-PCR. Ribosomal 18S RNA levels were measured in parallel reactions to calculate the relative abundance of mRNA transcripts. Results: In WM but not in the cerebral cortex, expression of Notch3, AAH, insulin/ IGF receptors, smooth muscle actin and endothelin-1 was reduced. Conclusions: 1.) Molecular abnormalities in CADASIL appear to be restricted to WM and WM vessels. 2.) End-stage disease is associated with impaired expression of insulin/IGF receptors in WM vessels. 3.) Decreased receptor expression correlates with decreased Notch and AAH and degeneration of vascular smooth muscle actin and endothelial cells. 4.) Secondary WM degeneration may be associated with loss of astrocytes and oligodendroglia.