Background: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. Methods: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer’s pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2–8.3 years) and older (17.0–22.7 years) primates ( M mulatta ) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10–12 months). Results: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: −0.427, P =0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD ( P <0.017), including age as a covariate and either clinical hypertension ( P <0.030) or neuropathological SVD diagnosis ( P <0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals ( P =0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. Conclusions: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.
ObjectivesTo test whether collagen 4A1 in cerebral small arteries associated with age, hypertension or small vessel disease (SVD).DesignNeuropathology cohort study.SubjectsOlder people age >65 years with minimal Alzheimer’s Disease.MethodsWe examined subcortical white matter in archived brain tissue from older people (n=34, 15F/19M, median age 84, range 65–99 y) and from experimental non-human primates (NHP, Macaca mulatta) that were young adults (n=9, age 6.2–8.3 y) or older adults (n=8, age 17.0–22.7 y). Some of the primates (5 young, 3 older) were chronically hypertensive. Vascular collagen 4A1 immunohistochemical labelling was examined qualitatively and quantified as percent area fraction.ResultsCollagen 4A1 labelling was common in arterial myocytes and in the adventitial layer in human and primate brain arteries, as well as in basement membrane, which frequently exhibited replication. Among older people, collagen 4A1 associated with neuropathological SVD severity (sclerotic index; r=−0.461, p=0.0409, least squares) and with radiological SVD severity (leukoaraiosis; p=0.0455, 1-way ANOVA) but not with age or clinical history of hypertension. In NHP, age but not hypertension was significantly associated with collagen-4A1 labelling (p=0.0396, 0.232 respectively, 2-way ANOVA).ConclusionsIn this small cohort, vascular collagen 4A1 was related to SVD severity in older humans, in accord with genetic associations of COL4A1 with SVD phenotypes.
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Contrary to current thinking our evidence suggests that the probability of a tumour remaining stable appears to increase over time.Our complication rates highlight hearing loss as the most common adverse event with approximately 50% of patients experiencing a deterioration. This figure has been noted in other studies in this patient population (3) . Similarly, reported rates of facial palsy range between 8-21% (3,5) , comparable to our observations. Although tumour control rates are lower than those observed in non-NF2 population we advocate that GKS remains a viable treatment modality for enlarging VS in NF2. A non-invasive option is of particular relevance in this patient group most often presenting at a younger age with multifocal tumour burden.
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