Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary arteriopathy caused by mutations of the Notch3 gene. The risk factors for cerebral microhaemorrhages (CM), their relationship to other MRI lesions in the disease and their potential clinical impact have not been previously defined. Our purpose was to examine the frequency, number and location of microhaemorrhages in a multicentre cohort study, defining predisposing factors and associated radiographic markers in CADASIL patients. We collected clinical data from 147 consecutive patients enrolled in an ongoing prospective cohort study. Degree of neurological disability and cognitive impairment were assessed by standardized scales. T(1)-weighted, FLAIR and T2*-weighted gradient-echo (GE) MRI sequences were performed. Volume and location of lacunar infarcts and white matter hyperintensity (WMH) were assessed. Number and location of CM were recorded. CM were present in 35% patients, most commonly occurring in the thalamus, brainstem and basal ganglia. The location of CM qualitatively differed from areas of lacunar infarction and WMH. There was a significant association between the presence of CM and a history of hypertension (P = 0.005), systolic blood pressure (SBP) (P = 0.014), haemoglobin A1c (HbA1c) (P = 0.004) and the volume of lacunar infarcts (P = 0.010) and WMHs (P = 0.046). The number of CM was independently associated with SBP (P = 0.005), the diagnosis of hypertension (P = 0.0004), volume of WMH (P = 0.0005) and lacunar infarcts (P = 0.004). In contrast, no association was found between blood pressure or HbA1c and the load of WMH or lacunar infarcts. The presence of CM was independently associated with increased modified Rankin scores. CM are independently associated with blood pressure and HbA1c as well as with lacunar infarct and WMH volume in CADASIL. Both the vascular risk factors and regional distribution of CM appear distinct from those associated with other MRI markers, suggesting a distinct pathological process. These lesions have a potential clinical impact in CADASIL. These findings further suggest that modulation of blood pressure and glucose levels might influence the course of the disease.

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…The authors suggested that this could have pathogenic implication in the development of cerebral ischemic complications. The development of microbleeds (but not of ischemic lesions or the volume of white matter changes) in CADASIL seems to be correlated with a history of hypertension and the levels of systolic blood pressure (and glicated hemoglobin) 70 . These arguments in favor of reducing BP routinely in CADASIL, however, should be confronted with evidence that these patients have problems in autoregulation of cerebral blood flow (CBF) (see section on pathogenesis).…”

“…Asymptomatic microbleeds (predominantly in the thalamus, basal ganglia and brainstem) are even more common, and seem to increase in incidence with advancing age of the patients [67][68][69] (Fig 2). Predisposing factors for cerebral bleeding are poorly understood but may include, in addition to microhemorrhages, the extent of white matter changes and ischemic lesion burden, the use of antiplatelet agents, disturbances in glucose metabolism and hypertension 68,70 .…”

Topography of dilated perivascular spaces in subjects from a memory clinic cohort

“…19 The total volume of WMH was normalized to the intracranial compartment (ICC) in each patient (normalized volume of WMH or nWMH 5 [volume of WMH/volume ICC] 3 100) 20 and logarithmically transformed due to its non-normal distribution.…”

“…We have previously reported a high inter-rater concordance within our group for MB, 21 WMH, 19 and lacunar infarcts. 20 Regarding DPVS, 15 scans randomly chosen were handed to a second rater (E.A.) for evaluation, and intraclass correlation coefficients were calculated.…”

p.Arg332Cys Mutation of NOTCH3 Gene in Two Unrelated Japanese Families with CADASIL

“…While CADASIL is considered to be a primarily ischemic form of cerebral vascular disorder, microbleeds have recently been reported in 31-69% of symptomatic NOTCH 3 mutation carriers (19,20). Viswanathan et al (21) reported that hypertension and HbA1c are associated with microbleeds in CADASIL. Because Patient 2 did not exhibit either hypertension or DM, ticlopidine might have been associated with his ICH.…”