Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy
Background and Purpose—Early markers for cerebral amyloid angiopathy are largely unknown. We aimed to identify which magnetic resonance imaging (MRI) (performed at 7 and 3T) and cognitive markers are an early sign in (pre) symptomatic subjects with hereditary cerebral hemorrhage with amyloidosis-Dutch type.
Methods—Twenty-seven DNA-proven Dutch-type mutation carriers (15 symptomatic and 12 presymptomatic) (mean age of 45.9 years) and 33 controls (mean age of 45.6 years) were included. 7T and 3T MRI was performed, cerebral amyloid angiopathy and small-vessel disease type MRI markers were estimated, and cognitive performance was assessed. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education.
Results—In symptomatic patients, all established cerebral amyloid angiopathy MRI markers (microbleeds, intracerebral hemorrhages, subarachnoid hemorrhages, superficial siderosis, microinfarcts, volume of white matter hyperintensities, and dilated perivascular spaces in centrum semiovale) were increased compared with controls (P<0.05). In presymptomatic subjects, the prevalence of microinfarcts and median volume of white matter hyperintensities were increased in comparison to controls (P<0.05). Symptomatic patients performed worse on all cognitive domains, whereas presymptomatic subjects did not show differences in comparison with controls (P<0.05).
Conclusions—White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages.
A major problem in diagnosing sporadic cerebral amyloid angiopathy (sCAA) is the absence of reliable, noninvasive diagnostic tests. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant disease, and the chemical composition and underlying pathology of the amyloid deposits is similar to that in sCAA.1 Clinically, the symptomatic stage of both sCAA and HCHWA-D is characterized by recurrent hemorrhagic strokes and cognitive impairment,2 and common radiological manifestations are microbleeds, intracerebral hemorrhages, superficial siderosis, convexity subarachnoid hemorrhages,3 greater volumes of white matter hyperintensities (WMHs),4,5 and microinfarcts.6 Because sCAA and HCHWA-D are subtypes of small-vessel disease, other small-vessel disease markers such as lacunar infarcts and dilated perivascular spaces might also be more prevalent in sCAA and HCHWA-D. Previous studies suggested that in patients with sCAA and HCHWA-D, cognitive impairment may also be an early disease marker, preceding stroke or any other brain lesion.2,7 The goal of our study is to identify which markers are an early sign of HCHWA-D using the most sensitive magnetic resonance imaging (MRI) techniques at 3T and 7T and to assess whether cognitive decline and neuropsychiatric abnormalities are an early sign of the disease.
Materials and Methods
HCHWA-D and control subjects were recruited via the HCHWA-D patient association in Katwijk (the Netherlands) and outpatient clinic of the Department of Neurology of the Leiden University Medical Center. Twenty-seven DNA-proven HCHWA-D mutation carriers and 33 controls were included (symptomatic [n=15] and presymptomatic [n=12] mutation carriers). Subjects were considered symptomatic when they had experienced signs of the disease reported to a general practitioner. At 7T, T2*-weighted gradient-echo scans and fluid-attenuated inversion recovery sequences were performed. At 3T, fluid-attenuated inversion recovery, T1-weighted images, and T2-weighted images were acquired. Microbleeds, intracerebral hemorrhages, superficial siderosis, and convexity subarachnoid hemorrhages were assessed at 7T T2*-weighted sequences. Cortical microinfarcts were scored as previously described.8 Because counting microinfarcts is a relatively new technique, these lesions were scored by 2 independent experienced raters, and inter-rater reliability was calculated. At 3T, WMHs, dilated perivascular spaces in the basal ganglia and centrum semiovale, and lacunar infarcts were assessed. A battery of neuropsychological and neuropsychiatric tests was performed (online-only Data Supplement).
Mann–Whitney U testing was used to assess differences in age between groups, univariate general linear modeling analysis was used to assess differences in blood pressure measurements, adjusted for age and sex, and χ2 tests were used to assess differences in sex, educational level, and percentage cardiovascular risk factors between groups. For assessment of microinfarcts, interobserver variability was calculated. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education (online-only Data Supplement).
The characteristics of the presymptomatic mutation carriers and symptomatic mutation carriers versus controls are shown in Table I in the online-only Data Supplement. All symptomatic patients clinically experienced one or multiple strokes as first symptomatic sign of the disease. None of the symptomatic patients experienced objective cognitive impairment as first sign of the disease. None of the presymptomatic mutation carriers reported cognitive complaints or showed objective cognitive impairment.
The κ value for interobserver agreement was almost perfect for detecting presence of cortical microinfarcts, κ=0.88 (P<0.001). The prevalence and median count of microbleeds, intracerebral hemorrhages, convexity subarachnoid hemorrhages, superficial siderosis, microinfarcts, median volume of WMHs, and dilated perivascular spaces-centrum semiovale are significantly higher in the symptomatic mutation carriers than in controls, adjusted for age and sex (P<0.05; Table 1). In presymptomatic mutation carriers, the prevalence of microinfarcts (P=0.044) and median volume of WMHs (P=0.000) is significantly increased compared with controls adjusted for age and sex. As illustrated in Figure, our cross-sectional data suggest that patients start developing changes on MRI at ≈5 years before developing their first symptoms (at age of 45 years).
All cognitive tests were performed significantly worse by symptomatic mutation carriers than controls, adjusted for age, sex, and education (P<0.05). They also showed a higher score on the Hospital Anxiety and Depression Scale (HADS) anxiety and depression scale (P<0.05). Presymptomatic mutation carriers did not show any significant differences compared with controls on the cognitive and neuropsychiatric tests (Table 2).
Of all sCAA markers, WMHs and cortical microinfarcts (ischemic manifestations of CAA) are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages, whereas other sCAA MRI-related markers are only more prevalent in symptomatic patients. Microinfarcts are a new finding likely related to the fact that 7T MRI was not available in previous studies. Although it has been suggested that in sCAA amyloid-β deposition alone could cause cognitive impairment7 and that in HCHWA-D mutation carriers cognitive deterioration can precede the first clinical stroke,2 we showed that cognitive abnormalities are not present in presymptomatic subjects with HCHWA-D. The generalizability of these findings to sCAA remains to be established because it occurs in older individuals in whom there is a closer association with amyloid plaques and the clinical features of Alzheimer disease. Using the most sensitive MRI techniques for all lesions, we found several abnormal MRI characteristics in the presymptomatic phase but no cognitive deficits suggesting that HCHWA-D starts with abnormalities in the brain caused by amyloid-β deposition, which then causes cognitive deficits.
Sources of Funding
This work was supported by NIH (R01 NS070834).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.014418/-/DC1.
- Received July 4, 2016.
- Revision received August 23, 2016.
- Accepted September 28, 2016.
- © 2016 American Heart Association, Inc.
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