Showing papers by "Mark A. van Buchem published in 2016"

Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease

Abstract: MR imaging was used to show global, diffusely distributed leakage of the blood-brain barrier in patients with early Alzheimer disease, which suggests that a compromised blood-brain barrier is part of the early pathology of Alzheimer disease and might be part of a cascade of pathologic events that eventually lead to cognitive decline.

Cerebral blood flow in small vessel disease: A systematic review and meta-analysis.

Abstract: White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies (n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross-sectional studies (n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference-0.71, 95% CI -1.12, -0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies (n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Abstract: Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1 , which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies. * Abbreviations : AGS : Aicardi-Goutieres syndrome MC : mutation carrier RVCL(-S) : retinal vasculopathy with cerebral leukoencephalopathy (and systemic manifestations)

Changes in regional brain activation related to depressive state: a 2-year longitudinal functional mri study

Abstract: BACKGROUND: Abnormal brain activations during processing of emotional facial expressions in depressed patients have been demonstrated. We investigated the natural course of brain activation in response to emotional faces in depression, indexed by functional magnetic resonance imaging (fMRI) scans preceding and following change in depressive state. We hypothesized a decrease in activation in the amygdala, anterior cingulate cortex (ACC), and insula with a decrease in depressive pathology. METHODS: A 2-year longitudinal fMRI study was conducted as part of the Netherlands Study of Depression and Anxiety. We included 32 healthy controls and 49 depressed patients. During the second scan, 27 patients were in remission (remitters), the other 22 were not (nonremitters). All participants viewed faces with emotional expressions during scanning. RESULTS: Rostral ACC activation during processing of happy faces was predictive of a decrease in depressive state (PFWE =.003). In addition, remitters showed decreased activation of the insula over time (PFWE =.016), specifically during happy faces. Nonremitters displayed increased abnormalities in emotion recognition circuitry during the second scan compared to the first. No effect of selective serotonin reuptake inhibitor use was observed. CONCLUSIONS: Our results demonstrate that rostral ACC activation may predict changes in depressive state even at 2-year outcome. The association between change in depressed state and change in insula activation provides further evidence for the role of the insula in a network maintaining emotional and motivational states. Language: en

Brain Volume as an Integrated Marker for the Risk of Death in a Community-Based Sample: Age Gene/Environment Susceptibility—Reykjavik Study

Abstract: Background T otal brain volume is an integrated measure of health and may be an independent indicator of mortality risk independent of any one clinical or subclinical disease state We investigate the association of brain volume to total and cause-specific mortality in a large nondemented stroke-free community-based cohort Methods The analysis includes 3,543 men and women (born 1907–1935) participating in the Age, Gene, Environment Susceptibility—Reykjavik Study Participants with a known brain-related high risk for mortality (cognitive impairment or stroke) were excluded from these analyses Quantitative estimates of total brain volume, white matter, white matter lesions, total gray matter (GM; cortical GM and subcortical GM separately), and focal cerebral vascular disease were generated from brain magnetic resonance imaging Brain atrophy was expressed as brain tissue volume divided by total intracranial volume, yielding a percentage Mean follow-up duration was 72 (0–10) years, with 647 deaths Cox regression was used to analyze the association of mortality to brain atrophy, adjusting for demographics, cardiovascular risk factors, and cerebral vascular disease Results R educed risk of mortality was significantly associated with higher total brain volume (hazard ratio, 95% confidence interval = 071, 065–078), white matter (085, 078–093), total GM (074, 068–081), and cortical GM (078, 070-087) Overall, the associations were similar for cardiovascular and noncardiovascular-related deaths Conclusions Independent of multiple risk factor s and cerebral vascular damage, global brain volume predicts mortality in a large nondemented stroke-free community-dwelling older cohort Total brain volume may be an integrated measure reflecting a range of health and with further investigation could be a useful clinical tool when assessing risk for mortality