Cerebral small vessel disease is the most common cause of vascular cognitive impairment. It typically manifests with lacunar infarcts and ischaemic white matter lesions. However, little is known about how these lesions relate to the cognitive symptoms. Previous studies have found a poor correlation between the burden of ischaemic lesions and cognitive symptoms, thus leaving much of the variance in cognitive performance unexplained. The objective of the current study was to investigate the relationship between the location of subcortical ischaemic lesions and cognitive symptoms in small vessel disease. We applied a voxel-based lesion-symptom mapping approach to data from 215 patients with CADASIL, a genetically defined small vessel disease with mutations in the NOTCH3 gene. All patients were examined by magnetic resonance imaging and comprehensive neuropsychological testing. Lacunar lesions and white matter lesions were segmented on three-dimensional T(1) and fluid-attenuated inversion recovery sequences, respectively. One hundred and forty-five subjects had a total of 854 lacunar lesions (range 1-13 per individual). The normalized volume of white matter hyperintensities ranged from 0.0425% to 21.5% of the intracranial cavity. Significant clusters for cognitive performance were detected for both lacunar lesions and white matter hyperintensities. The most prominent results were obtained on a compound score for processing speed, the predominantly affected cognitive domain in this group of patients. Strategic locations included the anterior parts of the thalamus, the genu and anterior limb of the internal capsule, the anterior corona radiata and the genu of the corpus callosum. By combining the lesion-symptom mapping data with information from a probabilistic white matter atlas we found that the majority of the processing speed clusters projected on the anterior thalamic radiation and the forceps minor. In multivariate models that included demographic parameters, brain atrophy and the volume of ischaemic lesions, regional volumes of lacunar lesions and white matter hyperintensities in the anterior thalamic radiation predicted performance in processing speed tasks, whereas there was no independent contribution of the global volume of ischaemic lesions. These observations emphasize the importance of lesion location for both lacunar and ischaemic white matter lesions. Our findings further highlight the anterior thalamic radiation as a major anatomical structure impacting on processing speed. Together these findings provide strong support for a central role of frontal-subcortical circuits in cerebral small vessel disease and vascular cognitive impairment.
Background and Purpose-Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease. Methods-Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models. Results-Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death. The clinical and imaging characteristics of CADASIL much resemble those of the most severe forms of sporadic SVD. We, thus, reasoned that information derived from a longitudinal study in CADASIL might offer insights relevant to SVD in general. Here, we report the final results of this study obtained in a large cohort of patients followed up for 3 years. Conclusions-Clinical Methods Study CohortSubjects were prospectively recruited between September 2003 and April 2011 through 2 major referral centers for CADASIL (University Hospital Lariboisière, Paris [n=178] and Ludwig Maximilians Universität, Munich [n=112]). They were included regardless of whether they had clinical manifestations of the disease if they were at least 18 years of age, had a documented mutation in the NOTCH3 gene, and were willing to be followed up. Details of the study protocol have been reported elsewhere.11 A follow-up interval of 3 years was chosen based on previous longitudinal data showing that significant changes in clinical scores can be detected within an interval of 2 years 8 when following up patients seen at major referral centers and to obtain a sufficient number of clinical events. In brief, clinical and demographic data were collected at study entry and included age, sex, years of education, and vascular risk factors (hypertension, diabetes mellitus, hypercholesteremia, smoking, and alcohol use). Blood pressure was measured at baseline and at follow-up.A history of transient ischemic attack...
AIM The objective of this study was to investigate which attentional components are of predictive utility in differentiating children with attention-deficit-hyperactivity disorder, combined type (ADHD-C) from their peers without ADHD.METHODS Thirty-four children participated in the study: 17 males with ADHD-C (mean age 10y 4mo, SD 1y 9mo) and 17 comparison children (12 males, 5 females; mean age 10y 8mo, SD 1.7y). Attentional functions were assessed using a computer-administered, child-friendly test series in German (i.e. Testbatterie zur Aufmerksamkeitsprü fung fü r Kinder; KITAP). The KITAP measures several attentional components, including alertness and executive attention (inhibition, divided attention, flexibility). RESULTSThe variable best able to discriminate between children with and without ADHD-C was found to be response time variability in a go ⁄ no go task, followed by, in order, number of errors in a divided attention task and response time variability in an alertness task. However, group discrimination was not facilitated by differences in either response latency or accuracy of response in visuospatial attention and attentional flexibility tasks. INTERPRETATIONThe assessment of attentional functions proved to be a powerful instrument for discriminating between children with and without ADHD-C. Notably, the discriminative power of executive attention was found to be task dependent and dependent on processing demands.Attention is one of the most fundamental cognitive processes. Over the years, different conceptualizations of attention have emerged; some of them are rather general (attention as a pool of resources), 1 whereas others are more specific (attention as enhanced processing of relevant stimuli). 2 The hypothesized underlying neural mechanism is the top-down guidance of attention, which has been studied extensively by means of electrophysiological 3 and functional brain imaging studies. 4,5 The latter reveal that neural activity in task-relevant regions is higher in response to attended than to unattended stimuli.Attention is not a unitary construct but, rather, comprises a multicomponential set of neurocognitive functions and processes. 6 According to Posner and Peterson 2 and Rothbart and Posner, 7 attention is best conceptualized by three interrelated neurofunctional networks, namely orienting, alerting, and executive control. The orienting network mediates visuospatial attention and is responsible for detecting sensory input. It is thought to be modulated by acetylcholine and is supported by posterior attentional networks (including the superior parietal lobe and the temporoparietal junction). 8 The alerting network mediates the employment and maintenance of the alert state and is supported by frontoparietal regions of the right hemisphere, possibly modulated by noradrenergic neurotransmitters. 8 The executive network is enrolled in attention shifting, inhibitory control, and conflict monitoring. It is thought to be modulated by dopamine and is subserved by prefrontal networks including t...
To better characterize the clinical spectrum related to white-matter hyperintensities (WMH) in small vessel disease, 66 patients with WMH but without any lacunar infarct were selected out of a cohort of 248 CADASIL individuals. Characteristics of these patients were compared to those of patients with lacunar infarcts. Relationships between the normalized volume of WMH (nWMH), presence of microhemorrhages, brain parenchymal fraction (BPF). and cognitive performances were assessed. The Trail Making Test (TMT) A and B times, Mattis Dementia Rating Scale (MDRS) total score, attention subscore, verbal fluency score and delayed memory recall were significantly correlated with nWMH but not with BPF. Presence of microhemorrhages was associated with worse TMT B time and attention MDRS subscore after adjustment for WMH. All subjects had Mini-Mental Status Examination scores ≥24 and presented with no or only mild disability. These results suggest that CADASIL patients with isolated WMH can present with executive and attention deficit but not with severe disability and that additional lesions are needed to cause significant disability and/or dementia.
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