Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study.

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. CONCLUSIONS: Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other's onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers.

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.

Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment.

Patients with vascular cognitive impairment (VCI) commonly exhibit deficits in processing speed. This has been attributed to a disruption of frontal-subcortical neuronal circuits by ischemic lesions, but the exact mechanisms and underlying anatomical structures are poorly understood. We set out to identify a strategic brain network for processing speed by applying graph-based data-mining techniques to MRI lesion maps from patients with small vessel disease. We studied 235 patients with CADASIL, a genetic small vessel disease causing pure VCI. Using a probabilistic atlas in standard space we first determined the regional volumes of white matter hyperintensities (WMH) and lacunar lesions (LL) within major white matter tracts. Conditional dependencies between the regional lesion volumes and processing speed were then examined using Bayesian network analysis. Exploratory analysis identified a network of five imaging variables as the best determinant of processing speed. The network included LL in the left anterior thalamic radiation and the left cingulum as well as WMH in the left forceps minor, the left parahippocampal white matter and the left corticospinal tract. Together these variables explained 34% of the total variance in the processing speed score. Structural equation modeling confirmed the findings obtained from the Bayesian models. In summary, using graph-based models we identified a strategic brain network having the highest predictive value for processing speed in our cohort of patients with pure small vessel disease. Our findings confirm and extend previous results showing a role of frontal-subcortical neuronal circuits, in particular dorsolateral prefrontal and cingulate circuits, in VCI.

White-matter lesions without lacunar infarcts in CADASIL.

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.

Longitudinal changes of cortical morphology in CADASIL.

In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy), a genetic model of subcortical ischemic vascular dementia (SIVD), clinical status was previously found related to cortex morphology. In the present report, alterations of cortex morphology and their links to clinical worsening were investigated in 190 CADASIL patients followed during 24.4 months. Linear models were used to test relationships between: (1) clinical worsening and changes of depth of cortical sulci and of cortical thickness; (2) alterations of cortical morphology and changes of volume of white matter hyperintensities (WMH(v)) and of lacunar lesions (LL(v)). Reduction of sulcal depth was independently associated with increased time to complete trail making test A and B (p < 0.0001 and p = 0.004) and that of cortical thickness to increased disability (modified Rankin's scale, p = 0.008), while brain atrophy was only related to global cognitive worsening (Mattis dementia rating scale, p = 0.002). The impact of volume of lacunar lesions on cortical alterations was larger than that of volume of white matter hyperintensities. Cortical alterations, mainly related to lacunar lesions, evolve parallel to clinical worsening. These results further support the eventual role of cortical alterations in subcortical ischemic vascular dementia.

Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL.

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.

Predictive validity of attentional functions in differentiating children with and without ADHD: a componential analysis.

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 Aufmerksamkeitsprüfung für Kinder; KITAP). The KITAP measures several attentional components, including alertness and executive attention (inhibition, divided attention, flexibility). RESULTS: The 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. INTERPRETATION: The 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.

Neural correlates of primary and reflective consciousness of spatial orienting.

Using functional magnetic resonance imaging, we asked participants to perform a visual target detection task with peripheral cues. In the first part of the experiment, cues were not predictive of the side of occurrence of the incoming target. In the second part of the experiment, unbeknownst to the participants, cues became 80% predictive, thus inducing an endogenous orienting of spatial attention. Confirming previous results, in the second part response times (RTs) decreased for validly cued trials and increased for invalid trials. Half of the participants were subsequently able to correctly describe the cue-target relationships ('verbalizers'), thus demonstrating reflective consciousness of endogenous orienting. Also non-verbalizer participants showed a similar RT pattern, indicating the occurrence of endogenous orienting without reflective consciousness. Both groups of participants showed fronto-parietal activity typically observed in spatial attention tasks. Verbalizers, in addition, demonstrated stronger activity in the anterior cingulate cortex (ACC), consistent with the proposed role of this structure in purposeful behaviour and in the monitoring of its consequences. The extensive pattern of connectivity of the ACC is ideally suited to integrate the activity of the large neural assemblies necessary for reflective consciousness to emerge.