The Pattern of Cognitive Performance in CADASIL: A Monogenic Condition Leading to Subcortical Ischemic Vascular Dementia

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, D-81377 Munich, Germany. .
American Journal of Psychiatry (Impact Factor: 12.3). 12/2005; 162(11):2078-85. DOI: 10.1176/appi.ajp.162.11.2078
Source: PubMed


Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects.
A cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 matched comparison subjects (mean age=47.2 years, SD=14.0) was conducted. Participants underwent a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring.
CADASIL subjects had pronounced impairments of the timed measures (Stroop II and III, Trail Making Test, symbol digit, digit cancellation). Measures of error monitoring (Stroop III, Trail Making Test, symbol digit, maze task) were also significantly affected but to a lesser extent. Prominent deficits further included verbal fluency and ideational praxis. Recall, orientation, and receptive language skills were largely preserved. Subgroup analyses indicated a similar profile in subjects with early and advanced impairment of global cognitive performance.
The findings highlight processing speed as the most substantial area of cognitive impairment in CADASIL subjects, with less pronounced yet significant deficits in other aspects of executive performance and attention. This profile of cognitive impairment is present at an early stage and enables the construction of targeted test batteries for clinical trials. It is hypothesized that the profile of dysfunction described here represents the core of the cognitive syndrome associated with small vessel disease and subcortical ischemic vascular lesions.

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    • "He showed no evidence of a sound or reasonable strategy about how to gain money in the fictitious game and consequently behaved randomly with respect to his choices. The findings of impairments in executive functions (planning, problem solving, set-shifting, cognitive flexibility, categorization, error detection, and monitoring) are in agreement with reports in the literature (Peters et al., 2005; Buffon et al., 2006). Contrary to other descriptions, we did not find evidence of relative preservation of performance on letter fluency tasks in comparison to category fluency tasks (Amberla et al., 2004; Dichgans, 2009). "
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    ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - is the most common genetic source of vascular dementia in adults, being caused by a mutation in NOTCH3 gene. Spontaneous de novo mutations may occur, but their frequency is largely unknown. Ischemic strokes and cognitive impairments are the most frequent manifestations, but seizures affect up to 10% of the patients. Herein, we describe a 47-year-old male scholar with a genetically confirmed diagnosis of CADASIL (Arg133Cys mutation in the NOTCH3 gene) and a seemingly negative family history of CADASIL illness, who was investigated with a comprehensive neuropsychological testing battery and neuroimaging methods. The patient demonstrated on one hand severe and accelerated deteriorations in multiple cognitive domains such as concentration, long-term memory (including the episodic-autobiographical memory domain), problem solving, cognitive flexibility and planning, affect recognition, discrimination and matching, and social cognition (theory of mind). Some of these impairments were even captured by abbreviated instruments for investigating suspicion of dementia. On the other hand the patient still possessed high crystallized (verbal) intelligence and a capacity to put forth a façade of well-preserved intellectual functioning. Although no definite conclusions can be drawn from a single case study, our findings point to the presence of additional cognitive changes in CADASIL in middle adulthood, in particular to impairments in the episodic-autobiographical memory domain and social information processing (e.g., social cognition). Whether these identified impairments are related to the patient's specific phenotype or to an ascertainment bias (e.g., a paucity of studies investigating these cognitive functions) requires elucidation by larger scale research.
    Full-text · Article · Jun 2014 · Frontiers in Behavioral Neuroscience
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    • "Cognitive decline may also commence insidiously before the onset of symptomatic ischemic episodes in CADASIL [13]. These impairments are suggestive of dysfunction in the subcortical-frontal network [12,14]. Memory and other cognitive functions are relatively preserved at the early stages of CADASIL [12]. "
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    ABSTRACT: Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine, recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological testing by psychologists. Case presentation A 53 year old woman developed symptoms of mania in her 50s leading to a personality change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be helpful in treating her manic symptoms and for behavior control. Conclusion We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
    Full-text · Article · Jun 2014 · BMC Psychiatry
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    • "Deficits in information processing speed are common in elderly subjects (Eckert, 2011; Salthouse, 2000) and a typical feature of vascular cognitive impairment (O'Brien et al., 2003). They are frequently related to cerebral small vessel disease (SVD) (Jokinen et al., 2009; Peters et al., 2005b; Prins et al., 2005), but the mechanisms are insufficiently understood. "
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    ABSTRACT: Slowed processing speed is common in elderly subjects and frequently related to cerebral small vessel disease. Previous studies have demonstrated associations between processing speed and subcortical ischemic lesions as well as cortical alterations but the precise functional-anatomical relationships remain poorly understood. Here we assessed the impact of both cortical and subcortical changes on processing speed by measuring regional cortical thickness and regional lesion volumes within distinct white-matter tracts. To limit confounding effects from age-related pathologies we studied patients with CADASIL, a genetic small vessel disease. General linear model analysis revealed significant associations between cortical thickness in the medial frontal and occipito-temporal cortex and processing speed. Bayesian network analysis showed a robust conditional dependency between the volume of lacunar lesions in the left anterior thalamic radiation and cortical thickness of the left medial frontal cortex, and between thickness of the left medial frontal cortex and processing speed, whereas there was no direct dependency between lesion volumes in the left anterior thalamic radiation and processing speed. Our results suggest that the medial frontal cortex has an intermediate position between lacunar lesions in the anterior thalamic radiation and deficits in processing speed. In contrast, we did not observe such a relationship for the occipito-temporal region. These findings reinforce the key role of frontal-subcortical circuits in cognitive impairment resulting from cerebral small vessel disease.
    Full-text · Article · Dec 2013 · Clinical neuroimaging
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