CADA-PRO: A Patient Questionnaire Measuring Key Cognitive, Motor, Emotional, and Behavioral Outcomes in CADASIL.

BACKGROUND: Cerebral small vessel disease (cSVD) of ischemic type, either sporadic or genetic, as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), can impact the quality of daily life on various cognitive, motor, emotional, or behavioral aspects. No instrument has been developed to measure these outcomes from the patient's perspective. We thus aimed to develop and validate a patient-reported questionnaire. METHODS: In a development study, 79 items were generated by consensus between patients, family representatives, and cSVD experts. A first sample of patients allowed assessing the feasibility (missing data, floor and ceiling effect, and acceptability), internal consistency, and dimensionality of a first set of items. Thereafter, in a validation study, we tested a reduced version of the item set in a larger sample to assess the feasibility, internal consistency, dimensionality, test-retest reliability, concurrent validity, and sensitivity to change. RESULTS: The scale was developed in 44 patients with cSVD and validated in a second sample of 89 individuals (including 43 patients with CADASIL and 46 with another cSVD). The final CADASIL Patient-Reported Outcome scale comprised 18 items covering 4 categories of consequences (depression/anxiety, attention/executive functions, motor, and daily activities) of the disease. The proportion of missing data was low, and no item displayed a major floor or ceiling effect. Both the internal consistency and test-retest reliability were good (Cronbach alpha=0.95, intraclass correlation coefficient=0.88). In patients with CADASIL, CADASIL Patient-Reported Outcome scores correlated with the modified Rankin Scale, Starkstein Apathy Scale, Hospital Anxiety and Depression scale, Working Memory Index, and trail making test times. In patients with other cSVDs, CADASIL Patient-Reported Outcome correlated only with Hospital Anxiety and Depression scale and Starkstein Apathy Scale. CONCLUSIONS: The CADASIL Patient-Reported Outcome may be an innovative instrument for measuring patient-reported outcomes in future cSVD trials. Full validation was obtained for its use in patients with CADASIL, but further improvement is needed for its application in other cSVDs.

Diffusion prepared pseudo-continuous arterial spin labeling reveals blood-brain barrier dysfunction in patients with CADASIL.

OBJECTIVES: Diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) is a newly proposed MRI method to noninvasively measure the function of the blood-brain barrier (BBB). We aim to investigate whether the water exchange rate across the BBB, estimated with DP-pCASL, is changed in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and to analyze the association between the BBB water exchange rate and MRI/clinical features of these patients. METHODS: Forty-one patients with CADASIL and thirty-six age- and sex-matched controls were scanned with DP-pCASL MRI to estimate the BBB water exchange rate (kw). The MRI lesion burden, the modified Rankin scale (mRS), and the neuropsychological scales were also examined. The association between kw and MRI/clinical features was analyzed. RESULTS: Compared with that in the controls, kw in patients with CADASIL was decreased at normal-appearing white matter (NAWM) (t = - 4.742, p < 0.001), cortical gray matter (t = - 5.137, p < 0.001), and deep gray matter (t = - 3.552, p = 0.001). After adjustment for age, gender, and arterial transit time, kw at NAWM was negatively associated with the volume of white matter hyperintensities (ß = - 0.754, p = 0.001), whereas decreased kw at NAWM was independently associated with an increased risk of abnormal mRS scale (OR = 1.058, 95% CI: 1.013-1.106, p = 0.011) in these patients. CONCLUSIONS: This study found that the BBB water exchange rate was decreased in patients with CADASIL. The decreased BBB water exchange rate was associated with an increased MRI lesion burden and functional dependence of the patients, suggesting the involvement of BBB dysfunction in the pathogenesis of CADASIL. CLINICAL RELEVANCE STATEMENT: DP-pCASL reveals BBB dysfunction in patients with CADASIL. The decreased BBB water exchange rate is associated with MRI lesion burden and functional dependence, indicating the potential of DP-pCASL as an evaluation method for disease severity. KEY POINTS: • DP-pCASL reveals blood-brain barrier dysfunction in patients with CADASIL. • Decreased BBB water exchange rate, an indicator of BBB dysfunction detected by DP-pCASL, was associated with MRI/clinical features of patients with CADASIL. • DP-pCASL can be used as an evaluation method to assess the severity of disease in patients with CADASIL.

The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia.

OBJECTIVES: Executive dysfunction is a predominant cognitive symptom in cerebral small vessel disease (SVD). The Institute of Cognitive Neurology Frontal Screening (IFS) is a well-validated screening tool allowing the rapid assessment of multiple components of executive function in Spanish-speaking individuals. In this study, we examined performance on the IFS in subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited condition leading to the early onset of SVD. We further explored associations between performance on the IFS and magnetic resonance imaging (MRI) markers of SVD. METHODS: We recruited 24 asymptomatic CADASIL subjects and 23 noncarriers from Colombia. All subjects underwent a research MRI and a neuropsychological evaluation, including the IFS. Structural MRI markers of SVD were quantified in each subject, together with an SVD Sum Score representing the overall burden of cerebrovascular alterations. General linear model, correlation, and receiver operating characteristic curve analyses were used to explore group differences on the IFS and relationships with MRI markers of SVD. RESULTS: CADASIL subjects had a significantly reduced performance on the IFS Total Score. Performance on the IFS correlated with all quantified markers of SVD, except for brain atrophy and perivascular spaces enlargement. Finally, while the IFS Total Score was not able to accurately discriminate between carriers and noncarriers, it showed adequate sensitivity and specificity in detecting the presence of multiple MRI markers of SVD. CONCLUSIONS: These results suggest that the IFS may be a useful screening tool to assess executive function and disease severity in the context of SVD.

Not Described Variant of Notch3 Gen for Cadasil Disease.

Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein.

Relationship between changes in resting-state spontaneous brain activity and cognitive impairment in patients with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mainly manifests with cognitive impairment. Cognitive deficits in patients with CADASIL are correlated with structural brain changes such as lacunar lesion burden, normalized brain volume, and anterior thalamic radiation lesions, but changes in resting-state functional brain activity in patients with CADASIL have not been reported. METHODS: This study used resting-state functional magnetic resonance imaging (fMRI) to measure the amplitude of low-frequency fluctuation (ALFF) in 22 patients with CADASIL and 44 healthy matched controls. A seed-based functional connectivity (FC) analysis was used to investigate whether the dysfunctional areas identified by ALFF analysis exhibited abnormal FC with other brain areas. Pearson's correlation analysis was used to detect correlations between the ALFF z-score of abnormal brain areas and clinical scores in patients with CADASIL. RESULTS: Patients with CADASIL exhibited significantly lower ALFF values in the right precuneus and cuneus (Pcu/CU) and higher ALFF values in the bilateral superior frontal gyrus (SFG) and left cerebellar anterior and posterior lobes compared with controls. Patients with CADASIL showed weaker FC between the areas with abnormal ALFF (using peaks in the left and right SFG and the right Pcu/CU) and other brain areas. Importantly, the ALFF z-scores for the left and right SFG were negatively associated with cognitive performance, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment scores (MoCA), respectively, whereas those of the right Pcu/CU were positively correlated with the MMSE score. CONCLUSIONS: This preliminary study provides evidence for changes in ALFF of the right Pcu/CU, bilateral SFG and left cerebellar anterior and posterior lobes, and associations between ALFF values for abnormal brain areas and cognitive performance in patients with CADASIL. Therefore, spontaneous brain activity may be a novel imaging biomarker of cognitive impairment in this population.

Reduced resting-state brain functional network connectivity and poor regional homogeneity in patients with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests principally as a suite of cognitive impairments, particularly in the executive domain. Executive functioning requires the dynamic coordination of neural activity over large-scale networks. It remains unclear whether changes in resting-state brain functional network connectivity and regional homogeneities (ReHos) underly the mechanisms of executive dysfunction evident in CADASIL patients. METHODS: In this study, 22 CADASIL patients and 44 matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). Independent component analysis (ICA) was used to measure functional brain network connectivity, and ReHos were calculated to evaluate local brain activities. We used seed-based functional connectivity (FC) analyses to determine whether dysfunctional areas (as defined by ReHos) exhibited abnormal FC with other brain areas. Relationships among the mean intra-network connectivity z-scores of dysfunctional areas within functional networks, and cognitive scores were evaluated using Pearson correlation analyses. RESULTS: Compared to the controls, CADASIL patients exhibited decreased intra-network connectivity within the bilateral lingual gyrus (LG) and the right cuneus (CU) (thus within the visual network [VIN)], and within the right precuneus (Pcu), inferior frontal gyrus (IFG), and precentral gyrus (thus within the frontal network [FRN]). Compared to the controls, patients also exhibited significantly lower ReHos in the right precuneus and cuneus (Pcu/CU), visual association cortex, calcarine gyri, posterior cingulate, limbic lobe, and weaker FC between the right Pcu/CU and the bilateral parahippocampal gyrus (PHG), and between the right Pcu/CU and the right postcentral gyrus. Notably, the mean connectivity z-scores of the bilateral LG and the right CU within the VIN were positively associated with compromised attention, calculation and delayed recall as revealed by tests of the various cognitive domains explored by the Mini-Mental State Examination. CONCLUSIONS: The decreases in intra-network connectivity within the VIN and FRN and reduced local brain activity in the posterior parietal area suggest that patients with CADASIL may exhibit dysfunctional visuomotor behaviors (a hallmark of executive function), and that all visual information processing, visuomotor planning, and movement execution may be affected.

CADASIL and Bipolar Affective Disorder.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare monogenic disorder caused by mutations in the NOTCH3 gene. The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines. However, psychiatric manifestations which mainly include mood disturbances have also been reported in CADASIL. Manic symptoms and bipolar disorders are rarely documented in CADASIL and existing reports generally lack detailed descriptions of the psychiatric evaluation. We discuss a case of Bipolar Affective Disorder (BD) in a British woman with a family history of CADASIL. This case provides insight into the diagnosis and management of BD as well as the possible underlying aetiologies that should be considered. The similarities between BD and CADASIL in terms of imaging, genetic, and therapeutic aspects raise the possibility of common dysfunctional pathways. BD in CADASIL may warrant greater consideration by both psychiatrists as well as non-psychiatric specialists and further studies are required to understand the pathological significance.

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.

Do Attachment Style and Emotion Regulation Strategies Indicate Distress in Predictive Testing?

Predictive genetic testing for a neurogenetic disorder evokes strong emotions, and may lead to distress. The aim of this study is to investigate whether attachment style and emotion regulation strategies are associated with distress in persons who present for predictive testing for a neurogenetic disorder, and whether these psychological traits predict distress after receiving test results. Self-report scales were used to assess attachment insecurity (anxiety and avoidance) and maladaptive emotion regulation strategies (self-blame, rumination, catastrophizing) in adults at 50 % risk for Huntington's Disease (HD), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Hereditary Cerebral Hemorrhage With Amyloidosis - Dutch type (HCHWA-D), when they presented for predictive testing. Distress was measured before testing and twice (within 2 months and between 6 and 8 months) after receiving test results. Pearson correlations and linear regression were used to analyze whether attachment style and emotion regulation strategies indicated distress. In 98 persons at risk for HD, CADASIL, or HCHWA-D, attachment anxiety and catastrophizing were associated with distress before predictive testing. Attachment anxiety predicted distress up to 2 months after testing. Clinicians may consider looking for signs of attachment anxiety and catastrophizing in persons who present for predictive testing, to see who may be vulnerable for distress during and after testing.

Influence of vascular risk factors and neuropsychological profile on functional performances in CADASIL: results from the MIcrovascular LEukoencephalopathy Study (MILES).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease that may lead to disability and whose phenotype modulators are still unknown. METHODS: In the MIcrovascular LEukoencephalopathy Study (MILES), we assessed the influence of vascular risk factors and the effect of different cognitive domains (memory, psychomotor speed and executive functions) performances on functional abilities in CADASIL in comparison with age-related leukoencephalopathy (ARL). RESULTS: We evaluated 51 CADASIL patients (mean age 50.3 ± 13.8 years, 47.1% males) and 68 ARL patients (70.6 ± 7.4 years, 58.8% males). Considering vascular risk factors, after adjustment for age, CADASIL patients had higher mean BMI values than ARL patients. Stroke history frequency was similar in the two groups. After adjustment for age, more CADASIL patients were disabled (impaired on ≥ 2 items of the Instrumental Activities of Daily Living scale) in comparison with ARL patients, and CADASIL patients had worse functional performances evaluated with the Disability Assessment for Dementia (DAD) scale. In CADASIL patients, hypertension was related to both DAD score and disability. The cognitive profile of CADASIL and ARL patients was similar, but on a stepwise linear regression analysis functional performances were mainly associated with the memory index (ß = -0.418, P < 0.003) in CADASIL patients and the executive function index (ß = -0.321, P = 0.028) in ARL. CONCLUSIONS: This study suggests that hypertension may contribute to functional impairment in CADASIL and that memory impairment has a large influence on functional decline in contrast with that observed in a sample of subjects with ARL.

CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations of the NOTCH3 gene, which result in degeneration of vascular smooth muscle cells, arteriolar stenosis, and impaired cerebral blood flow. For clinicians this is the commonest hereditary adult-onset condition causing stroke and vascular dementia at middle age. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Coexistence of autoimmunity is atypical and has been described only in occasional patients. METHODS: Three members of a Greek family from the island of Lesvos of North East Greece were evaluated. The patients come from a four-generation family in which there were at least seven members with clinical data suggestive of CADASIL. We describe here the clinical, imaging and biochemical findings in this family with R169C mutation at exon 4 and presenting additional clinical and biochemical findings suggestive of autoimmune disorder. DNA was extracted from whole blood using standard procedures for sequencing. RESULTS: Three affected members of this family carried the R169C. In a phenotypic analysis of affected individuals from four generations with CADASIL, the disease was characterized by migraine attacks, recurrent subcortical infarcts, and cognitive decline with typical anterior temporal lobe white matter lesions. At least 3 mutation carriers from two generations had increased antinuclear antibody (ANA) titers and various combinations of rash, joint pains, photosensitivity, and renal involvement. CONCLUSION: This is a rare description of the coexistence of autoimmunity in CADASIL patients with possible worsening clinical effects. The study extends the spectrum of atypical presentation of CADASIL. The coexistence of autoimmunity does not necessarily exclude CADASIL, but may cause an additional diagnostic and therapeutic challenge. This autoimmune disorder may have increased the severity of the disease and, additionally, may be related to the pathogenetic mechanisms of CADASIL. It is possible that the NOTCH3 mutation alone is not enough to trigger autoimmunity since, in the case of our family, the R169C mutation has already been described in other families with no evidence of coexistent autoimmunity. Other genetic or environmental factors or interactions and/or common pathways between the vascular and immune systems are probably co-operating. Further, prospective studies are needed to clarify the prevalence and types of autoimmune disorders present in CADASIL families.

Dilated perivascular spaces in small-vessel disease: a study in CADASIL.

BACKGROUND AND AIM: Dilated perivascular spaces (dPVS) have previously been associated with aging and hypertension-related cerebral microangiopathy. However, their risk factors, radiological features and clinical relevance have been poorly evaluated in CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology of ischemic small-vessel disease. The purpose of this study was to investigate these different aspects in a large cohort of patients with this disorder. METHODS: Demographic and MRI data of 344 patients from a prospective cohort study were analyzed. The severity of dPVS was evaluated separately in the anterior temporal lobes, subinsular areas, basal ganglia and white matter, using validated semiquantitative scales. Logistic and multiple linear regression models were used to determine the risk factors associated with the severity of dPVS in these different regions and their relationships with cognition, disability and the MRI markers of the disease (white matter hyperintensities (WMH) lacunar infarcts, microbleeds and brain parenchymal fraction (BPF)). RESULTS: The severity of dPVS was found to increase with age regardless of cerebral area (p<0.001). In contrast with dPVS in other locations, the severity of dPVS in the temporal lobes or subinsular areas was also found strongly and specifically related to the extent of WMH (p<0.001). Conversely, no significant association was detected with lacunar volume, number of microbleeds or BPF. A high degree of dPVS in the white matter was associated with lower cognitive performances independently of age and other MRI markers of the disease including BPF (p≤0.04). CONCLUSIONS: In CADASIL, the progression of the hereditary microangiopathy with aging may promote the dilation of perivascular spaces throughout the whole brain but with variable extent according to cerebral location. In temporal lobes and subinsular areas, dPVS are common MRI features and may share a similar pathogenesis with the extension of WMH during the course of the disease. dPVS may also participate in the development of cognitive decline in this model of small-vessel disease, and their large number in white matter may alert clinicians to a higher risk of cognitive decline in CADASIL.

Emotional disturbance in CADASIL: its impact on quality of life and caregiver burden.

BACKGROUND AND PURPOSE: Recurrent strokes and cognitive dysfunction are the major symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, emotional disturbances in CADASIL patients are incompletely understood. The aim of this study was to investigate emotional disturbances in CADASIL and their impact on the patients' quality of life (QOL) and caregiver burden. METHODS: From 54 patients who were diagnosed as CADASIL between January 2000 and August 2012 in the Asan Medical Center, Seoul, Korea, 23 patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale was used for the assessment of depressive emotional disturbances (DED). For nondepressive emotional disturbances (NDED), the criteria of Kim and Choi-Kwon [Neurology 2000;54:1805-1810] were used for emotional incontinence (excessive/inappropriate expression of laughing or crying), and the modified Spielberger Trait Anger Scale was used for anger proneness (excessive/inappropriate expression of anger). Patients' QOL and caregiver burden were assessed with stroke-specific emotional QOL and the Sense of Competence Questionnaire (SCQ), respectively. Functional disability was assessed by the modified Rankin scale (mRS), and white matter ischemic changes and microbleeds were analyzed using brain magnetic resonance images. RESULTS: Twelve patients (52.2%) had various emotional disturbances including DED (n=10, 43.5%) and NDED (n=7, 30.4%). The presence of any emotional disturbances was associated with thalamic (p=0.012) and cortical (p=0.037) microbleeds, mRS (p=0.001), cognitive impairment (p=0.002), patients' low QOL (p=0.009) and increased caregiver burden (p=0.002). DED was associated with multiple (≥10) microbleeds (p=0.039), cognitive impairment (p=0.030) and mRS (p=0.030), and negatively influenced all domains of patients' QOL and caregiver burden. NDED was associated with cortical microbleeds (p=0.017) and mRS (p=0.014). Unlike DED, NDED was not associated with patients' poor QOL, except for thinking domain, but was significantly related to total SCQ and subscales 1 and 2 of SCQ (p=0.012). CONCLUSIONS: More than half the CADASIL patients had emotional disturbances, either DED or NDED. Both are associated with patients' poor QOL and increased caregiver burden, the former more markedly than the latter. Considering that CADASIL is a progressive disease with deteriorating patients' QOL, physicians have to pay more attention to emotional problems in CADASIL patients. Treatment strategies should be investigated in this regard to improve patients' QOL and reduce caregiver burden.

Cognitive profile of CADASIL patients with R544C Notch3 mutation.

BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. In the present study, we aimed to analyze cognitive and neuroimaging profiles of CADASIL patients with R544C mutation. METHODS: Fifty-eight consecutive patients with R544C mutation and 26 normal controls were investigated. The patients were divided into two groups depending on the presence (CADASIL with dementia: CADASIL-D) or absence of dementia (CADASIL no dementia: CADASIL-ND). We applied the same neuropsychological test to the three groups. Brain magnetic resonance images were obtained from 58 patients with R544C mutation. Linear regression models were used to assess the impact of lacunes and white matter hyperintensities on cognitive function in the CADASIL-ND group. RESULTS: Compared to controls, the CADASIL-ND group demonstrated significant difficulties concerning measures of attention, executive function, and motor control. The CADASIL-D group was impaired in all cognitive domains that were assessed, except the language domain. After correction for age and educational level, the number of lacunes was associated with lower scores in the Alzheimer's Disease Assessment Scale cognitive subtest and Stroop color test in the CADASIL-ND group. CONCLUSIONS: Non-Caucasian CADASIL patients with R544C mutation and Caucasian CADASIL patients show similar patterns of cognitive impairment.

Abnormal sensorimotor plasticity in CADASIL correlates with neuropsychological impairment.

OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease of the brain caused by mutations in the NOTCH3 gene. CADASIL progresses, in some cases, to subcortical dementia with a particular cognitive impairment. Different diseases in the dementia spectrum share a central cholinergic and sensorimotor plasticity alteration. We aimed to study different intracortical circuits and sensorimotor plasticity in CADASIL patients using transcranial magnetic stimulation protocols, and to determine whether these characteristics correlated with the results of clinical neuropsychological evaluation. METHODS: Ten CADASIL patients and 10 healthy subjects were included in the study. All subjects underwent a transcranial magnetic stimulation study examining different intracortical circuits. Sensorimotor plasticity was also assessed using a paired associative stimulation and extensive neuropsychological tests. RESULTS: CADASIL patients showed a lack of intracortical facilitation, short latency afferent inhibition and sensorimotor plasticity when compared with control subjects. CADASIL patients also showed an altered neuropsychological profile. Correlation between sensorimotor plasticity and neuropsychological alterations was observed in CADASIL patients. CONCLUSIONS: These results suggest that acetylcholine and glutamate could be involved in the dementia process in CADASIL and that abnormal sensorimotor plasticity correlates with the neuropsychological profile in CADASIL patients.

Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disease caused by alterations in the NOTCH3 gene. METHODS: We describe the clinical, instrumental, and genetic findings in CADASIL patients who carry novel NOTCH3 gene mutations. RESULTS AND CONCLUSIONS: This study broadens the spectrum of clinical manifestations and genetic alterations associated with this disease.

Effects of gender on the phenotype of CADASIL.

BACKGROUND AND PURPOSE: In the general population, migraine, cerebrovascular diseases, and vascular dementia differ in many aspects between men and women. CADASIL is considered a unique model to investigate migraine with aura, stroke, and dementia related to ischemic small vessel disease. This study aims to evaluate the effect of gender on the main clinical and neuroimaging characteristics of CADASIL. METHODS: Cross-sectional data from 313 CADASIL patients including various clinical and cognitive scores and MRI parameters were compared between men and women, and between those younger and older than the median age of the population corresponding to the usual age of menopause (51 years). RESULTS: At younger than 51 years, migraine with aura was 50% more prevalent in women and stroke was 75% more prevalent in men. After the fifth decade, men had higher National Institutes of Health Stroke Scale and Rankin scores than women and more severe executive dysfunction, although global cognitive scores were similar. Age at first stroke, the number of stroke events, and the prevalence of dementia and psychiatric symptoms did not differ between men and women. Brain volume was lower in men with a trend for a larger volume of lacunar infarcts. CONCLUSIONS: In CADASIL, migraine with aura is more frequent in women and stroke is more frequent in men before the age of menopause. This difference seems to vanish after this age limit but may result in a higher degree of cognitive impairment and cerebral atrophy in men at the late stage of the disease. The presumable role of ovarian hormones in these gender-related differences remains to be explored.

Carotid atherosclerotic markers in CADASIL.

PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations of the NOTCH3 gene. Marked variations in disease severity have raised the hypothesis that non-genetic factors may modulate the expressivity of the phenotype. The aim of the current study was to evaluate whether atherosclerosis, assessed by carotid duplex ultrasonography, is associated with variations in the clinical and MRI phenotype of CADASIL. METHODS: Data from 144 consecutive patients enrolled in an ongoing prospective cohort study were collected. Degree of disability was assessed by the modified Rankin Scale, that of cognitive impairment by the Mattis Dementia Rating Scale (MDRS). The total volume of the brain, of lacunar lesions and of white matter hyperintensities, the number of cerebral microhemorrhages, and parameters derived from histograms of apparent diffusion coefficient were measured on cerebral MRI. Atherosclerosis was evaluated by B-mode ultrasonography of carotid arteries. Both the carotid intima-media thickness (cIMT) and the presence of carotid plaques or stenosis were recorded. RESULTS: Higher cIMT was found to be independently associated with lower MDRS scores when this score was less than the quartile limit (p = 0.02). Only a trend for a positive association was detected between cIMT and the Rankin score (p = 0.06). There was no significant association between carotid markers and the occurrence of stroke or MRI parameters except for diffusion data. The mean and peak values of MRI diffusion histograms were found positively associated with the presence of plaques (p < 0.01). CONCLUSION: The results suggest that the severity of atherosclerosis may relate to cognitive decline in CADASIL and that this effect is possibly related to the degree of microstructural cerebral tissue lesions. Longitudinal studies are needed to confirm these results.

Major depression and bipolar disorders in CADASIL: a study using the DSM-IV semi-structured interview.

OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy characterized by migraine, cerebrovascular events, and cognitive impairment. Although recognized as a cardinal feature of the disease, psychiatric disturbances have rarely been the object of focused studies. We performed a structured evaluation of mood disorders in CADASIL. MATERIALS AND METHODS: Twenty-three patients with CADASIL (five men and 18 women) were assessed by psychiatrists using the Structured Clinical Interview for the DSM-IV, clinician version. For the quantitative assessment of current mood disorder symptoms, the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Scale (YMRS) were used. RESULTS: A lifetime depressive episode was recorded in 17/23 (73.9%) patients with CADASIL. Six (26.1%) patients with CADASIL reported a current depressive episode. A diagnosis of manic lifetime episode was made in 6 (26.1%) patients with CADASIL. The HRSD mean score in patients with current depression was 9.1 ± SD 8.1. The YMRS mean score was 14.2 ± SD 4.1 for manic CADASIL. CONCLUSION: This study confirms that mood disorders are frequent in CADASIL. The use of a structured psychiatric interview outlines a frequency of depression higher than that previously reported but also reveals a considerable frequency of bipolar disorders. If confirmed in larger series, these data suggest that a greater attention should be paid to the psychiatric aspects in CADASIL.

Intelligence impairment, personality features and psychopathology disturbances in a family affected with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small-vessel disease of the brain that is characterized by headache, recurring lacunar strokes, mood changes and progressive cognitive deterioration. The disease is transmitted with an autosomal dominant pattern and usually starts during midadulthood (at 30-50 years of age). Cognitive deficits in patients with CADASIL develop slowly. The dementia causes frontal-like symptoms and it typically develops after a history of recurrent stroke. We describe three patients from one Spanish family affected by this disease. All three cases underwent comprehensive clinical and neuropsychological examination, and were monitored for seven years. The results obtained in this study describe a) a significant loss of the intelligence quotient (IQ) and noticeable damage to abstract ability (g factor), b) mood and psychopathological disturbances (major depression and dysthymia), and c) a personality with neurotic features.