Association of silent lacunar infarct with brain atrophy and cognitive impairment.

OBJECTIVE: Silent lacunar infarct (SLI) is associated with cognitive decline and linked to an increased risk of stroke and dementia. We examined the association of SLI with MRI measures of cortical thickness, subcortical and lateral ventricular shapes and cognition in 285 ethnic Chinese elderly. METHODS: SLI, cortical thickness, shapes of subcortical and ventricular structures were quantified using MRI. The cognitive performance was assessed using comprehensive neuropsychological tests. Linear regression was used to examine associations among SLI, brain measures and cognition. RESULTS: SLI was associated with atrophy in multiple subcortical structures, ventricular enlargement and widespread cortical thinning. Both SLI and atrophy were independently related to poorer performance in attention, memory and language domains. Only SLI was associated with visuomotor speed and executive function, while atrophy mediated the association between SLI and visuoconstruction. CONCLUSIONS: Our findings support a vascular contribution to neurodegeneration and cognitive impairment.

Prediction of incident dementia: impact of impairment in instrumental activities of daily living and mild cognitive impairment-results from the German study on ageing, cognition, and dementia in primary care patients.

OBJECTIVES: There is an increasing call for a stronger consideration of impairment in instrumental activities of daily living (IADL) in the diagnostic criteria of Mild Cognitive Impairment (MCI) to improve the prediction of dementia. Thus, the aim of the study was to determine the predictive capability of MCI and IADL impairment for incident dementia. DESIGN: Longitudinal cohort study with four assessments at 1.5-year intervals over a period of 4.5 years. SETTING: : Primary care medical record registry sample. PARTICIPANTS: As part of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients, a sample of 3,327 patients from general practitioners, aged 75 years and older, was assessed. MEASUREMENTS: The predictive capability of MCI and IADL impairment for incident dementia was analysed using receiver operating characteristics, Kaplan-Meier survival analyses, and Cox proportional hazards models. RESULTS: MCI and IADL impairment were found to be significantly associated with higher conversion to, shorter time to, and better predictive power for future dementia. Regarding IADL, a significant impact was particularly found for impairment in responsibility for one's own medication, shopping, and housekeeping, and in the ability to use public transport. CONCLUSIONS: Combining MCI with IADL impairment significantly improves the prediction of future dementia. Even though information on a set of risk factors is required to achieve a predictive accuracy for dementia in subjects with MCI being clinically useful, IADL impairment should be a very important element of such a risk factor set.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified gene, along with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The exact prevalence of CARASIL is currently unknown, and to date approximately 50 patients have been reported, most of them from Japan and two from China. Genetically, no founder haplotype has been identified, and thus the disease is expected to be found more widely. The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-ß family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

[Vascular dementia]. / Vaskuläre Demenz.

Vascular dementia (VaD) constitutes the second most frequent cause of dementia following Alzheimer's disease (AD). In contrast to AD, VaD encompasses a variety of conditions and dementia mechanisms including multiple and strategic infarcts, widespread white matter lesions and hemorrhages. The diagnosis of VaD is based on the patient history, the clinical evaluation and neuroimaging. Treatment of VaD should account for the underlying vascular condition and is directed towards the control of vascular risk factors and stroke prevention. The need for early diagnosis and preventive treatment has promoted the concept of vascular cognitive impairment (VCI). Harmonization standards for the description and study of VCI have recently been published. A common and distinct subtype of VaD is subcortical ischemic vascular dementia (SIVD) which is related to cerebral small vessel disease. SIVD is clinically characterized by impairment of executive functions and processing speed with relatively preserved memory. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of SIVD, represents an important differential diagnosis and may serve as a model of SIVD.

Is the clock drawing test appropriate for screening for mild cognitive impairment?--Results of the German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

BACKGROUND: Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and are a target group for preventive interventions. Therefore, research aims at diagnosing MCI at an early stage with short, simple and easily administrable screening tests. Due to the fact that the Clock Drawing Test (CDT) is widely used to screen for dementia, it is questionable whether it is suited to screen for MCI. METHODS: 3,198 primary care patients aged 75+ were divided into two groups according to their cognitive status, assessed by comprehensive neuropsychological testing: individuals without MCI and individuals with MCI. The CDT scores, evaluated by the scoring system of Sunderland et al. [J Am Geriatr Soc 1989;37:725-729], of both groups were compared. Multivariate analyses were calculated and the sensitivity and specificity of the CDT to screen for MCI were reported. RESULTS: Significant differences were found for CDT results: MCI patients obtained worse results than cognitively unimpaired subjects. CDT has a significant impact on the diagnosis of MCI. However, sensitivity and specificity as well as receiver operating characteristic analyses are not adequate, meaning that the CDT could not be named as an exact screening tool. LIMITATIONS: Applying different CDT versions of administration and scoring could yield different results. CONCLUSIONS: CDT does not achieve the quality to screen individuals for MCI.

Neuroimaging predictors of cognitive impairment in confluent white matter lesion: volumetric analyses of 99 brain regions.

BACKGROUND: Although confluent white matter lesion (WML) is associated with cognitive impairment, the mechanism explaining this association is controversial. We aimed to investigate comprehensively the MRI predictors of cognitive impairment in confluent WML. METHODS: Among 45 lacunar stroke patients who had confluent WML, we evaluated the association of executive function [Mattis Dementia Rating Scale - Initiation/Perseveration subscale (MDRS I/P)] and global cognition [Mini-Mental State Examination (MMSE)] with the volume of WML, measures of lacunes and microbleeds, and the volumes of 99 other specific brain regions. RESULTS: Regression analyses showed that WML volume predicted performance on the MDRS I/P (beta = -0.34, p = 0.016) independent of age. Volumes of cortical gray matter (cGM; beta = 0.41, p = 0.003), the lateral fronto-orbital gyrus (beta = 0.38, p = 0.01), superior frontal gyrus (beta = 0.29, p = 0.04), lateral ventricle (beta = -0.30, p = 0.04), and posterior limb of the internal capsule (beta = 0.43, p = 0.002) predicted MDRS I/P performance independent of WML volume. Volumes of cGM, and the lateral fronto-orbital gyrus predicted MMSE performance as well. CONCLUSION: Atrophy along the frontosubcortical pathways and cGM predict cognition in confluent WML independent of WML volume.

Patterns of neuropsychological impairment in MCI patients with small subcortical infarcts or hippocampal atrophy.

We investigated whether MCI patients with hippocampal atrophy or multiple subcortical infarcts demonstrate neuropsychological patterns and markers considered typical of Alzheimer's disease (AD) and of vascular dementia (VD), respectively. An extensive neuropsychological battery, including tests of memory, visual-spatial and executive functions, language, attention, praxis and psychomotor speed, was administered to 36 mild cognitive impairment (MCI) patients with hippocampal atrophy and 41 MCI patients with multiple subcortical infarcts. Both groups of MCI patients were very mildly impaired and well matched in terms of MMSE scores. A clear, disproportionately severe, episodic memory disorder was observed in MCI patients with hippocampal atrophy. A less specific neuropsychological profile, consisting of impairment on an Action Naming task that is sensitive to frontal lobe lesions, was observed in MCI patients with multiple subcortical infarcts. In MCI patients, a disproportionately severe episodic memory impairment strongly points to an Alzheimer's type brain pathology, whereas the prevalence of executive deficits and other frontal lobe symptoms are a much weaker diagnostic marker of small vessel subcortical disease.

Vascular dementia.

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's dementia (AD). It is characterized by loss of executive function with milder memory loss as compared with AD and is associated with cerebral brain infarction or hemorrhage. Treatment is predominantly focused on cardiovascular risk factor reduction, but anticholinesterase inhibitors and memantine may play a role. The data is most robust for donepezil.

[Vascular dementia and mixed dementia]. / Démences vasculaires et démences mixtes.

The concept of vascular dementia has evolved over the past century to include multiple underlying pathophysiological mechanisms. Neuroimaging techniques offer new and better ways to identify the presence of cerebrovascular pathology, although they do not improve our ability to link these changes to the onset of clinical cognitive impairment. Clinical criteria for vascular dementia have also evolved but they remain imperfect. Most epidemiological studies define mixed dementia as the coexistence of Alzheimer's disease and vascular dementia. Clinicopathologic correlations show a clear association between the concomitant presence of vascular and Alzheimer lesions and the severity of cognitive impairment in mixed dementia and provide strong support for the validity of the mixed dementia concept. Mixed dementia is a very frequent disease that remains underdiagnosed, especially in the elderly. The diagnosis of vascular and mixed dementia remains a clinical challenge and cannot be improved without further studies of clinicopathological correlations and functional neuroimaging. Preventive therapeutic interventions include control of vascular risk factors and especially treatment of hypertension.

Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia.

BACKGROUND AND PURPOSE: Most previous studies addressed the cognitive impact of lacunar infarcts using radiologic correlations that are known to correlate poorly with neuropathological data. Moreover, absence of systematic bilateral assessment of vascular lesions and masking effects of Alzheimer disease pathology and macrovascular lesions may explain discrepancies among previous reports. To define the relative contribution of silent lacunes to cognitive decline, we performed a detailed analysis of lacunar and microvascular pathology in both cortical and subcortical areas of 72 elderly individuals without significant neurofibrillary tangle pathology or macrovascular lesions. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral assessment of microvascular ischemic pathology and lacunes; statistical analysis included multivariate models controlling for age, amyloid deposits, and microvascular pathology. RESULTS: Thalamic and basal ganglia lacunes were negatively associated with CDR scores; cortical microinfarcts, periventricular and diffuse white matter demyelination also significantly affected cognition. In a multivariate model, cortical microinfarcts and thalamic and basal ganglia lacunes explained 22% of CDR variability; amyloid deposits and microvascular pathology explained 12%, and the assessment of thalamic and basal ganglia lacunes added an extra 17%. Deep white matter lacunes were not related to cognitive status in univariate and multivariate models. CONCLUSIONS: In agreement with the recently proposed concept of subcortical ischemic vascular dementia, our autopsy series provides important evidence that gray matter lacunes are independent predictors of cognitive decline in elderly individuals without concomitant dementing processes such as Alzheimer disease.

Effect of acetaminophen on behavior, well-being, and psychotropic medication use in nursing home residents with moderate-to-severe dementia.

OBJECTIVES: To evaluate the effect of regularly scheduled administration of analgesic medication on behavior, emotional well-being, and use of as-needed psychotropic medications in nursing home residents with moderate-to-severe dementia. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Nursing-home based. PARTICIPANTS: Twenty-five nursing home residents with moderate-to-severe dementia. INTERVENTION: Participants received 4 weeks of acetaminophen (3,000 mg/d) and 4 weeks of placebo. MEASUREMENTS: Behavior and emotional well-being were assessed using Dementia Care Mapping, an observational method that quantifies time spent in behaviors across 26 domains (e.g., social interaction, unattended distress) and assesses emotional state while behaviors are being observed. Agitation was measured using the Cohen-Mansfield Agitation Inventory. As-needed psychotropic medication use was aggregated from medication logs. RESULTS: Participants spent more time in social interaction, engaged with media, talking to themselves, engaged in work-like activity, and experiencing unattended distress when they received acetaminophen than they did when they received placebo. Participants also spent less time in their rooms, less time removed from the nursing home unit, and less time performing personal care activities when they received acetaminophen. There were no effects on agitation, emotional well-being, or as-needed psychotropic medication use. CONCLUSION: Untreated pain inhibits activity in nursing home residents with moderate-to-severe dementia. Pain treatment in this group may facilitate engagement with the environment.

[Usefulness of some neurophysiological methods in different type of dementia]. / Przydatnosc niektórych badan elektrofizjologicznych do oceny stanów otepiennych.

Dementia--this is a clear reduction of obtained mental level fitness which make difficult to function independently in normal conditions of life. It is assumed that 50% of dementia makes up Alzheimer's disease (AS), 17% is cerebrovascular dementia and 18% is so called mixed type. The degree of patient's dementia intensifications depends on the intellectual level and mental activity. The neurophysiological examinations which were tried to use for diagnosis are: brain bioelectrical activity, transcranial Doppler sonography, evoked potentials, cerebral refraction time. It was tried to estimate above mentioned neurophysiological methods from the point of view of their avalibility, simplicity of examination, repetition and usefulness in distinguishing states of dementia.

CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.

Prolonged cerebral transit time in CADASIL: a transcranial ultrasound study.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmophilic material in the vicinity of degenerating vascular smooth muscle cells. In this study, we measured the arteriovenous cerebral transit time (CTT) to identify changes related to the microangiopathy in CADASIL. METHODS: CTT is the time that a contrast agent needs to pass from a cerebral artery to its corresponding vein. CTT was measured in 17 CADASIL individuals (mean age, 50.2+/-12.3 years) and an equal number of age- and sex-matched control subjects (mean age, 48.9+/-13.0 years) with transcranial color-coded duplex sonography. The intensity curves were recorded in the P2 segment of the posterior cerebral artery and the vein of Galen after injection of the ultrasound contrast agent Levovist. RESULTS: CTT was significantly prolonged in individuals with CADASIL (4.4+/-1.9 seconds) compared with control subjects (1.3+/-0.5 seconds, P<0.0001). This difference was also significant when only nondisabled CADASIL individuals (Rankin score=0, n=9) were analyzed (P<0.0001). There was a nonsignificant trend for a correlation between Rankin score and CTT (r=0.39, P=0.11). CONCLUSIONS: The prolonged CTT likely reflects microvascular changes in CADASIL. Measurements of the CTT may be used clinically to disclose small-vessel disease. Studies comparing CADASIL subjects with other patient populations seem warranted to determine possible differences in CTT between different types of small-vessel disease.

Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. METHODS: Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. RESULTS: A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at < or =65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). CONCLUSIONS: Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.

Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: a study with whole brain histogram analysis.

BACKGROUND AND PURPOSE: In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a large increase in water diffusion has been found both inside and outside the cerebral lesions as detected on conventional MRI. The aim of the present study was to assess the sensitivity of diffusion tensor imaging for monitoring the progression of cerebral tissue damage during the course of CADASIL. METHODS: With the use of diffusion tensor imaging, whole brain trace of the diffusion tensor [Trace(D)] histograms were obtained in 22 CADASIL patients and 12 age-matched controls at baseline, in 14 patients after a mean delay of 21 months, and in 5 controls after a mean delay of 29 months. Parameters derived from these histograms (mean value, peak height, and peak location) were analyzed at baseline and during the follow-up. RESULTS: At baseline, all the histogram parameters differed between patients and controls and were found to be significantly correlated with both the Mini-Mental State Examination score and Rankin Scale score in the patient group. The follow-up study showed a decrease in the peak height associated with an increase in the mean value of whole brain Trace(D) histograms in the 14 CADASIL patients scanned twice. The diffusion changes appeared larger in the patients whose Rankin score increased during the study period. CONCLUSIONS: These results suggest that the measurement of water diffusion over time is a sensitive marker for the progression of tissue damage in the brain. Thus, quantitative diffusion MRI can be used to monitor disease progression in CADASIL and possibly in other types of small-vessel brain disorders.

Diffusion tensor imaging study of subcortical gray matter in cadasil.

BACKGROUND AND PURPOSE: In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), water diffusion changes suggestive of microstructural tissue alterations have been recently reported in abnormal- and normal-appearing white matter as seen on T2-weighted images. In the subcortical gray matter, typical lacunar infarcts are repeatedly observed. Whether microstructural tissue changes are also present outside these lesions within the putamen or thalamus remains unknown. METHODS: We used diffusion tensor imaging, an MRI method highly sensitive to cerebral microstructure, in 20 CADASIL patients and 12 controls. Both the trace of the diffusion tensor [Tr(D)] and an anisotropic diffusion index (volume ratio) of diffusion were measured within the putamen and thalamus outside typical lacunar infarcts as detected on both T1- and T2-weighted images. RESULTS: A significant increase in Tr(D) and a decrease in anisotropy were observed in the putamen and thalamus in patients. The right/left indices of Tr(D) in the thalamus, but not in the putamen, were strongly correlated with the corresponding indices calculated in the white matter of the centrum semiovale. In addition, the diffusion increase in the thalamus was positively correlated with Tr(D) and with the load of small deep infarcts within the white matter and negatively correlated with the Mini-Mental State Examination score. CONCLUSIONS: Our results suggest that microstructural tissue alterations are present in the putamen and thalamus, outside the typical lacunar infarcts in CADASIL. In the thalamus, these microstructural changes appear constant and are even observed in asymptomatic subjects. Some of these thalamic changes appear to result from degeneration of thalamocortical pathways secondary to ischemic white matter damage. The importance of this degenerative phenomenon in the pathophysiology of CADASIL requires further investigation.

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.

BACKGROUND AND PURPOSE: CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. METHODS: The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. RESULTS: The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. CONCLUSIONS: Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Abnormal vasoconstrictor responses to angiotensin II and noradrenaline in isolated small arteries from patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by ultrastructural abnormalities in small cerebral and systemic vessels. We assessed vasomotor function in systemic small arteries in CADASIL. METHODS: We studied 10 CADASIL patients and 10 control subjects. Resistance arteries isolated from gluteal biopsies were mounted on small-vessel myographs, and concentration responses were determined for vasoconstrictors (noradrenaline, angiotensin II, and endothelin-I) and vasodilators (acetylcholine, bradykinin, spermine-NONOate, and nifedipine). Maximum data are shown as percent potassium contraction. RESULTS: There was reduced potency for noradrenaline in CADASIL (CADASIL [38 arteries]: EC50, 240 nmol/L; control subjects [27 arteries]: EC50, 100 nmol/L; 2-way analysis of variance, F=9.76, P=0.002). Maximum response to angiotensin II was greater in CADASIL (120+/-8% versus 97+/-5% in control subjects; F=4.28, P=0.043). Tachyphylaxis to angiotensin II occurred in all control subjects studied but in only 3 of 9 CADASIL subjects (P=0.011, Fisher's exact test). Vasodilation was similar in CADASIL patients compared with control subjects for endothelium-dependent dilators (acetylcholine and bradykinin) and endothelium-independent dilators (spermine-NONOate and nifedipine). CONCLUSIONS: These results suggest a selective systemic microvascular vasoconstrictor abnormality in CADASIL in noradrenaline and angiotensin II pathways that is not explained by vasodilator impairment in endothelium or vascular smooth muscle. This could have important implications for prophylaxis and treatment of CADASIL.