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Background and Purpose— In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia. Methods— Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts. Results— After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories ( P =0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions ( P P P Conclusions— Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies.

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 Aβ-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.

Background and Purpose— Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes repeated ischemic attacks leading to subcortical vascular dementia. The aim of this study was to characterize cognitive function in subjects with a C475T (R133C) mutation in the Notch3 gene, leading to CADASIL. Methods— Prestroke (n=13) and poststroke (n=13) mutation carriers and mutation carriers with dementia (n=8) were compared with healthy noncarriers from the same families using a comprehensive set of neuropsychological tests. Results— Changes in working memory and executive function were observed in the very early phase of the disease before transient ischemic attack (TIA) or stroke. Later, in the poststroke phase, the cognitive impairment concerned also mental speed and visuospatial ability. Finally, the subjects with dementia had multiple cognitive deficits, which engaged even verbal functions, verbal episodic memory, and motor speed. The 2 mutation carrier groups without dementia and the controls could be reliably distinguished using 3 tests that assessed working memory/attention, executive function, and mental speed. Episodic memory was relatively well-preserved late in the disease. Conclusion— A deterioration of working memory and executive function was already observed in the prestroke phase, which means that cognitive decline may start insidiously before the first onset of symptomatic ischemic episodes.

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]: EC 50 , 240 nmol/L; control subjects [27 arteries]: EC 50 , 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.

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 ≤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.

Background and Purpose— There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods— We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results— We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions— These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO 2 levels and systemic blood pressure in CADASIL.

Background and Purpose — Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-artery disease that clinically involves only the brain. Particularly early in the disease, patients can show substantial or complete recovery after individual strokes. Cortical functional reorganization may contribute to limiting disability with such ischemic injury. We sought to test whether the extent of any functional changes in the motor cortex increases with greater brain axonal injury from CADASIL. Methods — Functional MRI (fMRI) was used to characterize cortical activation during a simple hand-tapping task. Disease-associated pathology in subcortical white matter was assessed with the use of conventional fluid-attenuated inversion recovery (FLAIR) MRI and MR spectroscopic imaging for measurement of N -acetyl aspartate decreases, a relatively specific measure of axonal injury. Results — There was evidence for variable but substantial hyperintense white matter signal in all of the patients with FLAIR imaging. With the use of fMRI, the brain regions activated during motor tasks were similar for the 9 CADASIL patients and 7 controls, except that most (6 of 9) patients showed primary motor cortex activation both ipsilateral and contralateral to the hand moved, a finding in only 1 of 7 healthy controls. Ipsilateral motor cortex activation increased ( r =−0.77, P r =0.68, P N -acetyl aspartate concentration) in a region of interest including descending motor fibers of the corticospinal pathway. Conclusions — The extent of functional reorganization of motor cortex increases with increasing axonal injury, consistent with an adaptive role for these changes. Increased functional recruitment of cortex ipsilateral to the limb moved therefore may contribute to limiting motor impairment from the subcortical injury of CADASIL.

Background and Purpose — An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. Methods — Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. Results — Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects ( P r =0.71, P =0.002) and total lesion volume ( r =0.75, P =0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. Conclusions — This study shows a high frequency and multiplicity of MBs in individuals with CADASIL. Our results suggest that MBs and ischemic lesions are largely independent manifestations of the underlying angiopathy. The pattern of MBs shows a significant overlap with that reported in other types of small-vessel disease.

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.

Background and Purpose —We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. Methods —Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. Results —All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. Conclusions —PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.

Background and Purpose —Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3 . Cerebral microvessels show an accumulation of granular osmiophilic material in the vicinity of degenerating vascular smooth muscle cells. To study cerebrovascular function in CADASIL, we performed measurements on cerebral hemodynamics by using transcranial Doppler sonography. Methods —Middle cerebral artery (MCA) mean blood flow velocity (MFV), cerebrovascular CO 2 reactivity, and the resistance index were measured by bilateral transcranial Doppler sonography in 29 CADASIL individuals (mean age, 49.0±2.4 years) and an equal number of age- and sex-matched control subjects. Results —Compared with control subjects, CO 2 reactivity was reduced in CADASIL (33.4±2.7% versus 45.3±3.0%; P P 2 reactivity was significantly lower in disabled than in nondisabled CADASIL individuals (24.5±2.7% versus 36.8±3.4%; P P r =−0.314; P r =−0.339; P P =0.42). Conclusions —In CADASIL, there is a reduction of both CO 2 reactivity and basal MCA MFV. The reduced CO 2 reactivity suggests functional impairment of cerebral vasoreactivity probably related to vascular smooth muscle cell dysfunction. The reduction of CO 2 reactivity in nondisabled CADASIL individuals suggests an early role of impaired cerebral vasoreactivity in the evolution of the disease.

Background and Purpose —The extent of white matter high-intensity lesions (WMLs) on T2-weighted MR images may be an indicator of cognitive impairment, especially impairment related to frontal lobe dysfunction. However, it is unclear whether the extent of WMLs is an independent predictor of cognitive impairment. In patients with extensive WMLs, atrophy of the corpus callosum may be an important predictor of global cognitive impairment. The purpose of this study was to investigate the relation of the extent of WMLs and callosal size with cognitive functions in a patient population with a wide range of extent of WMLs. Methods —We studied 62 patients, aged 49 to 86 years, who underwent MRI because of neurological symptoms and were diagnosed as having lacunar stroke or no specific neurological disease: 28 with lacunar infarcts and 34 without. Multivariate analysis was used to test the independent predictive value of patient age, sex, educational level, other medical illness, lacunar infarct, corpus callosum area, and extent of WMLs with respect to scores of Mini-Mental State Examination or verbal fluency task. Results —Only callosal size and age were significant independent predictors of the scores of the Mini-Mental State Examination, while only the extent of WMLs was an independent predictor of the score of the verbal fluency task. Conclusions —Callosal atrophy may be an important predictor of global cognitive impairment in patients with WMLs, whereas the extent of WMLs per se may be related to impairment of frontal lobe function independent of callosal atrophy.

Background and Purpose Vascular dementia (VD) has been an ill-defined term thus far. Recently detailed criteria for the diagnosis of VD have been proposed (Alzheimer’s Disease Diagnostic and Treatment Centers [ADDTC], 1992; Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV], 1994; International Classification of Diseases, 10th revision [ICD-10], 1992, 1993; and National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences [NINDS-AIREN], 1993). Until now the clinical feasibility of these diagnostic guidelines has not been evaluated. Methods This study aimed to compare these criteria in an unselected sample of 167 elderly patients (mean age, 72.0±9.9 years) admitted with probable dementia. Results The number of cases that could be classified as VD differed widely between the various diagnostic guidelines. According to DSM-IV criteria, 45 cases were diagnosed as VD. Twenty-one cases fulfilled the ICD-10 research criteria, but only 12 met the NINDS-AIREN criteria for VD. Twenty-three cases were classified as ischemic VD as defined by the ADDTC criteria. The concordance was very poor since only 5 cases met the criteria for VD of all diagnostic guidelines. Conclusions Our results show that the classification according to different diagnostic guidelines yields rather distinct groups of patients. The reasons responsible for these findings are as follows: (1) different criteria for dementia, (2) limitation to ischemic VD in the ADDTC criteria, (3) no further differentiation of VD into subtypes according to CT or MRI findings (DSM-IV), and (4) the multifactorial etiopathology of VD. Major diagnostic difficulties ensue from the very frequent cases with white matter lesions, since their etiology and classification remain widely unknown.

The differentiation between the Alzheimer and multi-infarct types of dementia may still be equivocal considering clinical criteria, neuropsychological tests, and imaging techniques. Cerebral microangiopathic alterations underlying multi-infarct dementia should allow the characterization of dementia subgroups. Patients with a diagnosis of multi-infarct dementia (n = 17; mean age, 69.1 +/- 8.5 years) or Alzheimer dementia (n = 24, mean age, 65.8 +/- 9.0 years) according to standard testing criteria, clinical findings, and neuroimaging techniques (computed tomography and magnetic resonance imaging) were investigated prospectively by transcranial Doppler sonography and compared with a normal reference group (n = 64; mean age, 61.0 +/- 11.1 years). Transcranial Doppler sonography allows an indirect evaluation of peripheral flow resistance in the microcirculatory bed by quantifying pulsatility characteristics, as reflected in the effective pulsatility range (time-averaged mean blood flow velocity minus the peak-systolic to end-diastolic amplitude, in centimeters per second). A total of 204 vessels were investigated in 105 subjects. Mean and diastolic blood flow velocities as well as the effective pulsatility range were significantly lower in the multi-infarct dementia group compared with the Alzheimer and the normal reference groups (p < 0.001). By using receiver operating characteristic analysis, a cutoff point for effective pulsatility range values of -5 cm/sec gives a side-dependent sensitivity of 90.48-95.24% and a specificity of 64.71-70.59% in diagnosing Alzheimer-type dementia; the corresponding sensitivity and specificity for a value of -2 cm/sec are 82.35-88.24% and 80.95-90.48%, respectively. Pulsatility changes as reflected by the effective pulsatility range are a noninvasive additional criterion in the differential diagnosis of dementia.

Using a noninvasive portable blood pressure recorder, we compared 24-hour variations of blood pressure among 1) 35 patients with Binswanger-type dementia, 2) 43 with lacunar-type dementia, 3) 26 with a single lacunar stroke, and 4) 30 controls. Each group was divided into antihypertensive-treated and -untreated subgroups. Among the untreated subgroups, patients with Binswanger-type dementia had significantly greater 24-hour mean systolic blood pressures, 24-hour systolic blood pressure standard deviations, and maximal systolic blood pressure variations than the controls (p less than 0.05). Among the treated patients, blood pressure variability increased similarly in all subgroups with cerebrovascular lesions compared with the controls (p less than 0.05). The nocturnal blood pressure decreases seen in the controls were absent among both untreated and treated patients with Binswanger- or lacunar-type dementia (p less than 0.05). Our results suggest the importance of hypertension, short-term variations in blood pressure, and a sustained nighttime elevation of blood pressure for the pathogenesis of both Binswanger-type and lacunar-type dementia in patients receiving antihypertensive medication.

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 P 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.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited condition that causes repeated small-scale strokes in adults. CADASIL is caused only by mutations in the human NOTCH3 gene that increase or decrease the number of cysteines within the epidermal growth factor (EGF) repeats of the NOTCH3 protein. Drosophila: lethal-Abruptex is a similar condition because it is also caused only by mutations that increase or decrease the number of cysteines within the EGF repeat portion of the Notch protein.Drosophila: lethal-Abruptex and human CADASIL are precisely analogous at the molecular level, and both are genetically dominant. These precise similarities, together with the fact that the structure and function of Notch has been highly conserved throughout the animal kingdom, provide an animal model for the molecular and genetic aspects of human CADASIL. It also provides support for Spinner's proposal that CADASIL results from dominant inhibition of the Notch pathway.Because the phenotypes of Notch mutations are cell-autonomous, the symptoms of CADASIL indicate that adult vascular smooth muscle cells require the continuing function of the NOTCH3 pathway in the adult. For this reason, further analysis of the NOTCH3 pathway may provide more general insights into the biology of vascular smooth muscle cells. In the case of CADASIL, the powerful genetic tools available in Drosophila: should help to facilitate future research.

Background and Purpose —Information on the neuropathological changes underlying ischemic leukoaraiosis is only available postmortem, and there are limited data on histological appearances early in the disease. Diffusion tensor imaging allows determination of the directionality of diffusion, which is greater in the direction of white matter bundles. Therefore, the technique might be expected to show loss of anisotropy (directional diffusion) in leukoaraiosis. Methods —Nine patients with ischemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke) and 10 age-matched controls were studied. Diffusion tensor imaging was performed, and maps of diffusion trace and fractional anisotropy were constructed. Mean values of trace and fractional anisotropy were determined in standard regions of the anterior and posterior white matter in both hemispheres. Results —In all patients with ischemic leukoaraiosis, a characteristic abnormal pattern was found, with loss of anisotropy and increased trace in the white matter. For example, in the right anterior white matter mean (SD) trace/3 was 1.12 (0.33) ×10 −3 mm 2 s −1 in patients and 0.75 (0.11) in controls ( P =0.001). In the same region, fractional anisotropy was 0.53 (0.11) in patients and 0.78 (0.09) in controls ( P r =−0.92, P Conclusions —The characteristic pattern found on diffusion tensor imaging in this patient group is consistent with axonal loss and gliosis leading to impairment to and loss of directional diffusion. The “in vivo histological” information obtained may be useful in monitoring disease progression and in investigating the pathogenesis of the cognitive impairment that may be present.

Background Cognitive impairment associated with vascular disease may be the only preventable form of dementia of late life. Identification of risk factors for dementia associated with stroke may be a prelude to improved intervention. Summary of Review I reviewed putative risk factors for dementia associated with stroke. These included demographic, atherogenic, stroke-related, and genetic factors. Key studies from the English literature were reviewed and graded according to quality of evidence ratings (classes I, II, and III). Although many of the cardiovascular disease risk factors are logical antecedents of dementia associated with stroke, age was the only factor that could be considered a well-documented risk factor. Conclusions We should continue to support efforts directed at primary stroke prevention and the brain-at-risk and predementia stages. Additional rigorous epidemiological study is needed to clarify risk factors for dementia associated with stroke.

Leukoaraiosis (LA), the presence of rarefaction of the white matter originally described on CT1 but now more commonly recognized on MRI, was originally largely ignored as an inconsequential finding seen in association with cerebrovascular disease. More recently, it has become clear that LA impairs cognition.2 When LA is sufficiently prominent to be seen on CT, its associated cognitive impairment is readily detected. When seen only on MRI, a more sensitive technique, more sensitive cognitive tools are needed.3 At least as important is the effect of one cognitive disorder to accelerate another, and LA may causally accelerate the progression of Alzheimer disease, for example.4 LA is therefore not the unimportant phenomenon it was once considered. LA encompasses a wide range of histological changes ranging from local edema5 to demyelination, loss of axons and oligodendroglia, and mild reactive gliosis without cavitation but does not include frank infarction. The mechanism is not considered to be chronic low perfusion as cerebral blood flow in affected …

We investigated the hypothesis that patients with one or more asymptomatic lacunar infarcts and those with only one symptomatic lacunar infarct represent two clinically distinct lacunar infarct entities. In a prospective series of 100 lacunar infarct patients, univariate and multivariate logistic regression analysis was performed on clinical features, vascular risk factors, and leukoaraiosis between patients with and without asymptomatic lacunar infarcts. Patients with asymptomatic lacunar infarcts had hypertension significantly more often (71% versus 43%; [crude] odds ratio, 3.31; 95% confidence intervals, 1.16-9.43; p < 0.05) and had leukoaraiosis significantly more often (71% versus 19%; [crude] odds ratio, 10.67; 95% confidence intervals, 3.81-32.10; p < 0.001) than those with only a symptomatic lacunar infarct. After multivariate logistic regression analysis, only leukoaraiosis was significantly associated with the presence of asymptomatic lacunar infarcts. The asymptomatic lacunar infarcts differed in location, involved vascular territory, and volume from the symptomatic infarcts. Two distinct lacunar infarct entities might be broadly distinguished during life: lacunar infarct patients with a single, symptomatic lacunar infarct, and patients with multiple lacunar infarcts and a high frequency of hypertension and leukoaraiosis, in which the underlying small-vessel vasculopathy might be different.

We recently described an autosomal dominant syndrome characterized mainly by recurrent strokes and neuroimaging evidence of leukoencephalopathy. We now report the pathological findings in one of the affected subjects. A 40-year-old woman experienced her first grand mal seizure in 1971. From 1983 on she suffered recurrent strokes, seizures, and psychiatric disturbances with depressions, manic episodes, and dementia. In 1988, after her fourth stroke, she became tetraplegic with a severe pseudobulbar palsy, and she died in 1990. Pathological examination disclosed a recent capsulolenticular hematoma, multiple small deep infarcts, a diffuse myelin loss and pallor of the hemispheric white matter, and a widespread vasculopathy of the small arteries penetrating the white matter. The arterial wall was markedly thickened with an extensive nonamyloid eosinophilic deposit in the media and reduplication of the internal elastic lamella. The underlying lesion of this hereditary disorder is located in the small arteries and is of unknown etiology. It differs from arteriosclerotic and amyloid angiopathies but is similar to that described in some cases of hereditary multi-infarct dementia.

We compared cranial computed tomography findings among 58 multi-infarct dementia index cases and 74 multi-infarct control subjects without cognitive impairment to identify potential determinants of multi-infarct dementia. The cranial computed tomography records of acute ischemic stroke patients with a history of multiple cerebral infarcts were compared to determine the number, location, and size of cerebral infarcts; the pattern of infarction; brain volume loss; and the degree of white matter lucency, sulcal enlargement, and ventricular enlargement. Multi-infarct patients were divided into two groups: 1) index cases were defined as those with multi-infarct dementia as defined by the Diagnostic and Statistical Manual of Mental Disorders, edition 3 (DSM-III) criteria; and 2) control subjects were defined as those multi-infarct patients without dementia or multi-infarct dementia according to DSM-III criteria. Overall, multi-infarct index cases had more cerebral infarcts, more cortical and subcortical left hemisphere infarcts, higher mean ventricular volume to brain volume ratio, more extensive enlargement of the body of the lateral ventricles and cortical sulci, and a higher prevalence of white matter lucencies. Among multi-infarct cases and control subjects the most frequent site of infarction was the subcortical region, and the most frequent pattern of infarction was lacunar. Stepwise logistic regression analysis examined cranial computed tomography as well as other factors and showed that level of education, stroke severity, left cortical infarction, and diffuse enlargement of the left lateral ventricle were the best overall predictors of multi-infarct dementia. Level of education, stroke severity, and left hemisphere infarction may be predictors of multi-infarct dementia.

Background and Purpose Silent brain infarctions (SBI) are common findings in advanced age, but their relationship to dementia is still uncertain. The present study was designed to evaluate whether SBI predict the development of dementia after first clinical ischemic stroke. Methods We blindly studied admission CT scans of 175 consecutive nondemented patients presenting with ischemic stroke that clinically was their first stroke episode. SBI were defined as CT evidence of infarcts not compatible with the acute event. The patients were subsequently followed for their mental state for 5 years. Survival analysis, wherein onset of dementia was the end point, was performed on the total sample population and conducted separately on those with and without SBI at admission. Results Dementia developed in 56 patients (32%), including 22 of the 63 (35%) with SBI and 34 of the 112 (30%) without SBI. Thus, dementia was not related to SBI. Conclusions Our data indicate that SBI do not predict the development of dementia after stroke.

Using magnetic resonance imaging and digitized brain computed tomography, we evaluated 33 elderly patients with documented lacunar stroke and divided them into three groups (nondemented, n = 15; borderline, n = 9; and demented, n = 9) by neuropsychological assessments and DSM III criteria. We evaluated the extent of white matter lesions and the degree of atrophy of specific anatomic structures, such as the corpus callosum, using magnetic resonance imaging and quantified the volumes of the ventricles, the subarachnoid spaces, and the brain parenchyma using digitized brain computed tomography. Our results show that both borderline and demented patients had significantly more extensive white matter lesions than nondemented patients, indicating a significant relation between the extent of white matter lesions and intellectual decline. In addition, borderline and demented patients had significantly larger ventricles and more brain atrophy than nondemented patients; demented patients also had significantly larger subarachnoid spaces than nondemented patients and more brain atrophy than borderline patients. Our findings suggest that in most patients with lacunar stroke, periventricular and subcortical white matter lesions with subsequent white matter atrophy first induce ventricular enlargement, followed by generalized brain atrophy, resulting in dementia.