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Recent researches have found that 7 Tesla SWI can detect the alteration of substantia nigra hyperintensity in Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The aim of this study was to investigate whether 3 Tesla SWI (3T SWI) can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in PD and vascular parkinsonism (VP), and whether the evaluation of abnormal signal can be used as a factor in the differential diagnosis of PD and VP. Using 3 Tesla MRI, we evaluated 38 healthy subjects, 33 patients with PD and 34 patients with VP. Two blinded readers independently assessed the images. We found that the dorsolateral nigral hyperintensity was absent in 31 of 33 patients with PD and 15 of 34 patients with VP. The dorsolateral nigral hyperintensity was present in 19 of 34 patients with VP and 35 of 38 healthy controls. Group comparisons of absence of dorsolateral nigral hyperintensity revealed significant differences between the patients with PD and those with VP (P

Multi-infarct dementia (MID), a prominent subtype of vascular dementia (VD), is responsible for at least 15 to 20 percent of dementia in the elderly. Mitochondrial dysfunctions and glutamate neurotoxicity due to chronic hypoperfusion and oxidative stress were regarded as the major risk factors in the pathogenesis. Kaixin San (KXS), a classic prescription of Beiji Qianjin Yaofang, was applied to treatment for “amnesia” and has been demonstrated to alleviate the cognitive deficit in a variety of dementias, including MID. However, little is known whether mitochondria and glutamate are associated with the protection of KXS in MID treatment. The aim of this study was to investigate the role of KXS in improving the cognitive function of MID rats through strengthening mitochondrial functions and antagonizing glutamate neurotoxicity via the Shh/Ptch1 signaling pathway. Our data showed that KXS significantly ameliorated memory impairment and hippocampal neuron damage in MID rats. Moreover, KXS improved hippocampal mitochondrial functions by reducing the degree of mitochondrial swelling, increasing the mitochondrial membrane potential (MMP), and elevating the energy charge (EC) and ATP content in MID rats. As expected, the concentration of glutamate and the expression of p-NMDAR1 were significantly reduced by KXS in the brain tissue of MID rats. Furthermore, our results showed that KXS noticeably activated the Shh/Ptch1 signaling pathway which was demonstrated by remarkable elevations of Ptch1, Smo, and Gli1 protein levels in the brain tissue of MID rats. Intriguingly, the inhibition of the Shh signaling pathway with cyclopamine significantly inhibited the protective effects of KXS on glutamate-induced neurotoxicity in PC12 cells. To sum up, these findings suggested that KXS protected MID rats from memory loss by rescuing mitochondrial functions as well as against glutamate neurotoxicity through activating Shh/Ptch1 signaling pathway.

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.

Brain energy disorders and oxidative stress due to chronic hypoperfusion were considered to be the major risk factors in the pathogenesis of dementia. In previous studies, we have demonstrated that acupuncture treatment improved cognitive function of VaD patients and multi-infarct dementia (MID) rats. Acupuncture therapy also increased the activities of glycometabolic enzymes in the brain. But it is not clear whether acupuncture treatment compensates neuronal energy deficit after cerebral ischemic through enhancing the activities of glucose metabolic enzymes and preserving mitochondrial function, and whether acupuncture neuroprotective effect is associated with activations of mitochondrial antioxidative defense system. So, the effect of acupuncture therapy on cognitive function, cerebral blood flow (CBF), mitochondrial respiratory function and oxidative stress in the brain of MID rats was investigated in this study. The results showed that acupuncture treatment significantly improved cognitive abilities and increased regional CBF of MID rats. Acupuncture elevated the activities of total SOD, CuZnSOD and MnSOD, decreased the level of malondialdehyde (MDA) and superoxide anion, regulated the ratio of reduced glutathione (GSH) and oxidized glutathione (GSSG) in mitochondria, and raised the level of the respiratory control index (RCI) and P/O ratio and the activities of mitochondrial respiratory enzymes of MID rats. These results indicated that acupuncture treatment improved cognitive function of MID rats; and this improvement might be due to increased CBF, which ameliorated mitochondrial dysfunction induced by ischemia and endogenous oxidative stress system of brain.

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.

SPECT images of the brain can be obtained using either 123I labelled amines or 99mTc-hexamethylpropyleneamineoxime (HM-PAO). Both materials produce images which are blood flow dominated and so appear similar in normal subjects, although the respective mechanisms of uptake are not yet finally established. It seems likely, however, that the different mechanisms of uptake are responsible for recent reports of some differences seen in images obtained with the two types of agent in patients with cerebral pathology, mainly cerebrovascular disease. In this study, 12 demented patients, 6 with dementia of the Alzheimer type (DAT) and 6 with multi infarct dementia (MID), were imaged with 123I-isopropylamphetamine (IMP) and 99mTc-HM-PAO and the images compared. Significantly more lesions were seen with IMP than HM-PAO (P less than 0.02); out of a possible 120 sites, 41 lesions were seen with IMP compared to 28 with HM-PAO, 23 being seen with both agents. However, it is concluded that either agent can be used for the differential diagnosis of dementia, a task for which the new cerebral blood flow agents seem well suited.

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 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.

Journal of Stroke and C 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 theHTRA1 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-b 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.

Acupuncture has exhibited therapeutic effects on vascular dementia in our previous research. The mechanism of its anti-dementia effects involves energy metabolism. For brain cells, glucose metabolism is almost the only source of energy, and glucose metabolism disorders are early signs of dementia. In addition, glucose metabolism associates closely with glycometabolic enzymes, thereby maintains normal energy supply in brains and neurological and mental activities. In order to investigate its anti-dementia mechanism, we studied the effects of acupuncture on behavior of multi-infarct dementia (MID) rats and glycometabolic enzymes protein expression and activities in their brains. Results showed acupuncture improved the cognitive disorder, and increased the activities of hexokinase, pyruvate kinase, and glucose 6 phosphate dehydrogenase. Accordingly, it suggests that the anti-dementia effects of acupuncture may be mediated by up regulation of hexokinase, pyruvate kinase, and glucose 6 phosphate dehydrogenase activities, influencing energy metabolic system and thus overcoming the dysfunctional cognition of MID.

Vascular dementia accounts for approximately 15-20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of ((3)H)-WAY 100635 binding to 5-HT(1A) receptors and ((3)H)-ketanserin binding to 5-HT(2A) receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT(1A) and 5-HT(2A) receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT(1A) receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT(1A) receptor in mediating cognition.

Long-term survival was examined for 218 patients with Alzheimer's disease (AD) and 115 patients with multi-infarct dementia (MID). The 14-year survival rate for AD was 2.4% versus an expected rate of 16.6%, and for MID 1.7% versus 13.3% expected. MID showed a more malignant natural course than AD. Men carried a less favourable survival prognosis than women, both in AD and MID: the relative risk of dying for women was half that for men in both diseases. In MID, advanced disability indicated a relative risk of dying over twice as high. In both diseases the risk of death was substantially higher in the event of occurrence of primitive reflexes.

Cerebrovascular accidents (CVAs) and multi-infarct dementia have rarely been reported as presenting symptoms of giant cell arteritis (GCA), although 3%-4% of patients with GCA may present with CVAs during the course of the disease. We describe 7 patients with biopsy-proven GCA who presented with stroke or multi-infarct dementia. Most of them had other symptoms of GCA when the disease began that were misdiagnosed or not noticed. The internal carotid arteries were involved in 4 patients and the vertebrobasilar arteries in 3, with bilateral vertebral artery occlusion in 1. Small cerebral infarction foci on cranial computed tomography (CT) scan and magnetic resonance imaging (MRI) were found in 5 cases, and cerebellar infarction, in 2. MR angiography showed intracranial arteritis in 4 cases. Treatment with glucocorticoids and adjunctive antiplatelet or anticoagulant therapy was given in all cases, with neurologic improvement in 5. Two patients died. Necropsy demonstrated generalized GCA involving the medium and small cerebral vessels in 1 case. Central nervous system involvement is a rare complication in GCA but is important to recognize, as it can be reversible if diagnosed and treated promptly. Suspicion should arise in elderly patients suffering from strokes with a quickly progressing stepwise course and associated headache, fever, or inflammatory syndrome. In these cases, temporal artery biopsy should be performed without delay. Early diagnosis of GCA and immediate initiation of corticosteroid treatment may prevent progressive deterioration and death. Additional antiplatelet or anticoagulant therapy should be evaluated according to the individual risk and benefit to the patient under care.

There is evidence that brain lateralization underlying hemispheric specialization can be observed also at biochemical level. However, hemispheric differences in nitric oxide mediator system have not yet been evaluated. The hippocampus and planum temporale are highly asymmetrical regions but the degree of their laterality is altered in demented or psychotic people. In the study, l-glutamate/l-arginine/l-citrulline concentrations, nitric oxide synthase activities/expressions and nitrites/nitrates levels were estimated in autoptic hippocampi. Right/left laterality in endothelial synthase activity and in nitrites/nitrates was observed in controls. Lateral changes were estimated in patients with Alzheimer disease (a marked increase in activities of constitutive synthases and in expression of inducible enzyme in the left side) and schizophrenia (an increase in activities of all enzymes especially in the right side). Significant shifts from positive to negative correlations were found between laterality of some components of nitric oxide pathway and of planum temporale volumetry under pathological conditions. The hippocampal nitric oxide system appears to be globally right/left lateralized, especially via actions of highly asymmetrical endothelial synthase. The results suggest a specific involvement of all synthases in the development of selected diseases and show that lateral analyses are of sufficient sensitivity to reveal subtle links. The volumetric asymmetry of the planum temporale as a marker of handedness is not probably simply linked to brain laterality at biochemical level but reflects alterations due to pathological processes.

Background and purpose: We investigated whether patients with a lacunar infarct (LI) syndrome exhibiting unique LI or multiple LI on magnetic resonance imaging (MRI) examinations differed in terms of topography and severity of white matter hyperintensities (WMH) ratings. Methods: Forty consecutive patients with a first-ever acute LI, who presented a lacunar syndrome according to Miller–Fishers classification were recruited and were classified into a group presenting isolated LI on MRI (n = 17) or multiple LI (n = 23). Results: Despite equivalent demographic, clinical and cognitive characteristics, patients with multiple LI had increased ratings of WMH in frontal, occipital and subcortical regions. No significant correlations could be evidenced between the number of LI and WMH ratings. Conclusions: Present findings provide support to previous hypothesis considering single and multiple LI MRI presentations of lacunar infarct patients as distinct entities.

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer's disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.

The present study aimed to determine whether Nicotiflorin, a natural flavonoid extracted from coronal of Carthamus tinctorius, has a protective effect on cerebral multi-infarct dementia in rats. The multi-infarct dementia model rats were prepared by injecting man-made micro-thrombi into the right hemisphere. The administration groups were treated once daily with 30, 60 and 120 mg/kg Nicotiflorin (i.g.) from 5 days before ischemia operation to 3 days after the operation for biochemical examination, 10 days for Morris water maze study and morphological observations and 20 days for eight-arm radial maze task. 2,3,5-triphenyltetrazolium chloride (TTC) staining showed that infarct volume of each Nicotiflorin administration group was much smaller than that of vehicle-treated multi-infarct dementia group, and hematoxylin and eosin (HE) staining showed that histopathological abnormalities of each Nicotiflorin group were also much lighter than that of vehicle-treated multi-infarct dementia group. Each Nicotiflorin group showed much better spatial memory performance in Morris water maze tests and eight-arm radial maze task compared with the vehicle-treated multi-infarct dementia group, significantly attenuated the elevation of lactic acid and malondialdehyde (MDA) contents and the decrease in lactate dehydrogenase (LDH), Na(+)K(+)ATPase, Ca(2+)Mg(2+)ATPase and superoxide dismutase (SOD) activity in the brain tissue which was composed of striatum, cortex and hippocampus of the ischemia hemisphere at day 3 after ischemia operation. These results suggest that Nicotiflorin has protective effects on reducing memory dysfunction, energy metabolism failure and oxidative stress in multi-infarct dementia model rats.

Non-atherosclerotic cerebrovascular disorders are considered to occur less frequently than those caused by embolic or thrombotic disease. Such sporadic disorders resulting from direct effects on the cerebral or peripheral vasculature include hypertensive small vessel disease, vascular inflammatory conditions, aneurysms and arteriovenous malformations. Remarkably, some of these are also inherited in an autosomal dominant manner and appear to entail degeneration or abnormal differentiation of blood vessel wall elements such as smooth muscle, endothelial cells, pericytes and the perivascular nerve plexus. Two intensively investigated examples of these include the cerebral amyloid angiopathies and distinct primary arteriopathies such as CADASIL. The identification of novel genes associated with the hereditary forms of cerebrovascular disorders has been invaluable to understanding of the pathogenesis and management of sporadic disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migrane, recurrent stroke, subcortical dementia, and pseudobulbar palsy. It begins with migraine with aura in -33% of patients. CADASIL is commonly overlooked or misdiagnosed owing to its recent identification. The pathological hallmark of angiopathy is the presence of multiple, small, deep cerebral infarcts, leucoencephalopathy, and nonatherorosclerotic, nonamyloid angiopathy involving mainly small, deep perforating cerebral arteries. Changes also are present in vascular smooth muscle cells and consist in the presence of granular osmiophilic material (GOM). The defective gene in CADASIL is Notch 3, which encodes a large transmembrane receptor. Magnetic resonance imaging shows high intensity signal lesions, often confluent, and areas of cystic degeneration of subcortical white matter and basal ganglia. Diagnostic strategies in CADASIL are matter of discussions because the electron microscopic demonstration of GOM was reported in 100% of symptomatic patients of French authors, but only in 45% of a British study. GOMs are not present in presymptomatic patients.

We describe and present a videotape of a 57-year-old woman admitted to our Neurological Clinic at 46 years of age due to extrapyramidal manifestations suggesting Parkinson's disease (PD) and with a brain magnetic resonance imaging scan showing multi-infarctual leukoencephalopathy. Various investigations led to the diagnosis of Anderson Fabry's disease (AFD). We discuss the possibility of correlation between the patient's parkinsonism and AFD.

The term ‘vascular dementia’ (VaD) corresponds to a clinicoradiological syndrome that can be defined with more or less restriction. VaD can result from: (1) cortical or subcortical ischemic lesions related to the occlusion of large vessels, (2) lacunar infarcts with or without white-matter lesions at the subcortical level related to small-vessel diseases, (3) ischemic lesions related to hypoperfusion or anoxic-ischemic encephalopathy or (4) hemorrhagic lesions. The prevention of VaD is based on stroke prevention which implies risk factor manipulation and use of antithrombotic drugs among which the most widely used are antiplatelet drugs. The efficiency of these drugs to prevent cognitive impairment and dementia is not proven. Prospective studies are needed to investigate their potential in patients at risk of VaD: after ischemic stroke, in the presence of cognitive impairment of vascular origin or when MRI shows ‘silent’ ischemic white-matter lesions and/or infarcts.

Recent studies have demonstrated that acupuncture is feasible to treat vascular dementia (VD). The aim of this study was to present behavioral evidence that acupuncture could improve the learning and memory of multi-infarct dementia rats. The pattern of multi-infarct dementia in rats was made by injecting homogeneous emboli into the internal carotid artery. Of them the rats which showed damage in learning and memory (n = 43) were randomly allocated to 3 groups: impaired group (n = 14), acupuncture group (n = 15) and placebo-acupuncture group (n = 14). Moreover, normal group (n = 15) and sham-operated group (n = 15) were set as control groups. The acupuncture group was given acupuncture, which consisted of Tanzhong (CV17), Zhongwan (CV12), Qihai (CV6), Zusanli (ST36) and Xuehai (SP10). Morris water maze test was employed to assess spatial discriminational ability per group respectively and to analyze the curative effects of acupuncture. Compared to the impaired and placebo-acupuncture groups, no cognition impairment was found in the normal and sham-operated groups, and the statistic analysis showed that there were significant differences between normal and impaired groups in ANOVA. Shortened mean escape latency was detected in the acupuncture group compared with the impaired group during the same trial days. Search strategy changed from random pattern adopted by impaired and placebo-acupuncture rats to tendency or linear pattern popular in normal group. The present results suggested that the acupuncture exerted a protective effect on cognitive impairment caused by cerebral multi-infarction in rats, and acupuncture has a specificity of cure. Acupuncture as a potential clinic method in treating VD should be developed and investigated in the future.

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.

Objective To assess the prevalence of physical aggression against caregivers by Alzheimer's patients. Method One hundred and ninety-eight individuals with dementia, primarily Alzheimer's disease (AD) were evaluated with the Cohen-Mansfield Agitation Inventory, the Mini Mental Status Examination, two measures of Activities of Daily Living, portions of the Conflict Tactics Scale to measure physical aggression against partner, questions about conduct problems during childhood/adolescence of the patients, and chart records of delusion and paranoia. Results 25% of the patients engaged in physical aggression against their caregivers in the past year, and 33% of the patients engaged in some act of physical aggression against any individual in the past two weeks. Physical aggression against a caregiver was more likely in the middle (34%) than the early stage of AD (4%). Physical aggression against a partner and agitation were more likely if the patient had a history of symptoms of conduct disorder. Delusions and paranoia were both associated with general physical aggression and general verbal aggression but not physical aggression against a caretaker. Conclusions 25% of Alzheimer's disease and Multi-Infarct dementia patients engaged in acts of physical aggression against their caregivers. The rate of aggression seen in this clinical sample was much higher than the rate of physical aggression in a community sample of the elderly. Copyright © 2005 John Wiley & Sons, Ltd.

This study investigates the role of excitotoxicity in Alzheimer's disease and in multiinfarct dementia by examining, via immunohistochemical methods, the number of cells that are positive for N-methyl-D-aspartate (NMDA) receptor and the degree of colocalization between NMDA receptor and apoptosis markers such as TUNEL or activated caspase-3 in the frontal cortex of individuals with these two conditions, comparing the results with those from subjects who died of normal aging. We showed an increased number of NMDA receptor-positive cells and an increased number of TUNEL-labeled cells in the frontal cortex of subjects with Alzheimer's disease, especially in the deeper layers of the cortex. However, only about 10% of cells showed colocalization of NMDA receptor with the apoptosis markers studied, suggesting that NMDA-mediated excitotoxicity does not play a major role in neuronal apoptosis in Alzheimer's disease or in multiinfarct dementia.

The clinical phenotype in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), an autosomal dominant cerebral arteriopathy, is variable, but the reasons for this remain uncertain. Possible factors include the mutation site and the influence of additional modulating factors, which could include both epistatic interactions and interactions with cardiovascular risk factors known to cause sporadic small vessel disease. In a large prospectively recruited cohort of CADASIL subjects we determined relationships between phenotype and mutation site, the apoE genotype and cardiovascular risk factors. In addition to clinical features, disease severity was assessed by MRI lesion volume, measured both semiquantitatively (Scheltens scale) and quantitatively. One hundred and twenty-seven CADASIL cases from 65 families with 17 different mutations were studied. Site of mutation was not associated with the presence or age of onset of stroke, migraine, dementia, dependency or MRI lesion load. There was no evidence of intrafamilial clustering of particular phenotypes. Amongst subjects with stroke/transient ischaemic attack, smoking at the time of the event was independently associated with earlier age of onset (P = 0.01). There were no associations between age of onset or presence of stroke and other cardiovascular risk factors, including homocysteine. Homocysteine levels were higher in migraineurs [mean (SD) 12.8 (5.6) versus 9.8 (3.4) micromol/l, P = 0.02)] and elevated homocysteine was independently associated with an earlier age of onset of migraine (P = 0.01). No relationship was found between MRI lesion volume and risk factors, or between apoE genotype and phenotype. Our results show no notch 3 genotype-phenotype correlations. This implies that modulating factors influence phenotype. Smoking appears to increase the risk of stroke, while high homocysteine levels are associated with an increased risk of migraine.

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.

A probe technique requiring convergent and divergent semantic behavior and representing five levels of communicative responsibility served as the research tool. Stimuli were presented to adults identified as having Alzheimer disease or multi-infarct dementia. Within each group differences were observed on the semantic task (convergent and divergent) and on communicative responsibility. Group characteristics are compared with data previously published in 1994 on aphasic and schizophrenic adults responding to the same stimuli.

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.

Objectives: Although stroke associated with small vessel disease (SSVD) can induce both motor and cognitive impairment, the latter has received less attention. We aimed to evaluate the frequency of the varying severity levels of cognitive impairment, the determinants of severe cognitive impairment, and the association of cognitive impairment with functional outcome after SSVD. Methods: Consecutive patients admitted to hospital because of SSVD were assessed at 3 months after stroke. We performed a semi-structured clinical interview to screen for cognitive symptoms. Severity of cognitive symptoms was graded according to the Clinical Dementia Rating Scale (CDR). Performance on psychometric tests (Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale (cognition subscale), Mattis Dementia Rating Scale (initiation/perseverence subscale; MDRS I/P)) of patients of different CDR gradings was compared with that of 42 healthy controls. Basic demographic data, vascular risk factors, stroke severity (National Institute of Health Stroke Scale; NIHSS), pre-stroke cognitive decline (Informant Questionnaire on Cognitive Decline in the Elderly; IQCODE), functional outcome (Barthel index; BI), Instrumental Activities Of Daily Living; IADL), and neuroimaging features (site of recent small infarcts, number of silent small infarcts, white matter changes) were also compared among the groups. Regression analyses were performed to find predictors of severe cognitive impairment and poor functional outcome. Results: Among the 75 included patients, 39 (52%) complained of cognitive symptoms. The number of patients in each CDR grading was as follows: 39 (52%) had a CDR of 0, 26 (34.7%) had a CDR of 0.5, 10 (13.3%) had a CDR of ⩾1. Pre-stroke IQCODE and previous stroke predicted CDR⩾1. The NIHSS was associated with more impaired BI. The NIHSS and MDRS I/P contributed most to impaired IADL. Conclusions: Half of the patients with SSVD complained of varying severity of cognitive problems 3 months after stroke. Pre-stroke cognitive decline and previous stroke predict severe cognitive impairment post stroke. Stroke severity and executive dysfunction contribute most to a poor functional outcome.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterized by the degeneration of smooth-muscle cells in small cerebral arteries. CADASIL is caused by mutations in NOTCH3 , one of the four mammalian homologs to the Drosophila melanogaster NOTCH gene. Disease-associated mutations are distributed throughout the 34 epidermal growth factor–like repeats (EGFRs) that compose the extracellular domain of the Notch3 receptor and result in a loss or a gain of a cysteine residue in one of these EGFRs. In human adults, Notch3 expression is highly restricted to vascular smooth-muscle cells. In patients with CADASIL, there is an abnormal accumulation of Notch3 in the vessel. Molecular pathways linking NOTCH3 mutations to degeneration of vascular smooth-muscle cells are as yet poorly understood. In this study, we investigated the effect of CADASIL mutations on Notch3 activity. We studied five naturally occurring mutations: R90C and C212S, located in the previously identified mutational hotspot EGFR2–5; C428S, shown in this study to be located in the ligand-binding domain EGFR10–11; and C542Y and R1006C, located in EGFR13 and EGFR26, respectively. All five mutant proteins were correctly processed. The C428S and C542Y mutant receptors exhibited a significant reduction in Jagged1-induced transcriptional activity of a RBP/JK responsive luciferase reporter, relative to wild-type Notch3. Impaired signaling activity of these two mutants arose through different mechanisms; the C428S mutant lost its Jagged1-binding ability, whereas C542Y retained it but exhibited an impaired presentation to the cell surface. In contrast, the R90C, C212S, and R1006C mutants retained the ability to bind Jagged1 and were associated with apparently normal levels of signaling activity. We conclude that mutations in Notch3 differently affect Jagged1 binding and Notch3 signaling via the RBP/JK pathway.

Objectives: Frontal Assessment Battery (FAB) is a valid and reliable screening test for evaluating executive dysfunction among whites with frontal and subcortical degenerative lesions. We studied the properties of a Chinese version of FAB (CFAB) in evaluating executive dysfunction among Chinese stroke patients with small subcortical infarct. Methods: Concurrent validity was evaluated using Wisconsin Card Sorting Tst (WCST) and Mattis Dementia Rating Scale– Initiation/Perseveration Subset (MDRS I/P) among 41 controls and 30 stroke patients with small subcortical infarct. Discriminant validities of CFAB and its subitems were compared with those of MiniMental State Examination (MMSE). Internal consistency, test-retest, and interrater reliability of CFAB were evaluated. Results: The CFAB had low to good correlation with various executive measures: MDRS I/P (r = 0.63, p < 0.001), number of category completed (r = 0.45, p < 0.001), and number of perseverative errors (r = �0.37, p < 0.01) of WCST. Among the executive measures, only number of category completed had significant but small contribution (6.5%, p = 0.001) to the variance of CFAB. A short version of CFAB using three items yielded higher overall classification accuracy (86.6%) than that of CFAB full version (80.6%) and MMSE (77.6%). Internal consistency (alpha = 0.77), test-retest reliability (rho = 0.89, p < 0.001), and interrater reliability (rho = 0.85, p < 0.001) of CFAB were good. Conclusion: Although CFAB is reliable, it is only moderately valid in evaluating executive dysfunction among Chinese stroke patients with small subcortical infarct. The clinical use of CFAB in the evaluation of executive dysfunction among this group of patients cannot be recommended at this stage.

Objective: The familial aggregation of late-onset Alzheimer’s disease (AD) might be caused by the clustering of genetic risk factors in families. This study investigates the influence of variants of candidate genes on the familial aggregation of AD. Methods: The occurrence of AD was examined in 1,420 first-degree relatives of 70 AD patients and 144 nondemented controls classified by the presence of AD and relevant candidate genes in index subjects. Results: Relatives of nondemented controls with an apolipoprotein E4 or a cathepsin D T allele had a higher cumulative lifetime incidence of AD than relatives of subjects without the respective alleles. This effect was not detected in relatives of AD patients. Variants of the interleukin-6, bleomycin hydrolase and α2-macroglobulin genes did not significantly influence the (age-adjusted) risk of AD in relatives. Conclusions: Familial aggregation of late-onset AD is likely to be caused by several genetic risk factors. Variants of the apolipoprotein E and cathepsin D genes influenced the risk of AD in relatives of nondemented control subjects. The lack of an influence of these genotypes on the risk of AD in relatives of AD subjects may be the consequence of complementary reductions of other genetic risk factors such as various, yet unknown susceptibility genes in patients and, consequently, in their first-degree relatives.

This study aims to clarify the association between apolipoprotein E gene (ApoE) polymorphism, ischemic cerebrovascular diseases (ICVD) and vascular dementia (VaD) in Taiwan Chinese. 277 patients with ICVD, 49 patients with probable VaD and 112 controls were recruited for this study. Distributions of ApoE Ε4 carriers and allele frequencies were 28.5 and 14.5% for patients with ICVD, 20.4 and 10.2% for patients with VaD, whereas these values were 22.9 and 11.6% for controls. Distributions of ApoE Ε2 carriers and allele frequencies were 10.1 and 5.2% for ICVD patients, 6.1 and 3.1% for VaD patients, but 12.5 and 8.0% for controls. There were no differences between ICVD patients and controls, or VaD patients and controls in their Ε4 carriers. Those patients aged 65 and under, carrying the Ε2 allele, had a lower risk of developing ICVD and VaD than did their counterparts. These findings suggest that ApoE Ε4 plays no significant role in the development of ICVD and VaD, but that ApoE Ε2 has a protective effect with regard to the development of ICVD and VaD for Taiwan Chinese below the age of 65.

Mutations in Notch3 cause the syndrome CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The mechanism by which these mutations result in a CADASIL phenotype has been widely speculated upon. A first step toward understanding a disease mechanism is to learn whether the mutations result in the loss of Notch3 function, in particular, its role in signaling or in the gain of a novel function. Notch3 genomic sequences were analyzed for sites of conservation across species. We present here a bioinformatic analysis of the Notch paralogs and orthologs that suggest that CADASIL mutations result in a gain of function. This finding diminishes the likelihood that a Notch3 signaling deficit is responsible for the phenotype and increases the likelihood that CADASIL joins the growing list of neurological diseases with protein deposits due to misfolding and aggregation.

To depict various brain lesions that have been described in patients who have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with prospective standardized magnetic resonance (MR) imaging in patients of different age groups.Forty patients with CADASIL in different age groups (20-30 years, n = 5; 31-40 years, n = 4; 41-50 years, n = 16; 51-60 years, n = 15) underwent transverse MR imaging with T1-weighted dual fast spin-echo, fluid-attenuated inversion-recovery, and T2*-weighted gradient-echo sequences. Images were analyzed by one neuroradiologist for the presence of areas of hyperintensity, lacunar infarcts, microbleeds, and subcortical lacunar lesions (SLLs) in different anatomic locations. Descriptive statistics were obtained for the presence of MR imaging abnormalities in various brain areas and for distribution according to age.The mean age of the 40 mutation carriers (21 women, 19 men) was 45 years +/- 10 (SD). In patients with CADASIL who were 20-30 years old, characteristic hyperintense lesions in the anterior temporal lobe (100% [five of five]) and SLLs (20% [one of five]) were the only abnormalities seen on MR images. In patients who were 30-40 years old, lacunar infarcts were found in 75% (three of four) of cases. More areas of hyperintensity were noted, and they frequently involved the external capsule, basal ganglia, and brainstem. In patients 41-50 years old, microbleeds were observed in 19% (three of 16). In patients older than 50 years, areas of hyperintensity (100% [15 of 15]), SLLs (73% [11 of 15]), lacunar infarcts (93% [14 of 15]), and microbleeds (47% [seven of 15]) were frequently observed.The four types of brain lesions that are observed in patients with CADASIL were seen in patients of different age groups.

The past several years have been marked by significant progress in identifying genetic anomalies in stroke-prone probands. These advances have occurred in both highly penetrant single-gene disorders and in common stroke, which is influenced by risk/susceptibility genes. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be challenging to diagnose because of the wide range of notch 3 mutations that can cause disease, but a new immunohistochemical technique using a skin biopsy sample appears to be highly sensitive and specific. In a landmark Icelandic study, linkage was established between stroke and a locus on chromosome 5q12 designated STRK1. Association studies continue to identify polymorphisms that predispose to stroke and to markers for cerebrovascular atherosclerosis, such as intima-media thickness. Intense interest now surrounds genes involved in inflammation, including genes that encode for the interleukin-1 receptor antagonist and paraoxonase-1. In the foreseeable future, prevention, diagnosis, and treatment will incorporate genetic data to refine and individualize management of cerebrovascular disease.

Top of pageAbstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 10 years) and 22 nonmutated family members (mean age 39 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities. Keywords: CADASIL, Magnetic resonance imaging, White matter hyperintensities, Cerebral blood flow

The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in organisms as diverse as insects, nematodes, echinoderms and mammals. Disruptions in conserved developmental pathways frequently result in inherited congenital anomalies in humans. Mutations in genes encoding Notch pathway components underlie three inherited human diseases: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mouse models for these three diseases have been developed, and are leading to novel insights into the pathology of these diseases in humans.

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.

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.

We report a case of primary cutaneous histoplasmosis in a fifty-year-old African-American woman with diabetes and multi-infarct dementia. The patient developed fever and crusted, nodulo-ulcerative lesions of the skin after accidental superficial trauma to the forehead. The biopsy revealed suppurative granulomatous inflammation with intracellular and extracellular yeast-like cells with associated clear halo measuring 3-4 mm in size. Systemic involvement was not found. The lesions cleared after treatment with itraconazole 200 mg twice a day for 3 weeks. The medication was continued for a total period of 3 months, with no signs of recurrence after one-year of follow-up.

Whether peripheral inflammatory molecules can be considered markers of dementia is still an open issue. We have investigated the presence of circulating cytokines and the ability of blood cells to release them in response to an inflammatory stimulus in patients with different types of dementia and in age-matched controls. A significant increase in circulating interleukin-1β in moderate Alzheimer and in multiinfarct (145 and 224 times control concentration, respectively) dementia and in circulating tumor necrosis factor-α concentration in multiinfarct dementia patient group (156%) were found. Tumor necrosis factor-α and interleukin-6 released from blood cells after exposure to lipopolysaccharide were significantly reduced in moderate Alzheimer (60%, both cytokines) and multiinfarct patients (71 and 50%, respectively), while interleukin-10 was decreased only in multiinfarct patients (61%). The results show that patients with Alzheimer disease or multiinfarct dementia have an upregulation of circulating cytokines and a downregulation of cytokines released by blood cells.

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.

Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain. Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus. Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3. The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.

Hypothermia is generally defined as a core body temperature less than 35 degrees C (95 degrees F). Hypothermia is one of the most common environmental emergencies encountered by emergency physicians. Although the diagnosis will usually be evident after an initial check of vital signs, the diagnosis can sometimes be missed because of overreliance on normal or near-normal oral or tympanic thermometer readings. The classic and well-known electrocardiographic (ECG) manifestations of hypothermia include the presence of J (Osborn) waves, interval (PR, QRS, QT) prolongation, and atrial and ventricular dysrhythmias. There are also some less known (ECG) findings associated with hypothermia. For example, hypothermia can produce ECG signs that simulate those of acute myocardial ischemia or myocardial infarction. Hypothermia can also blunt the expected ECG findings associated with hyperkalemia. A thorough knowledge of these findings is important for prompt diagnosis and treatment of hypothermia. Six cases are presented that show these important ECG manifestations of hypothermia.