Connexin43 null mutation increases infarct size after stroke.

Glial-neuronal interactions have been implicated in both normal information processing and neuroprotection. One pathway of cellular interactions involves gap junctional intercellular communication (GJIC). In astrocytes, gap junctions are composed primarily of the channel protein connexin43 (Cx43) and provide a substrate for formation of a functional syncytium implicated in the spatial buffering capacity of astrocytes. To study the function of gap junctions in the brain, we used heterozygous Cx43 null mice, which exhibit reduced Cx43 expression. Western blot analysis showed a reduction in the level of Cx43 protein and GJIC in astrocytes cultured from heterozygote mice. The level of Cx43 is reduced in the adult heterozygote cerebrum to 40% of that present in the wild-type. To assess the effect of reduced Cx43 and GJIC on neuroprotection, we examined brain infarct volume in wild-type and heterozygote mice after focal ischemia. In our model of focal stroke, the middle cerebral artery was occluded at two points, above and below the rhinal fissure. Four days after surgery, mice were killed, the brains were sectioned and analyzed. Cx43 heterozygous null mice exhibited a significantly larger infarct volume compared with wild-type (14.4 +/- 1.4 mm(3) vs. 7.7 +/- 0.82 mm(3), P < 0.002). These results suggest that augmentation of GJIC in astrocytes may contribute to neuroprotection after ischemic injury.

Migraine and the risks from angiography.

There is some suggestion in the literature that patients with migraine may be at an increased risk for developing complications as a result of cerebral angiography. To assess this risk, we reviewed the charts of 142 patients with migraine. A total of 149 angiograms were performed for acute headache (55), new focal symptoms (40), exertional (including coital) headaches (nine), hemiplegic migraine (three), ophthalmoplegic migraine (five), vertebrobasilar migraine (six), migraine accompaniments (three), and other causes (14). Transient events were seen in six patients and these were transient amnesia (one), hemisensory changes (two), hemiparesis (one), global confusion (one), and angina (one). One patient with a history of severe ischemic heart disease developed a myocardial infarction two hours after angiography. Focal cerebral events occurred in 2.6% of cases. This compares with a rate of complications of 2.8% caused by angiography in a prospective study of 1002 patients from our center. According to our findings, it appears that a history of migraine does not increase the risk of complications caused by angiography. Angiography during episodes of acute headaches would also appear to be a safe procedure. Transient focal neurologic symptoms, however, are not infrequent, especially in cases of classic migraine.

Leuko-araiosis.

Problems in the literature in the appraisal of brain deep white-matter changes are considered. The identification of the changes with Binswanger's disease alone is rejected, and evidence is reviewed that demonstrates that they are associated with cognitive impairment and, to some extent, with vascular disease. Possible causes of white-matter changes and their relationships to Alzheimer's disease are examined, and it is argued that a neutral term, exact enough to define white-matter changes, sufficient as a description or label, and demanding enough to require precise clinical and imaging descriptions is needed. We suggest herein the term "leuko-araiosis" on the basis of Greek etymology and Hippocratic usage.

Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors?

The entry characteristics of 1367 patients enrolled into the Extracranial/Intracranial Bypass Study were examined to determine if site differences in intracranial and extracranial arterial lesions among racial groups could be explained by differences in risk factors. Blacks were more often hypertensive, diabetic, or cigarette smokers, while whites had higher systolic blood pressure and hemoglobin values. Orientals had the lowest prevalence of vascular risk factors. Despite these differences in risk factors, multivariate analysis showed race to be an independent and strong predictor of the location of cerebrovascular lesions. To our knowledge, this study is unique in documenting risk factors prospectively and systematically in three racial groups simultaneously. Although generalization is limited by possible biases related to patient selection, the results affirm previous tentative conclusions about the role of race in determining the location of cerebrovascular disease.

Cerebrogenic cardiac arrhythmias. Cerebral electrocardiographic influences and their role in sudden death.

Electrocardiographic repolarization changes, comprising QT prolongation, T-wave flattening or inversion, and ST-segment alterations, are most commonly seen after subarachnoid and intracerebral hemorrhage, but may occur in other neurologic conditions. They may presage arrhythmias. The effects likely are mediated by the sympathetic nervous system. Cerebral arrhythmogenesis may underlie sudden death in both normal and epileptic populations. Experimental evidence suggests that the insula has a cardiac chronotropic organization, and may be involved in the genesis of arrhythmias seen in epilepsy or after cerebral hemorrhage or stroke.

Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging.

The pathologic correlates of increased signal in the white matter of the centrum ovale in postmortem magnetic resonance imaging were investigated in an unselected series of 15 autopsies. Two types of magnetic resonance imaging hyperintensities could be separated on the basis of size (10-mm cutoff): extensive and punctate. The pathologic basis of extensive hyperintensities was large areas of pallor with ill-defined margins, located in the central white matter and sparing the subcortical U fibers on both myelin and axonal stains. Microscopically, these areas showed diffuse vacuolation and significant reduction in the areal densities of glial cells. This change was never seen in areas that did not show extensive white matter hyperdensities on magnetic resonance imaging. The correlates of punctate magnetic resonance imaging hyperintensities were less well defined; dilated Virchow-Robin spaces probably represent a common cause of this phenomenon.

Patterns of deterioration in senile dementia of the Alzheimer type.

OBJECTIVE: To determine rates of decline in Alzheimer's disease. DESIGN: A longitudinal review of patients diagnosed as having dementia during life, tested serially with the Extended Scale for Dementia, and confirmed by autopsy as having Alzheimer's disease. SUBJECTS AND SETTING: Twenty-nine dead patients with Alzheimer's disease from the participants in the University of Western Ontario Dementia Study Project, confirmed at autopsy as having Alzheimer's disease. METHODS: Analysis of the Extended Scale for Dementia data according to a trilinear model. FINDINGS: In the middle phase of the trilinear model, there was a mean annual change of 13% (range, 2.5% to 51.7%). CONCLUSIONS: It is likely that the common method of averaging a group of different individual scores from the initial and middle phases of observation of Alzheimer's disease collapses together individuals at different stages of the disorder, some of whom are in the initial plateau phase and whose conditions are not declining rapidly. The trilinear model of decline avoids this difficulty and the present study provides postmortem confirmed figures on rate of change.

Sensitivity and specificity of the extended scale for dementia.

The Extended Scale for Dementia was introduced as a test for grading the intellectual function of patients with dementia. Its use in discriminating demented patients from nondemented control subjects has been explored. The test had a sensitivity of 93% and a specificity of 96% in patients over the age of 65 years, but the sensitivity fell to 75% in those younger than 65 years. The scale may be useful, particularly for patients over the age of 65 years, in helping to distinguish dementia from normality.

The clinical diagnosis of Alzheimer's disease.

Clinical and pathologic diagnoses are compared in 65 patients who had dementia and who had been studied longitudinally during life. The sensitivity of diagnosis for dementia of the Alzheimer type (DAT) without any other diagnosis was 87%, and the specificity was 78%. The ischemic scale score did not discriminate well between patients with pure multi-infarct dementia and those with both DAT and multi-infarct dementia. However, 35 of 38 cases of pure DAT had a score of 4 or less on the ischemic scale.

The electroencephalogram in Alzheimer-type dementia. A sequential study correlating the electroencephalogram with psychometric and quantitative pathologic data.

As part of a longitudinal cohort study of dementia, 139 patients with Alzheimer's disease (dementia of the Alzheimer type, senile dementia of the Alzheimer type, and mixed type [ischemic score, 4 to 7]) and 148 age-matched control subjects were evaluated for electroencephalographic (EEG) abnormalities and their evolution. Electroencephalograms were significantly different in the two groups; EEGs worsened overall in the two groups during a period of one to four years, but most subjects showed no alteration in their EEGs. Some patients showed improvement in their EEG findings during the follow-up period. A strong correlation between EEG grade and psychometric scores was consistently found over sequential studies. In a subgroup of patients on whom autopsies were performed, morphometric neuron loss correlated significantly with EEG severity.

Cardiac and arterial lesions in carotid transient ischemic attacks.

Two hundred fifty consecutive patients with carotid transient ischemic attacks (TIAs) and no previous stroke were assessed with cerebral angiography (95%), two-dimensional echocardiography (86%), electrocardiography (100%), and Holter monitoring (99 selected patients). Angiography disclosed a lesion appropriate to the TIAs in 84%. Lesions also occurred in the asymptomatic carotid artery, but stenosis of more than 75% of the lumen diameter and ulcers were significantly more frequent on the symptomatic side. Twenty-three percent of the patients had a potential source of emboli from the heart, usually in the context of symptomatic heart disease. Among the 205 patients who underwent full angiographic and cardiac investigations, 6% had an isolated potential cardiac source of emboli and 19% had a potential cardiac source of emboli associated with appropriate carotid disease. The search for a potential cardiac source of emboli is strongly indicated in patients with carotid TIAs and known heart disease. In the patients with no history of heart disease, the yield of this search is low, but our results suggest that at least 14 of such patients have an undetected potential cardiac source of emboli. Cardiac and arterial lesions commonly coexist in carotid TIAs.

Clinical predictors of cardiac and arterial lesions in carotid transient ischemic attacks.

In 205 patients with carotid transient ischemic attacks (TIAs) who underwent full angiographic and cardiac investigations, we found that ipsilateral carotid bruit and triggering of TIA by exertion or standing up suggested a carotid lesion. Angina pectoris or palpitations at onset of TIA suggested a cardiac source of emboli. Patients with only one TIA, multiple identical attacks, progression of symptoms over minutes, and appropriate infarct on computed tomograms (28%) were likely to show a potential arterial or cardiac cause for the TIAs in subsequent investigations. Transient monocular blindness correlated with carotid occlusion, but the severity of the carotid lesion did not influence the duration and repetition of attacks. Transient ischemic attacks in multiple territories, identical attacks, and multiple or silent infarcts on computed tomograms occurred equally in the patients with arterial lesions and those with cardiac lesions. These findings suggest that only a few, albeit important, conclusions regarding etiology can be drawn from the clinical characteristics of TIAs.

Effect of age on autonomic and cardiac responses in a rat stroke model.

The cardiovascular system and its responses change with increasing age. This has seldom been considered in experimental models of stroke, although most strokes occur in the elderly. We studied 57 male Wistar rats in three age groups: 47 to 70 days old (juvenile), 110 to 152 days old (young adult), and 186 to 245 days old (mature adult), each group being subdivided into experimental and sham operation groups. All rats underwent occlusion or sham occlusion of the left middle cerebral artery and monitoring of the mean arterial blood pressure, heart rate, sympathetic nerve activity, plasma catecholamine levels, and electrocardiogram. Eight of the 12 rats in the oldest group died within 6 hours of the middle cerebral artery occlusion; of these, the youngest was 186 days old. The mature adult rats that died before completion of the experiment showed the highest level of sympathetic nerve activity and the only significant increase in the QT interval of the electrocardiogram. Following middle cerebral artery occlusion, sympathetic nerve activity increased in the young adult rats but most strikingly in the mature adult rats that died before the end of the 6-hour experiments. Plasma norepinephrine levels were significantly elevated at 4 and 6 hours after middle cerebral artery occlusion in the oldest group and only at 6 hours in the juvenile rats. The results of this study are consistent with impaired sympathetic and cardiovascular regulation in the mature adult rat. High sympathetic activity may represent one mechanism leading to fatal cardiac arrhythmias. Age-related impairment of sympathetic regulation may contribute to the higher mortality seen among elderly patients with stroke.

Asymmetry of sympathetic consequences of experimental stroke.

Asymmetries of sympathetic regulation at the level of the inferior cervical ganglia have long been recognized. Lateralization of autonomic representation may also occur in the brain, since inactivation of the left and right hemispheres by intracarotid amobarbital produces an increase and decrease in heart rate, respectively. However, this conclusion has remained tentative, since the differential effect of lateralized brain lesions on sympathetic activity has not been studied systematically. Forty-eight urethan-anesthetized Wistar rats were divided into three groups: a group given left middle cerebral artery occlusion, and a group given sham operation. Heart rate, mean arterial blood pressure, renal sympathetic nerve discharge, and electrocardiogram were monitored throughout the 4-hour experiments. Plasma epinephrine and norepinephrine levels were measured at baseline and 1 and 4 hours after occlusion or sham occlusion. The mean arterial pressure decreased in the group given sham operation and to lesser extent in the group given left middle cerebral artery occlusion. By contrast, mean arterial pressure did not fall in the group given right middle cerebral artery occlusion and at 4 hours was significantly higher than control values in the sham-occluded rats. Renal sympathetic nerve discharge was decreased in the sham-occluded group, increased significantly from 20 minutes to 2 hours in the group given left middle cerebral artery occlusion, and increased from about 20 minutes to the end of the experiment in the group given right middle cerebral artery occlusion. The plasma norepinephrine level was significantly elevated at 1 hour (93%) and 4 hours (44%) only in the group given right middle cerebral artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer degeneration in Down syndrome. Electrophysiologic alterations and histopathologic findings.

Progressive electroencephalographic disorganization and decreased voltage amplitude in the late components of the averaged visual evoked potentials were recorded in the last two years of life of a patient with Down disease and Alzheimer degeneration. Taken together with quantitative histopathologic findings, the electrophysiologic alterations are interpreted in terms of recent evidence from an experimental animal model of dementia. Neurons with neurofibrillary degeneration become electrically inactive and contribute to the loss of voltage generators associated with neuron death in Alzheimer disease. Loss of voltage generators may result in disfacillitation and disinhibition of surviving neurons, thus causing the loss of normal rhythms.

Neuropathologic correlates of leuko-araiosis.

We describe the pathologic findings in 17 persons with dementia, 12 of whom exhibited leuko-araiosis on computed tomographic scan. The presence of white matter pallor was confirmed on autopsy in 11 of these 12 cases, 9 with Alzheimer's disease and 2 with multi-infarct dementia. Two further patients, 1 with Alzheimer's disease and 1 with multi-infarct dementia, proved to have white matter changes on pathologic examination. White matter pallor coexisted with cerebral amyloid angiopathy in the brains of the patients with Alzheimer's disease. The presence of severe white matter pallor in patients with Alzheimer's disease correlated with early death, while the presence of cortical scars was associated with prolonged survival. Because early death in patients with Alzheimer's disease has been linked with severe pathologic and chemical changes, the presence of white matter pallor may be further evidence of a particularly severe process in patients with early onset of Alzheimer's disease.

Lack of difference in brain hyperintensities between patients with early Alzheimer's disease and control subjects.

OBJECTIVE: To rate magnetic resonance image signal hyperintensities in clearly defined white and deep gray matter areas in patients with early Alzheimer's disease and controls. DESIGN: Prospective series. The National Institute for Neurological Disorders and Stroke--The Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease. Blinded assessment. SETTING: University hospital, dementia study group. SUBJECTS: Thirty-four patients with Alzheimer's disease. Thirty-eight age-matched healthy community volunteers. MEASURES: Frequency of hyperintensities in axial magnetic resonance images (1.5-T system) seen both in the proton density and T2-weighted scans examined in vascular centrencephalon, centrum semiovale, watershed, periventricular, and subcortical white matter. Periventricular hyperintensities classification include caps, thin lining, and smooth and irregular halo. Hyperintensities in other areas include small and large focal, focal confluent, and diffusely confluent. The hyperintensities were counted and rated using a five-point scale and the Fazekas method. RESULTS: No difference in the ratings, frequency, or extent of the hyperintensities between patients with early Alzheimer's disease and controls. Majority of patients and controls had two or fewer hyperintensities and they were mostly small foci, caps, and thin linings. The hyperintensities are associated with arterial hypertension, diabetes, cardiac disorder, and age in different combinations, but not with Alzheimer's disease. CONCLUSION: Tiny hyperintensities on magnetic resonance images are frequent both in patients with early Alzheimer's disease and in healthy controls; most of the lesions are not related to brain ischemia. When age and vascular risk factors were taken into account, no difference between patients with early Alzheimer's disease and control subjects could be detected.

Electroencephalography as an aid in the exclusion of Alzheimer's disease.

OBJECTIVE: To determine the usefulness or otherwise of the awake electroencephalogram (EEG) in the diagnosis of Alzheimer's disease (AD). DESIGN: Prospective collection of one or more awake EEGs in patients diagnosed as having AD or mixed AD and multi-infarct dementia according to current systematic criteria with analysis of those cases confirmed by postmortem examination. Systematized blind interpretation of EEGs. SETTING: Tertiary care practice with both ambulatory and hospitalized patients, ie, neurological department in general hospital and psychogeriatric unit in psychiatric hospital. PATIENTS: A series of 86 subjects with AD and 17 with mixed AD and multi-infarct dementia being those members of a consecutive series on whom postmortem information was available. Awake EEGs in 56 age- and sex-matched control subjects. RESULTS: Seventy-five patients with AD (87.2%) and 13 of the mixed group (76.5%) had abnormal EEGs on first testing, giving a sensitivity of 87.2% for uncomplicated AD. Ultimately, 79 (92%) of 86 patients with AD had abnormal EEGs. Twenty (35%) of 56 EEGs for matching control subjects were abnormal. Moderately abnormal or severely abnormal EEGs were found in 10 (50%) of 20 of the patients with AD of less than 4 year's duration compared with two (4.1%) of 49 of the control subjects, giving a specificity of 95.9% for EEGs with this degree of abnormality. The normal EEG had a negative predictive value of 0.825 with respect to the diagnosis of AD in these populations. CONCLUSIONS: Widespread availability, low cost, and high sensitivity support the use of the awake EEG in the diagnosis of AD.

Temporal lobe atrophy on magnetic resonance imaging in the diagnosis of early Alzheimer's disease.

OBJECTIVE: To evaluate the use of simple ratings and linear measures of atrophy in the temporal lobe structures obtained with magnetic resonance imaging coronal scans in the diagnosis of early Alzheimer's disease. DESIGN: Prospective series. The National Institute for Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease. Blinded assessment. SETTING: Dementia study in a university hospital. SUBJECTS: Patients with Alzheimer's disease (n = 34), scoring 150 or more on the Extended Scale for Dementia, and age-matched healthy community volunteers (n = 39) who had both magnetic resonance imaging coronal scans and a psychometric assessment using the Extended Scale for Dementia within 6 months were included. MAIN MEASURES: T1-weighted magnetic resonance imaging coronal scans, a 1.5-T system. The degree of atrophy rated (0 to 4) in both sides of the temporal neocortex, entorhinal cortex, hippocampal formation, temporal horns, third ventricle, lateral ventricles, and frontal and parietal cortex. Linear measures: the area of hippocampus and the maximal transverse width of temporal horns. RESULTS: Differentiation between patients with Alzheimer's disease and controls was limited by considerable variations in sensitivity and specificity. Receiver operating characteristics analysis revealed a clear order of discrimination, the entorhinal cortex and the temporal neocortex being the two best, followed by the temporal horns and hippocampal formation. For a given specificity of 90%, the corresponding sensitivity for the entorhinal cortex, temporal neocortex, temporal horns, and hippocampal formation was 95%, 63%, 56%, and 41%, respectively. Linear measures differed significantly but showed considerable overlap. CONCLUSION: The presence of rated atrophy in selected temporal structures makes the diagnosis of Alzheimer's disease more likely, but the absence does not rule out the possibility of early Alzheimer's disease.

Lack of relationship between leukoaraiosis and carotid artery disease. The North American Symptomatic Carotid Endarterectomy Trial.

OBJECTIVE: Leukoaraiosis (LA) (white matter changes) is frequently observed on computed tomographic scans of the brain of elderly patients at risk of stroke. A localized vascular-ischemic cause has been suggested for its underlying mechanism. Our aim was to assess whether high-grade carotid stenosis is associated with LA. DESIGN/SETTING: Patients enrolled in the North American Symptomatic Carotid Endareterectomy Trial (also known as NASCET) were evaluated for LA using a recently proposed grading scale. Ordinal regression analysis was used to assess the association between the severity of carotid artery stenosis and the extent of LA observed on computed tomographic scans. The patients' brain hemisphere was selected as the unit of analysis. RESULTS: Of the 2394 brain hemispheres contributed to the analyses, 352 (14.7%) had signs of LA. After controlling for known stroke risk factors in the ordinal regression analysis, only the history of stroke and increasing age were significantly related to LA. Severity of stenosis was observed to be unrelated (odds ratio [severe vs mild stenosis] = 1.08; 95% confidence interval, 0.73-1.62; P = .952) as were a history of hypertension and a history of myocardial infarction. CONCLUSION: Leukoaraiosis is not associated with severe carotid artery stenosis.