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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.

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 years' 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.

• 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.

• 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. MEASURES. —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.

Cardiac disorders associated with cerebral embolism including cardiac surgery, myocardial infarction, endocarditis and non-valvular atrial fibrillation (NVAF) are reviewed along with methods to detect cardioembolic sources. Warfarin and aspirin are effective in the primary prevention of stroke in NVAF but the relative efficacy remains to be determined.

• 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.

• 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.

• A series of patients referred to the University of Western Ontario, London, Dementia Study for investigation of possible dementia underwent computed tomographic scans, psychometric testing (Extended Scale for Dementia [ESD]), and neurologic examination. Thirty-nine of the 113 patients studied (ischemic score, ≤4) were found to have leuko-araiosis, which we have defined as patchy or diffuse lucencies in the white matter. Patients with leuko-araiosis had significantly lower mean scores on the ESD, 109.7 ± 61.2, compared with mean scores of 148.5 ± 78.0 in those without. However, only a trend toward lower scores on the ESD was observed when age, sex, education, and infarct were taken into account in the analysis of covariance. Leuko-araiosis was found to be associated with increasing age, hypertension, abnormalities of power in the limbs, and extensor-plantar responses in this sample of patients. In patients with Alzheimer's disease (AD) alone, diagnosed clinically, 29 out of 91 demonstrated leuko-araiosis on computed tomography, but scores on the ESD in this group overall were not significantly different when those with and without leukoaraiosis were compared. In less advanced cases, however, a highly significant trend was evident for leuko-araiosis to be associated with increased dementia in AD. The results are consistent with the hypothesis that leuko-araiosis is associated with dementia in AD, and that this is either most marked or most easily identifiable before the dementia becomes very severe.

• Leuko-araiosis was found in 49 of 140 demented patients compared with 12 out of 110 control subjects. Thirty-one of 95 patients with dementia of the Alzheimer's type had leuko-araiosis. A history of stroke was four times more frequent in patients with leuko-araiosis than in those without leuko-araiosis (17.4% and 4.4%, respectively). It occurred in 25% of controls with leuko-araiosis compared with only 2% of those without leuko-araiosis. Mean systolic blood pressure was associated with leuko-araiosis. No association was found for diastolic blood pressure, myocardial infarction, angina, diabetes, or carotid bruits. On logistic regression analysis, the strong association between dementia and leuko-araiosis was mainly explained by a history of stroke. There are common factors in leuko-araiosis and stroke, but stroke alone does not account for leuko-araiosis.

• As part of a prospective clinicopathologic study, a cohort of 105 "normal" elderly volunteers was investigated with computed tomographic scans, psychometric testing (Extended Scale for Dementia [ESD]) and neurologic examination. Computed tomographic scans were evaluated for the presence or absence of white matter lucencies, termed leuko-araiosis. These are defined as patchy or diffuse areas of decreased attenuation involving only white matter and with no change in adjacent ventricles or sulci. The nine controls with leuko-araiosis had lower scores on the ESD than the 96 controls without leuko-araiosis (mean ESD with leuko-araiosis, 227.1 ± 14; without leuko-araiosis, 237.1 ± 8), and the difference remains significant even after adjusting for the possible confounding effects of age, sex, education, and infarct detected on computed tomography. Significant differences were also found comparing subjects with leuko-araiosis and those without in respect to abnormal gait, limb power, plantar response, and the rooting and palmomental reflexes. Leuko-araiosis may represent a marker for early dementia. The pathophysiology of this finding remains uncertain. Our results suggest that white matter abnormalities play a role in the development of intellectual impairment in the elderly.

• 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 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.

• 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 right middle cerebral artery occlusion, one 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 a 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. Also, only the group given right middle cerebral artery occlusion showed a significant increase in the QT interval of the electrocardiogram, which our previous work has shown to presage fatal cardiac arrhythmias. Taken together, our data indicate that right hemisphere infarcts have greater sympathetic consequences than left hemisphere infarcts. This finding suggests lateralization of autonomic function and thus is of possible relevance to clinical stroke.

• We identified 85 patients in a longitudinal study of dementia who had uncomplicated Alzheimer's disease and in whom computed tomography of the head and psychometric testing were conducted within a 6-month period following their entry into the study. Thirty-four patients (40%) had leukoaraiosis, which was disproportionately common in female patients (62% vs 15% in male patients). Analysis of covariance demonstrated a relative reduction of scores on the Extended Scale for Dementia in those patients who had leukoaraiosis, after adjusting for the confounding effects of age, sex, educational level, and duration of illness. Leukoaraiosis was also much more common in women, even after adjusting for the possible confounding effects of age, duration of illness, Extended Scale for Dementia score, and hypertension. Multiple regression analysis showed that leukoaraiosis accounted for 11.6% of the variance of the Extended Scale for Dementia scores. Leukoaraiosis, together with duration of illness, accounted for 18.2% of the variance. Leukoaraiosis is associated with a greater degree of cognitive impairment in patients with Alzheimer's disease.

• We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.

• 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.

• 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.

• 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.

• Twenty-four patients of comparable age, blood pressure, and degree of dementia were classified by an "Ischemic Score" based on clinical features into "multi-infarct" and "primary degenerative" dementia. Regional cerebral blood flow (CBF) was measured by the intracarotid xenon 133 method. Both groups showed a decreased proportion of rapidly clearing brain tissue (largely gray matter). Cerebral blood flow per 100 gm brain per minute was normal in the primary degenerative group but low in the multi-infarct group. This suggests the blood flow is adequate for metabolic needs of the brain in patients with primary degenerative dementia but inadequate for those with multi-infarct dementia. There was no correlation between degree of dementia and CBF in the primary degenerative group but an inverse relationship existed in the multi-infarct group. Reactivity of blood vessels to reduction of arterial carbon dioxide pressure was normal in both groups.

• 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 disfacilitation and disinhibition of surviving neurons, thus causing the loss of normal rhythms.

• 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.

• 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 wiht 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.