Showing papers in "JAMA Neurology in 1993"

Frontal-subcortical circuits and human behavior.

Abstract: • Objective. —This synthetic review was performed to demonstrate the utility of frontal-subcortical circuits in the explanation of a wide range of human behavioral disorders. Data Sources. —Reports of patients with degenerative disorders or focal lesions involving frontal lobe or linked subcortical structures were chosen from the English literature. Individual case reports and group investigations from peer-reviewed journals were evaluated. Study Selection. —Studies were included if they described patient behavior in detail or reported pertinent neuropsychological findings and had compelling evidence of a disorder affecting frontal-subcortical circuits. Data Extraction. —Information was used if the report from which it was taken met study selection criteria. Data Synthesis. —Five parallel segregated circuits link the frontal lobe and subcortical structures. Clinical syndromes observed with frontal lobe injury are recapitulated with lesions of subcortical member structures of the circuits. Each prefrontal circuit has a signature behavioral syndrome: executive function deficits occur with lesions of the dorsolateral prefrontal circuit, disinhibition with lesions of the orbitofrontal circuit, and apathy with injury to the anterior cingulate circuit. Depression, mania, and obsessivecompulsive disorder may also be mediated by frontalsubcortical circuits. Movement disorders identify involvement of the basal ganglia component of frontal-subcortical circuits. Conclusions. —Frontal-subcortical circuits mediate many aspects of human behavior.

A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary

Abstract: This volume is a compilation of the neuropsychological tests currently used by the authors and their colleagues at the University of Victoria (Melbourne, Australia) Neuropsychology Laboratory. As pointed out by the authors (and well known to clinical neuropsychologists), many of the procedures currently in use were originally developed for other purposes and consequently lack a published manual containing substantial normative data. With the exception of approximately 12 commercially published tests of general intellectual ability, scholastic achievement, and memory, there are multiple (and sometimes obscure) sources of normative data for many neuropsychological tests in use. Numerous tables of normative data not available in published test manuals are reproduced in this volume. Consequently, publication of this compendium is especially timely and informative. Although the scope of the book reflects the authors' flexible, individualized approach to neuropsychological assessment, they include tests that are components of widely used batteries. Organized by the domain of

A clinicopathologic study of 100 cases of Parkinson's disease.

Abstract: The clinical details of 100 cases of histologically confirmed Parkinson's disease were examined and correlated with pathologic findings. Age at disease onset (mean, 62.4 years), disease duration (mean, 13.1 years), and age at death (mean, 75.5 years) were similar to those in previous smaller series. Asymmetric, tremulous onset was most common, although 23% of patients had no rest tremor. Motor fluctuations and dyskinesias occurred in 60% of levodopa-treated patients. All patients had clinical parkinsonism; however, 12 had atypical clinical features of Parkinson's disease, including severe early dementia, fluctuating confusional states, no response to levodopa, and early marked autonomic disturbance. Neuropathologic examination found coexistent Alzheimer-type change in 17 cases and striatal abnormality--mainly vascular--in 34 cases. Cortical Lewy bodies were present in all cases, but only four satisfied proposed criteria for diffuse Lewy body disease. Dementia occurred in 44% of cases; 29% had Alzheimer's disease, 10% had numerous cortical Lewy bodies, and 6% had a possible vascular cause; in 55% no definite pathologic cause was found. Nigral cell loss correlated with disease duration and severity. Although the general pattern of disease conformed to traditional descriptions, the findings broaden the present clinical and pathologic spectrum of Parkinson's disease.

White matter changes in healthy elderly persons correlate with attention and speed of mental processing.

Abstract: • Objective. —To evaluate the association between white matter changes (leukoaraiosis [LA]) seen on magnetic resonance imaging and cognitive functions. Design. —Survey of cohorts of neurologically healthy elderly subjects derived consecutively from a populationbased random sample. Setting. —General community, the Helsinki (Finland) Aging Brain Study. Subjects. —Cohorts of neurologically healthy subjects aged 55, 60, 65, 70, 75, 80, and 85 years (n=20,18,19,18, 17, 17, and 11 subjects, respectively; total N=120). Measures. —Leukoaraiosis was rated in the periventricular areas (0 to 24) and the centrum semiovale (0 to 24); also, a total LA score was obtained (0 to 48). The neuropsychological test battery covered memory, verbal intellectual and constructional functions, language, speed and attention, and speed of mental processing, as well as simple psychomotor speed. Results. —Low age-related LA scores and deterioration of cognitive functions were obtained in the normal subjects. When controlling for age, we found that speed and attention, together with the speed of mental processing measured by the Trail Making A and the Stroop tests, correlated with the total LA score. However, there was wide variation between subjects. Comparing groups with and without LA proved the association of LA with Trail Making A time, Stroop test result (words/time and difference/time), and the compound score of speed and attention. Presence of periventricular LA was especially related to speed of mental processing. Conclusion. —Leukoaraiosis could explain some of the intellectual impairment in the elderly, especially that of slowing of distinct motor and attentional functions, as well as slowing of mental processing. Mild LA in normal aged subjects could also signal brain at risk for further cognitive impairment.

Temporal Lobe Regions on Magnetic Resonance Imaging Identify Patients With Early Alzheimer's Disease

Abstract: • Objective. —The goal of the study was to examine the volume of selected brain regions in a group of mildly impaired patients with Alzheimer's disease (AD). Five regions were selected for analysis, all of which have been reported to show substantial change in the majority of patients with AD at some time in the course of disease. Design. —Case-control study with the experimenter "blinded." Setting. —Hospital-based magnetic resonance imaging center. Participants. —Fifteen subjects, eight patients with the diagnosis of probable dementia of the Alzheimer type made in concordance with National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria and seven age-matched healthy control subjects. Results. —Three of the volumetric measures were significantly different between patients with AD and controls: the hippocampus, the temporal horn of the lateral ventricles, and the temporal lobe. Two of the measures did not significantly differentiate patients with AD and controls: the amygdala and the basal forebrain. A discriminant function analysis demonstrated that a linear combination of the volumes of the hippocampus and the temporal horn of the lateral ventricles differentiated 100% of the patients and controls from one another. Conclusions. —The results suggest that the hippocampus and the temporal horn of the lateral ventricles may be useful as antemortem markers of AD in mildly impaired patients.

The Results of Clinical Trials in Stroke Rehabilitation Research

Abstract: • Research Problem and Methods. —There are currently 1.5 million stroke survivors in the United States. More than half of these individuals have significant residual physical disability and functional impairment. Survivors of stroke constitute the largest group of patients receiving rehabilitation services in this country. We examined existing clinical trials investigating the effectiveness of stroke rehabilitation programs to improve functional outcomes and discharge destination. One hundred twenty-four research reports were initially identified. From this sample, 36 trials meeting selected criteria were evaluated by the methods of meta-analysis. Results. —A total of 3717 patients participated in the 36 clinical trials included in the meta-analysis. The results revealed a mean d-index of 0.40±0.33. This effect size index was converted to a U 3 value of 65.5, indicating that the average patient receiving a program of focused stroke rehabilitation performed better than approximately 65.5% of those patients in comparison groups (95% confidence interval, 63.6% to 67.3%). The results also revealed a significant interaction between type of research design and method of recording the outcome of a clinical trial. Blind recording of the outcome measure appears to be an essential design characteristic in clinical trials that do not randomize patients to conditions. Conclusions. —Programs of focused stroke rehabilitation may improve functional performance for some patients who have experienced a stroke. The improvement in performance appears related to early initiation of treatment, but not to the duration of intervention. Improvements are also associated with the patient's age and the type of design. Research design should be considered an important moderator variable in planning and interpreting future clinical trials of treatment effectiveness in stroke rehabilitation.

Hippocampal Atrophy in Normal Aging: An Association With Recent Memory Impairment

Abstract: • Objective. —To estimate the prevalence of radiographically detectable hippocampal atrophy (HA) in a normal aging sample and to test whether such atrophy is associated with memory dysfunction. Design. —One hundred fifty-four medically healthy and cognitively normal elderly persons (aged 55 to 88 years) received magnetic resonance imaging and/or computed tomographic scans designed to identify HA. One hundred forty-five of these subjects also underwent psychometric tests of memory function. Multivariate analyses of variance were used to evaluate differences in memory performance between subjects with and without HA. Setting. —This study was conducted at a research clinic for the investigation of age-associated neuropsychological and neuroradiologic changes. Participants. —Based on the following criteria, 154 subjects were consecutively selected from a larger group of elderly research volunteers participating in a study of normal aging: age of 55 years or greater; Global Deterioration Scale score of 2 or less; and Mini-Mental State examination score of 28 or greater. Subjects with evidence for significant medical, psychiatric, or neurologic disease were excluded. Main Outcome Measure. —Outcome measurements included individual psychometric test scores and computed tomographic—magnetic resonance imaging hippocampal atrophy ratings. Results. —Nearly 33% of the subjects had radiographic evidence for HA. The prevalence of HA increased significantly with age and was more common in male than female subjects. After controlling for age, level of education, and vocabulary, subjects with HA were found to perform more poorly on tests of recent (secondary) verbal memory when compared with subjects without HA ( P Conclusion. —We conclude that HA is a common accompaniment of normal aging and is associated with mild memory impairment. Additional research is needed to determine whether HA constitutes a significant risk for future dementia.

Explicit Memory in Alzheimer's, Huntington's, and Parkinson's Diseases

Abstract: • Objective. —Comparing the pattern of spared and impaired memory functions in neurodegenerative diseases known to affect different brain structures. Design. —Various situations of acquisition (free encoding or controlled encoding) and retrieval (immediate and delayed free and cued recall, recognition) were used. Setting. —Referral center. Patients. —Fifteen for each disease (ie, senile dementia of the Alzheimer type [SDAT], Parkinson's, and Huntington's), matched for education, severity of dementia, and depression. Main Outcome Measures. —Comparison of free and controlled encoding situations, relationships between memory, executive, and linguistic functions test scores. Results. —In the free encoding situation: no difference among the three groups, but higher numbers of intrusions and false recognitions in SDAT. In the controlled situation: cued recall and recognition scores significantly higher in Parkinson's disease and Huntington's disease than in SDAT. Memory performances correlated with executive functions test scores in Huntington's disease and Parkinson's disease, but not in SDAT. All results significant at P Conclusions. —Clear distinction between the true amnesic syndrome of SDAT, compatible with lesions of hippocampus and temporal cortex, and the inefficient planning of memory processes of Huntington's disease and Parkinson's disease, which might result from a striatofrontal dysfunction.

Spectrum of Complications During Bacterial Meningitis in Adults: Results of a Prospective Clinical Study

Abstract: • Objective. —To determine systematically central nervous system and systemic complications during the acute phase of adult bacterial meningitis. Design. —Prospective clinical study. Setting. —University referral center, Department of Neurology. Patients. —A total of 86 consecutive patients between the ages of 15 and 87 years who had bacterial meningitis. Measurements. —Central nervous system complications, including brain swelling, hydrocephalus, brain abscess, subdural empyema, or subdural effusion (using computed tomography) and cerebrovascular involvement (using cerebral angiography), systemic complications, including septic shock, disseminated intravascular coagulation, adult respiratory distress syndrome, or septic or reactive arthritis, and typical complications arising during intensive care therapy. Results. —Of the 86 adult patients with bacterial meningitis, complications developed in 43 patients. The major central nervous system complications included angiographically documented cerebrovascular involvement (15.1% of the patients [13/86 patients]), brain swelling (14.0% [12/86]), hydrocephalus (11.6% [10/86]), and intracerebral hemorrhage (2.3% [2/86]), while septic shock (11.6% [10/86]), adult respiratory distress syndrome (3.5% [3/86]), and disseminated intravascular coagulation (8.1% [7/86]) dominated among the patients with systemic complications. Seven patients had cerebral herniation, three with a lethal course. The overall mortality was 18.6% [16/86] and was 10 of 30 (3.33%)in pneumococcal meningitis. Conclusions. —Clinical and autopsy studies showed that the major determinants for the lethal outcome were primarily central nervous system complications in six patients, systemic complications in five, and a combination of both in another five. The identification of the various complications and their time of expected occurrence may help to develop additional treatment regimens in bacterial meningitis in adults.

Idiopathic intracranial hypertension (pseudotumor cerebri). Descriptive epidemiology in Rochester, Minn, 1976 to 1990.

Abstract: • The medical records-linkage system of the Mayo Clinic was used to identify cases of idiopathic intracranial hypertension in the 15-year period, 1976 through 1990, among the population of Rochester, Minn. Nine patients (eight women and one man) were identified, corresponding to an average annual age-adjusted incidence rate per 100 000 of 0.9 for the total and 1.6 for the female population. In females aged 15 to 44 years, idiopathic intracranial hypertension occurred at a rate of 3.3 per 100 000 per year; for those defined as obese (body mass index >26), the rate rose to 7.9. Median follow-up was 2.7 years (range, 5 months to 15 years). Three of 18 eyes developed visual impairment; this was mild in all cases.

Cerebral Morphologic Distinctions Between Williams and Down Syndromes

Abstract: • Neurobehavioral studies of Williams syndrome (WS) and Down syndrome (DS) have revealed distinct profiles of cognitive strengths and weaknesses. In a previous report, we described several gross brain morphologic distinctions on magnetic resonance images between these two disorders. While the observed cerebral hypoplasia was of equal degree in the two groups, cerebellar size was entirely normal in the subjects with WS but dramatically reduced in subjects with DS. In WS, paleocerebellar vermal lobules subtended a smaller area on midsagittal sections, but neocerebellar lobules were actually larger. These results suggested important distinctions between WS and DS in terms of the action and anatomic targets of factors that alter brain development in these syndromes. The present study extends the earlier findings by focusing in detail on the morphologic features of the cerebral hemispheres, particularly cerebral gray matter. The results suggest that some frontal and temporal limbic structures are relatively preserved in WS, while some basal ganglia and diencephalic structures are relatively preserved in DS.

Anomalous Cerebral Structure in Dyslexia Revealed With Magnetic Resonance Imaging

Abstract: • Objective. —To develop quantitative methods for identifying cerebral anomalies on magnetic resonance images of subjects with language disorders and other learning disabilities. Design. —Partially blinded comparison of subjects with dyslexia, unaffected relatives, and a control group balanced for age and socioeconomic status. Criterion standard: clinical diagnosis of dyslexia by physician or learning disabilities specialist on the basis of clinical assessment and family history. Settings. —Hospital pediatric neurology clinic and private reading clinic. Patients and Other Participants. —Volunteers: individuals with dyslexia (seven male and two female, aged 15 to 65 years) from professional families; unaffected first- and second-degree relatives (four male and six female, aged 6 to 63 years) available in the geographical area; and controls (five male and seven female, aged 14 to 52 years). Interventions. —Gradient echo three-dimensional scan in Seimens 1-Tesla Magnetom; 128 1.25-mm consecutive sagittal images. Main Outcome Measures. —(1) Average length of the temporal (T) and parietal (P) banks of the planum temporale; (2) interhemispheric coefficients of asymmetry for T and P banks: Left-Right interhemispheric coefficients of asymmetry= (L-R)/[(L+R)/2]; (3) intrahemispheric coefficients of asymmetry=(T-P)/[(T+P)/2]; and (4) qualitative assessment of gyral variants in the parietotemporal operculum. Results. —All groups had left-sided asymmetry for the temporal bank and right-sided asymmetry for the parietal bank. The group with dyslexia had exaggerated asymmetries, owing to a significant shift of right planar tissue from the temporal to parietal bank. They also had a higher incidence of cerebral anomalies bilaterally (subjects with dyslexia, six of nine; relatives, two of 10; and controls, zero of 12). Conclusions. —Quantitative assessment of high-resolution magnetic resonance images can reveal functionally relevant variations and anomalies in cerebral structure. Further refinement of these measurement techniques should improve the diagnosis, classification, and treatment of language disorders and other learning disabilities.

Lymphocytic Infiltrates in the Spinal Cord in Amyotrophic Lateral Sclerosis

Abstract: • Objective. —Immunohistochemical examination was undertaken to assess the presence of lymphocytes and lymphocyte subsets in the spinal cord in amyotrophic lateral sclerosis (ALS). Design. —Twenty-seven consecutive ALS autopsy cases and 11 consecutive disease—control autopsy cases were examined. Tissue sections were reacted with mouse monoclonal antibody to human leukocyte common antigen, or monoclonal antibody to human B-cell L26 antigen, and detected with immunoperoxidase techniques. Unfixed sections were reacted with antihuman Leu-3a and Leu-3b/CD4 or antihuman Leu-2a/CD8 mouse monoclonal antibody and then detected with peroxidase techniques. Setting. —Tertiary care hospital. Cases. —Amyotrophic lateral sclerosis and non-ALS control autopsy specimens. Main Outcome Measure. —Detection of lymphocytes by histological and immunohistochemical reactivity. Results. —Perivascular and intraparenchymal lymphocytic infiltrates were found in the spinal cord of 18 of 27 consecutive ALS autopsy cases. The lymphocytes possessed only T-cell markers; no B-cell markers could be demonstrated. T-helper cells were found in proximity to degenerating corticospinal tracts, while T-helper and T-suppressor/cytotoxic cells were demonstrated in ventral horns. Lymphocytes were present in the spinal cord of only one control specimen (multiple sclerosis) and in none of the remaining 10 control specimens. In ALS tissue, the lymphocytic infiltrates did not correlate with the rate of progression or stage of the disease or with the presence or absence of terminal infections. Conclusions. —T-cell lymphocytes are present in the spinal cord of patients with ALS. T-helper cells are found in proximity to corticospinal tract degeneration, while T-helper and T-suppressor/cytotoxic cells are present in ventral horns. The role of these lymphocytes remains to be elucidated.

Neuropathological Indexes of Alzheimer's Disease in Demented and Nondemented Persons Aged 80 Years and Older

Abstract: • Subjects with clinically diagnosed senile dementia of the Alzheimer type (n=37) and healthy controls (n=5) were assessed clinically until death. Postmortem examination of the brain was performed at age 80 years or older. The brains of all of the group with dementia (except one that was found to have a non-Alzheimer dementia) had substantial densities of neocortical senile plaques regardless of dementia severity; the control brains had very few senile plaques. In those subjects with Alzheimer's disease, moderate correlations were found between dementia duration and severity (cognitive portion of the Blessed Dementia Scale and the Sum of Boxes from the Clinical Dementia Rating) and certain neuropathological lesions, both gross and microscopic. Densities of neocortical neurofibrillary tangles were related to degree of dementia; densities of neocortical senile plaques were unrelated. We conclude that (1) neocortical senile plaque densities differentiate very old subjects with Alzheimer's disease from nondemented controls, but there is a need for more postmortem studies of older persons who are free of dementia; and (2) among the microscopic lesions studied, densities of neocortical neurofibrillary tangles were most closely related to the degree and duration of dementia.

Interictal metabolic anatomy of mesial temporal lobe epilepsy.

Abstract: • Objective. —To examine patterns of temporal and extratemporal regional interictal glucose hypometabolism in individual patients with unilateral mesial temporal lobe epilepsy (TLE). Previous reports disagree on which extratemporal areas can be hypometabolic in TLE. Design. —Case series of patients with TLE who underwent interictal fludeoxyglucose F 18 positron emission tomography, compared quantitatively with normal positron emission tomography. Setting. —Patients referred for surgical treatment of medically refractory complex partial seizures. Patients and Other Participants. —Ten normal volunteers; 27 patients with TLE selected to exclude seizures of bilateral temporal or extratemporal onset. Results. —Regional hypometabolism occurred in 25 patients. Hypometabolic regions were ipsilateral to seizure onset and included lateral temporal (in 78% of patients), mesial temporal (70%), thalamic (63%), basal ganglial (41%), frontal (30%), parietal (26%), and occipital (4%). Specific patterns of temporal and extratemporal hypometabolism varied considerably across the TLE group. Conclusions. —Any of the previously reported anatomic areas of hypometabolism can occur in individual patients with TLE. The prevalence of thalamic hypometabolism suggests a pathophysiologic role for the thalamus in initiation or propagation of temporal lobe seizures or in the interictal cognitive dysfunction of TLE.

Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events

Abstract: • Objective. —A study was undertaken to determine whether cases of parainfectious-associated transverse myelitis (TM) and multiple sclerosis-associated TM could be distinguished on the basis of clinical criteria, radiologic features, or cerebrospinal fluid examination. A secondary objective was to determine the incidence of TM in a US population. Design. —A retrospective analysis of 33 cases was conducted. Cases were classified as being related to parainfectious multiple sclerosis, or spinal cord ischemia, or idiopathic. Setting. —All cases occurring in the Albuquerque, NM, area from 1960 through 1990 were reviewed. The population base was 500 000. Outcome Measures. —Clinical presentation, radiologic features, cerebrospinal fluid, recovery of ambulation and bladder function, and recurrence rates were compared. Results. —Thirty-three patients satisfied study criteria, corresponding to an incidence of 4.6 per million per year. Forty-five percent of these cases were categorized as parainfectious, 21 % as associated with multiple sclerosis, 12% as associated with spinal cord ischemia, and 21% as idiopathic. Patients with parainfectious TM suffered from spinal shock more frequently than did those with multiple sclerosis-associated TM. Patients with parainfectious TM showed evidence of spinal cord swelling, whereas patients with multiple sclerosis-associated TM had spinal cord plaques on magnetic resonance images but none showed swelling. Oligoclonal bands were absent in patients with parainfectious TM and present in three of five patients with multiple sclerosis-associated TM. Conclusions. —Parainfectious TM may be distinguishable from that associated with multiple sclerosis on the basis of presentation, findings on imaging, and the presence of cerebrospinal fluid oligoclonal bands.

Wallenberg's Lateral Medullary Syndrome: Clinical-Magnetic Resonance Imaging Correlations

Abstract: • Objective. —To correlate clinical and radiologic findings in patients with lateral medullary infarction. Design. —Case series with "blinded" evaluation of brain imaging. Setting. —Hospitalized and ambulatory patients at the Neurological Institute of New York (NY). Patients. —Thirty-three consecutive patients with lateral medullary syndrome were evaluated by the Stroke Center between 1983 and 1989. Results. —Ataxia (70%), numbness either of the ipsilateral face or of the contralateral body (64%), vertigo (51 %), and dysphagia (51%) were the most frequent symptoms at onset. Eleven patients had ocular symptoms (diplopia or blurred vision). Horner's syndrome was found in 91 %, ipsilateral ataxia in 85%, and contralateral hypalgesia in 85%. Nystagmus (61%) and facial weakness (42%) were less frequent. Head computed tomography was abnormal only when a cerebellar infarction was present (three cases). Magnetic resonance imaging, obtained in 22 cases, was normal in two; a lateral medullary infarction alone was present in 12, and a lesion extending beyond the lateral medulla was found in eight. No correlation was noted between facial weakness or ocular symptoms and infarction extending beyond the lateral medullary region. Vertebral artery disease was confirmed by vascular imaging or insonation studies in 73% of patients. Conclusions. —The triad of Horner's syndrome, ipsilateral ataxia, and contralateral hypalgesia will clinically identify patients with lateral medullary infarction. Facial weakness and ocular symptoms are frequent and do not necessarily imply that the infarction extends beyond the lateral medulla. Cerebellar infarcts only infrequently accompany lateral medullary syndrome, suggesting that most of the posterior inferior cerebellar artery territory is spared, despite the high frequency of vertebral artery occlusion.

Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention.

Abstract: The spatial distribution of directed attention is coordinated by a large-scale neural network. The three principal cortical components of this network are located in the region of the frontal eye fields, posterior parietal cortex, and the cingulate cortex. We injected a retrogradely transported fluorescent dye into the frontal eye fields and another into the posterior parietal cortex of the monkey brain. Large numbers of neurons in the cingulate cortex were retrogradely labeled with each of the two fluorescent dyes. The two types of retrogradely labeled neurons were extensively intermingled, but neurons labeled with both tracers constituted less than 1% of retrogradely labeled cingulate neurons. Other cortical areas that contained retrograde neuronal labeling included the premotor, lateral neuronal labeling included the premotor, lateral prefrontal, orbitofrontal, opercular, posterior parietal, lateral temporal, inferior temporal, parahippocampal, and insular regions. These areas contained neurons labeled with each of the two dyes but virtually no neurons labeled with both. In the thalamus, retrogradely labeled nuclei failed to display evidence of double labeling. The overlap between the two populations of retrogradely labeled neurons was far more extensive at the cortical than at the thalamic level. These observations show that cortical and thalamic projections to the frontal eye fields and posterior parietal cortex do not represent axonal collaterals of single neurons but originate from two distinct and partially overlapping populations of neurons.

The Neuropsychology of the Prefrontal Cortex

Abstract: Single photon emission computed tomography with the xenon inhalation technique is used to compare activation of regional cerebral blood flow in frontal brain regions during the performance of four widely used neuropsychological tests: the Continuous Performance Test, the Wisconsin Card Sorting Test, the Tower of London, and Porteus Mazes. Healthy normal volunteers performing these tasks show significant increases in frontal regions during the Continuous Performance Test, the Wisconsin Card Sorting Test, and the Tower of London, but not the Porteus Mazes. Activation produced by the Continuous Performance Test and the Tower of London are mesial and bilateral and may reflect stimulation of midline attentional circuits. The Wisconsin Card Sorting Test produces a left dorsolateral area of prefrontal activation. These findings indicate that regional activation of the frontal lobes occurs in response to cognitive challenges produced through performance of standard neuropsychological tests.

Time Until Institutionalization and Death in Patients With Dementia: Role of Caregiver Training and Risk Factors

Abstract: • Objective. —To determine which variables best predict prognosis—time to nursing home admission (NHA) and death—in patients with dementia. Design. —Survival analysis employing the Cox proportional hazards model with the use of risk variables pertaining to dementia severity and its rate of progression and caregiver functioning. Setting. —Patients and their caregivers participating in a controlled intervention study of training for caregivers in home management of dementia. Participants. —Patients with mild Diagnostic and Statistical Manual of Mental Disorders, Third Edition —defined dementia (N=91; 68 patients with Alzheimer-type dementia, 20 with vascular dementia, and three with other types) and their caregivers. Follow-up. —All subjects had repeated assessments in the first year to determine rates of change and thereafter annually to determine the date of NHA and/or death. Risk Variables. —(1) Caregiver training; (2) dementia severity at index assessment; (3) caregiver stress, neuroticism, and socialization; (4) changes in patients and caregivers during the first 12 months; and (5) patient characteristics. Results. —By 5 years' follow-up, 76% of patients had entered a nursing home and 42% had died. Dementia severity and rate of deterioration ("how far" and "how fast") and caregiver psychological morbidity significantly influenced rates of NHA and death. Training of caregivers was significantly associated with delayed NHA and reduced mortality. Greater patient age, non-Alzheimer's dementia, and, unexpectedly, greater caregiver psychological morbidity were associated with shorter survival to death. Conclusions. —Both severity ("how far") and rate of deterioration ("how fast") influence time to NHA and death. Caregiver training may have important ameliorating effects on the prognosis of dementia.

Information Processing Efficiency in Chronic Fatigue Syndrome and Multiple Sclerosis

Abstract: • Objective. —To compare the cognitive performance of subjects with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and healthy controls. All subjects were matched for age, education, and verbal intelligence, as previous neuropsychological studies of CFS had not used appropriate control groups. Design. —Case-control design. All subjects were given a neuropsychological battery and the test scores were compared among the groups. Setting. —Subjects with CFS and subjects with MS were recruited from private and institutional practice and from the community. Healthy subjects were recruited from the community. Patients/Other Participants. —Twelve subjects (all female) with CFS participated in the study. Chronic fatigue syndrome was diagnosed in these patients in accordance with the requirements outlined by the Centers for Disease Control as modified subsequently to not exclude patients with concurrent depression and/or anxiety. All subjects with CFS were referred for a neuropsychological examination to assess persistent cognitive complaints. Eleven subjects (10 female, one male) with the diagnosis of clinically stable MS were chosen from clinics and the community because of complaints of mild to moderate cognitive impairment. The subjects with MS and 11 healthy volunteers (10 female, one male) were matched to the group with CFS by age, education, and estimated verbal intelligence (based on the Vocabulary subtest of the Wechsler Adult Intelligence Scale-Revised). The subjects with MS had a mean Kurtzke Expanded Disability Status Scale score of 4.95 (SD, 1.95;range, 2.0 to 7.5). As a result of the matching procedure, there were no differences among the three groups in age (F[2,31]=0.32), education (F[2,31]=0.80), and verbal intelligence (F[2,31]=0.31). Interventions. —None. Main Outcome Measures. —These measures included the Beck Depression Inventory (BDI), the Paced Auditory Serial Addition Test (PASAT), Digit Span Test, and the Similarities Test of Verbal Abstract Reasoning. Results. —The mean number of correctly identified responses collapsed across the four PASAT trials was significantly different across groups (F[2,31 ]=4.03; P P P P P P r =−.21; MS, r =.13; control, r =.27), or between BDI and Digit Span Test (CFS, r =−.32; MS, r =−.40; control, r =−.19). Results of the PASAT and Digit Span Test were significantly correlated in the CFS group ( r =.71; P r =.06) or control groups ( r =.49). Conclusions. —These results indicate that subjects with CSF and subjects with MS show significant impairment on a test of complex concentration when compared with appropriate controls. The data suggest that subjects with CFS and subjects with MS have difficulty on tasks that require the simultaneous processing of complex cognitive information. Selective impairment in information processing efficiency may lie at the root of other cognitive complaints made by patients with CFS.

Hippocampal Neuron Loss and Memory Scores Before and After Temporal Lobe Surgery for Epilepsy

Abstract: • Objective. —To assess the relationship of hippocampal neuron loss to intellectual and memory measures before and after temporal lobe surgery. Design. —Pyramidal cell loss, as determined on the resected tissue, of hippocampal subregion CA1 correlated highest with other subregional cell loss and thus was used as the primary indicator of hippocampal neuron loss. Groups of patients with left and right temporal lobe seizures were subdivided according to degree of CA1 neuron loss. Behavioral performances of patient groups were compared before and after surgery. Setting. —Patient data were obtained from a university program of surgery for epilepsy. Cases. —Twenty-five patients who had intractable epilepsy. Main Outcome Measures.—Wechsler Adult Intelligence Scale IQ scores, verbal and nonverbal memory measures adapted from the Wechsler Memory Scale, and the Rey-Osterrieth recall score. Results. —Degree of hippocampal cell loss selectively related to learning of unrelated word pairs, both preoperatively and postoperatively, in patients with left but not right temporal lobe seizures. Patients with severe loss of left hippocampal neurons performed worse than those with mild-moderate neuron loss both before and after surgery. Immediate recall of logical prose did not relate to hippocampal neuron loss, although scores decreased following left temporal lobe surgery. Conclusion. —These findings support a role for the left hippocampus in rote verbal memory, ie, learning of unrelated word pairs. Semantically complex verbal learning, ie, recall of logical prose, is more dependent on extrahippocampal temporal lobe regions. Finally, patients with severe as compared with minimal left hippocampal neuron loss may be at risk for lower memory functioning postoperatively.

Risk Factors for Cerebrovascular Disease as Correlates of Cognitive Function in a Stroke-Free Cohort

Abstract: We investigated the relationship between risk factors for cerebrovascular disease and cognitive function in 249 stroke-free community volunteers (age, 70.8 +/- 6.7 years; education, 12.3 +/- 4.6 years) who were given tests of memory, language, visuospatial, abstract reasoning, and attentional skills. Using logistic regression analyses, we examined hypertension, diabetes mellitus, myocardial infarction, angina, hypercholesterolemia, and cigarette smoking as potential correlates of performance within these cognitive domains. Controlling for demographic factors within the logistic models, diabetes mellitus was a significant independent correlate of abstract reasoning deficits (odds ratio, 10.9; 95% confidence interval, 2.2 to 54.9) and visuospatial dysfunction (odds ratio, 3.5; confidence interval, 1.2 to 10.7), while hypercholesterolemia was a significant independent correlate of memory dysfunction (odds ratio, 3.0; confidence interval, 1.4 to 6.6). Prolonged exposure to vascular risk factors such as diabetes mellitus and hypercholesterolemia may lead to atherosclerotic disease, possibly resulting in "silent" infarctions or impaired cerebral blood flow and a decline in cognitive functioning.

Leber's hereditary optic neuropathy : new genetic considerations

Abstract: • Objective. —Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease that causes bilateral central visual loss, predominantly in young men. Recently, this disorder has been associated with point mutations in the mitochondrial genome. The clinical characteristics of LHON are reviewed with special attention to recent advances in mitochondrial genetics. Data Sources. —Literature from the mid-19th century to the present is reviewed. Study Selection. —Major review articles that include multiple large pedigrees in their analysis are featured. Special emphasis is placed on the recent reports on mitochondrial DNA abnormalities associated with this disease. Data Extraction. —The older literature is reviewed critically with an understanding that some of the patients included as examples of LHON may have had a different disease. The more current references are assessed in regard to their inclusion of appropriate and complete mitochondrial DNA analysis. Data Synthesis. —Leber's hereditary optic neuropathy, a maternally inherited disease primarily of young men, results in bilateral, acute or subacute, central visual loss and, ultimately, optic atrophy. Point mutations in the mitochondrial genes encoding proteins essential to oxidative phosphorylation have been associated with this disorder. Primary mutations include those found at positions 11778, 3460, and, possibly, 15257 and 14484. Mitochondrial, nuclear, and environmental factors may modify phenotypic expression. Conclusion. —Genetic analysis has allowed for a broader view of what constitutes the clinical phenotype of LHON.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography

Abstract: • Objective. —To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. Design. —Randomized double-blind, placebo-controlled trial. Setting. —Acute-care teaching hospital. Patients. —Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg (systolic) and 95 and 120 mm Hg (diastolic). Intervention. —Placebo (n=6), nicardipine hydrochloride (20 mg [n=5]), captopril (12.5 mg [n=3]), or clonidine hydrochloride (0.1 mg [n=2]) given every 8 hours for 3 days. Main Outcome Measures. —Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. Results. —Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo ( P Conclusions. —Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Predictive Value of Magnetic Resonance Imaging in Temporal Lobe Epilepsy Surgery

Abstract: • The predictive value of magnetic resonance imaging (MRI) was assessed by a prospective study of 34 patients selected for surgical treatment of temporal lobe epilepsy. The MRIs were interpreted using standardized visual diagnostic criteria and the imaging findings were correlated with the surgical outcome. Lateralized MRI abnormalities were found in 25 (74%) of 34 patients. Significant associations were found between either the presence of a restricted foreign-tissue lesion or hippocampal atrophy and an excellent surgical outcome. An abnormal MRI had an 82% predictive value and a normal MRI had a 56% predictive value for surgical success. A history of febrile convulsions and the presence of hippocampal atrophy best predicted outcome (predictive value, 86%). These results suggest that specific MRI findings in candidates for temporal lobe epilepsy surgery are predictive of surgical outcome. The information provided by MRI may be of value for counseling patients prior to surgical intervention.

Pathologic Correlates of Increased Signals of the Centrum Ovale on Magnetic Resonance Imaging

Abstract: • 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.

Locomotion of Autistic Adults

Abstract: Objective: To assess gait in patients with autism. Design: Clinical and physiologic assessment. Setting: Research hospital Patients and Subjects: Five adults with autism and five healthy, age-matched control subjects. Main Outcome Measure(s): Clinical and biomechanical assessment. Results: Clinical assessment showed mild clumsiness in four patients and upper limb posturing during gait in three patients. The velocity of gait, step length, cadence, step width, stance time, and vertical ground reaction forces were normal in all patients. The only significant abnormality was decreased range of motion of the ankle. Some patients exhibited slightly decreased knee flexion in early stance. Clinically, the gait appeared to be irregular in three patients, but the variability was not significantly increased. Conclusions: The findings in patients with autism indicate a nonspecific, neurological disturbance involving the motor system. The normal velocity of gait and the normal step length argue against a parkinsonian-type disturbance, whereas the clinical picture suggests a disturbance of the cerebellum.

Genetic and infectious prion diseases.

Abstract: Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases include scrapie of sheep and bovine spongiform encephalopathy of cattle as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and mouse (Mo) PrP genes were used to probe the molecular basis of the species barrier and the mechanism of scrapie prion replication. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum determines that prions are synthesized de novo, even though the cells express both PrP genes. Studies with artificial prions produced from chimeric Mo/SHaPrP transgenes underscore the concept that inoculated prion dictates which prion will be replicated. Discovery of mutations in the PrP genes of humans with GSS and familial CJD established that prion diseases are both genetic and infectious. Transgenic mice expressing high levels of MoPrP-P101L, corresponding to the GSS point mutation (P102L) in human PrP, spontaneously develop neurologic dysfunction, spongiform degeneration, and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg (MoPrP-P101L) mice produced neurodegeneration in recipient animals after prolonged incubation times. These results are in accord with those of other studies and argue that prions are devoid of foreign nucleic acid. Structural investigations of cellular prion protein (PrPC) and prion protein scrapie (PrPSc) suggest that the difference may be conformational. Conditions that diminished the beta-sheet content of PrPSc were the same as those identified previously that inactivate prion infectivity. Whether prion diversity as reflected by distinct "strains" producing different patterns of PrPSc accumulation is due to different conformers of PrPSc remains to be established. Advances in the purification and characterization of both PrPC and PrPSc seem to have identified the central event in PrPSc synthesis and prion propagation, ie, the unfolding of PrPC followed by its refolding into PrPSc. These findings underscore the fundamental features of prion structure and propagation that differentiate prions from other transmissible pathogens.

Effect of Age on D2 Dopamine Receptors in Normal Human Brain Measured by Positron Emission Tomography and 11C-Raclopride

Abstract: • Human postmortem and animal experimental results suggest a decline of the cerebral dopaminergic neuronal system with age. In this study, the radiotracer carbon 11-labeled-raclopride and positron emission tomography were applied to determine the effect of age on striatal D 2 dopamine receptors in 32 healthy volunteer subjects (age range, 21 to 68 years; median, 31 years). An index of specific 11 C-raclopride binding was calculated for putamen, caudate nucleus, and other brain regions in each subject. A significant decrease with age of the index for specific tracer uptake was found in putamen and caudate nucleus. The decrease was steep until 30 years, but slower afterward. After approximately 30 years of age, the decline of specific 11 C-raclopride binding in putamen was found to be 0.6% per year. Our results suggest that D 2 dopamine receptor binding sites (mainly postsynaptically located) decrease as a consequence of normal aging in parallel with the decline of the presynaptic nigrostriatal dopaminergic neuronal system.