Showing papers in "JAMA Neurology in 1998"
TL;DR: The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.
Abstract: Background: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. Objective: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Design: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Setting: Referral population to a hospital clinic between July 1988 and April 1996. Main Outcome Measures: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Results: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third ($14 µmol/L) compared with the bottom third (#11 µmol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E e4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Conclusions: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD. Arch Neurol. 1998;55:1449-1455
1,399 citations
TL;DR: It is posited that impaired washout is an important but neglected concept that intertwines hypoperfusion, embolization, and brain infarction.
Abstract: Objective To explore the relationship between hypoperfusion, embolism, and brain infarction. Design We studied 4 situations in which brain infarction is related to hypoperfusion: extracranial and intracranial occlusive vascular disease, reduced functional vascular reserve in patients with carotid artery occlusive disease, reduced collateral blood flow in patients given thrombolytic treatment, and cardiac surgery. We reviewed results of emboli monitoring using transcranial Doppler ultrasonography. Results Hypoperfusion is strongly linked to brain ischemia and infarction. The evidence includes close correlation of (1) the severity of arterial stenosis with brain infarction; (2) impaired functional blood flow reserve in patients with carotid artery disease and subsequent brain infarction; (3) reduced collateral blood flow with poor prognosis after thrombolysis; and (4) stroke-related neurologic deficits after cardiac surgery to hypoperfusion during surgery. Microembolization is common in patients with severe symptomatic carotid artery stenosis and during and after cardiac surgery. Conclusions Hypoperfusion and embolism often coexist and their pathophysiological features are interactive. Arterial lumenal narrowing and endothelial abnormalities stimulate clot formation and subsequent embolization. Reduced perfusion limits the ability of the bloodstream to clear or wash out emboli and microemboli and reduces available blood flow to regions rendered ischemic by emboli that block supply arteries. The brain border zones are a favored destination for microemboli that are not cleared. We posit that impaired washout is an important but neglected concept that intertwines hypoperfusion, embolization, and brain infarction.
810 citations
TL;DR: Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities, and the order of the strength of relationships between densities of histologic markers and dementia severity in AD is neuroFibrillary tangles greater than cored senile plaques greater than total senile Plaques.
Abstract: Objective To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Setting Washington University Alzheimer's Disease Research Center, St Louis, Mo. Design and Subjects Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Main Outcome Measures Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Results Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E ϵ4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to ϵ4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to ϵ4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. Conclusions (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E ϵ4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque–based neuropathologic criteria for AD are highly accurate.
647 citations
TL;DR: Severe deficits were found for both patients with AD and PD in each of the 3 olfactory domains relative to controls, however, no discriminating Olfactory deficits were seen between patient groups or among the 3 measured olf factory domains, suggesting a similar disturbance in olfaction function between patients withAD and PD.
Abstract: Background Olfactory deficits in Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) have been well established. Objective To clarify and review the literature by evaluating the evidence for olfactory deficits in 3 olfactory domains, including odor identification, recognition, and detection threshold. Data Sources A literature search of English-language studies of olfaction in AD, PD, and healthy controls was conducted via online databases (PsycInfo and MEDLINE) and reference lists from review articles. Study Selection To meet selection criteria for meta-analysis, each study required a control group and complete and usable data. This review yielded 26 publications of olfactory identification, recognition, and/or detection threshold. Because of the inclusion of more than 1 relevant study of olfaction in several of these publications (eg, both identification and threshold assessed), 43 studies were ultimately appropriate for meta-analysis. Data Extraction Effect sizes were calculated for each study by expressing differences between patient and control group means in SD units (Cohen's d ). Data Synthesis Extremely large effect sizes were shown across all tasks in both AD and PD groups. Both between-group analyses using the Mann-Whitney U test and within-group analyses using Friedman 2-way analysis of variance did not reveal any significant differences (all P >.30). Conclusions As expected, severe deficits were found for both patients with AD and PD in each of the 3 olfactory domains relative to controls. However, no discriminating olfactory deficits were seen between patient groups or among the 3 measured olfactory domains, suggesting a similar disturbance in olfactory function between patients with AD and PD.
616 citations
TL;DR: A reference range for intraepidermal nerve fiber density in normal humans is established by means of a simple quantitation method based on enumeration of individual intraepidersmal nerve fibers on vertical sections of punch skin biopsy specimens stained with the sensitive panaxonal marker anti-protein gene product 9.5.
Abstract: Background The sensitivity of neuron-specific antibodies permit the identification of the small unmyelinated nerve fibers within the skin. Objectives To develop a reference range of epidermal nerve fiber density in humans, and to evaluate their diagnostic efficiency for sensory neuropathies. Methods Ninety-eight normal controls (age range, 13-82 years) were examined with both directed neurologic examinations and quantitative sensory testing. The diagnostic utility was examined in 20 patients with sensory neuropathies. Each subject had 2 punch biopsies performed at each site in the thigh and distal part of the leg (total of 392 biopsies). After formalin fixation, 50-µm-thick free-floating sections were stained with a polyclonal antibody to neuron-specific ubiquitin hydrolase, anti–protein gene product 9.5. We enumerated intraepidermal nerve fibers per millimeter to derive a "linear density." The linear density technique was validated against a stereological technique that used the fractionator to measure the total length of intraepidermal nerve fibers per 3-mm punch. Results The biopsy technique was well tolerated, with no notable complications. The linear density quantitation was rapid and had high intraobserver and interobserver reliability. We determined that the density of intraepidermal fibers in normal controls was 21.1±10.4 per millimeter (mean±SD) in the thigh (fifth percentile, 5.2 per millimeter), and was 13.8±6.7 per millimeter at the distal part of the leg (fifth percentile, 3.8 per millimeter). Significantly higher intraepidermal fiber densities were seen in the youngest group ( P =.004), and we observed no significant effect of race, sex, height, or weight. The density at the thigh was significantly correlated with that at the distal part of the leg ( P =.01) and was consistently higher by about 60%, a reflection of the normal proximal-distal gradient. The results obtained with stereology and the linear density correlated significantly ( P =.001), providing internal validation for the technique. Epidermal nerve fiber density was significantly reduced ( P =.001) in patients with sensory neuropathies. With a cutoff derived from the fifth percentile of the normative range for the distal part of the leg, the technique had a positive predictive value of 75%, a negative predictive value of 90%, and a diagnostic efficiency of 88%. Conclusions We have established a reference range for intraepidermal nerve fiber density in normal humans by means of a simple quantitation method based on enumeration of individual intraepidermal nerve fibers on vertical sections of punch skin biopsy specimens stained with the sensitive panaxonal marker anti–protein gene product 9.5. The utility of the density measurement was confirmed for sensory neuropathy with a diagnostic efficiency of 88%. Skin biopsies may be useful to assess the spatial distribution of involvement in peripheral nerve disease and the response to neurotrophic and other restorative therapies.
535 citations
TL;DR: There is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in patients with Alzheimer disease.
Abstract: Objective To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. Methods An attempt was made to identify all English and non–English-language articles in which G biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition , or National Institute of Neurological Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system–active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. Results Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 ( P Conclusions Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.
534 citations
TL;DR: In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease and Silent lacunes are also associated with neurologic dysfunction.
Abstract: Objective To identify risk factors for and functional consequences of lacunar infarct in elderly people. Methods The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years or older, in which 3660 participants underwent cranial magnetic resonance imaging (MRI). Neuroradiologists read scans in a standard fashion without any clinical information. Lacunes were defined as subcortical areas consistent with infarcts measuring 3 to 20 mm. In cross-sectional analyses, clinical correlates were contrasted among groups defined by MRI findings. Results Of the 3660 subjects who underwent MRI, 2529 (69%) were free of infarcts of any kind and 841(23%) had 1 or more lacunes without other types present, totaling 1270 lacunes. For most of these 841 subjects, their lacunes were single (66%) and silent (89%), namely without a history of transient ischemic attack or stroke. In multivariate analyses, factors independently associated with lacunes were increased age, diastolic blood pressure, creatinine, and pack-years of smoking (listed in descending order of strength of association; for all, P P P P Conclusions In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease. Silent lacunes are also associated with neurologic dysfunction.
490 citations
TL;DR: Combined analysis of CSF Abeta42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging.
Abstract: Objective To evaluate cerebrospinal fluid (CSF) levels of amyloid β protein ending at amino acid 42 (Aβ42) and tau as markers for Alzheimer disease (AD) and to determine whether clinical variables influence these levels. Design Cohort study. Setting Six academic research centers with expertise in dementia. Subjects Eighty-two patients with probable AD, including 24 with very mild dementia (Mini-Mental State Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disorders, including dementia (ND group). Main Outcome Measures Levels of Aβ42 and tau were compared among AD, NC, and ND groups. Relationships of age, sex, Mini-Mental State Examination score, and apolipoprotein E (Apo E) genotype with these levels were examined using multiple linear regression. Classification tree models were developed to optimize distinguishing AD from NC groups. Results Levels of Αβ42 were significantly lower, and levels of tau were significantly higher, in the AD group than in the NC or ND group. In the AD group, Αβ42 level was inversely associated with Apo E ϵ 4 allele dose and weakly related to Mini-Mental State Examination score; tau level was associated with male sex and 1 Apo E ϵ 4 allele. Classification tree analysis, comparing the AD and NC subjects, was 90% sensitive and 80% specific. With specificity set at greater than 90%, the tree was 77% sensitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clinically and a high Apo E ϵ 4 allele frequency. Markers in CSF were used to correctly classify 12 of 13 patients who later underwent autopsy, including 1 with AD not diagnosed clinically. Conclusions Levels of CSF Αβ42 decrease and levels of CSF tau increase in AD. Apolipoprotein E ϵ 4 had a dose-dependent relationship with CSF levels of Αβ42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF Αβ42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging. In subjects in the ND group with an AD CSF profile, autopsy follow-up will be required to decide whether CSF results are false positive, or whether AD is a primary or concomitant cause of dementia.
454 citations
TL;DR: The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.
Abstract: Objective To determine the efficacy of the ketogenic diet in multiple centers. Design A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. Setting Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. Patients Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. Intervention The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. Main Outcome Measures Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. Results Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. Conclusion The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.
421 citations
TL;DR: The 7 Minute Screen appears highly sensitive to AD and may be useful in helping to make initial distinctions between patients experiencing cognitive changes related to the normal aging process and those experiencing cognitive deficits related to dementing disorders such as AD.
Abstract: Objective To determine the validity and reliability of a rapidly administered neurocognitive screening battery consisting of 4 brief tests (Enhanced Cued Recall, Temporal Orientation, Verbal Fluency, and Clock Drawing) to distinguish between patients with probable Alzheimer's disease (AD) and healthy control subjects. Subjects Sixty successive referrals to the Memory Disorders Clinic at Southwestern Vermont Medical Center, Bennington, who were diagnosed as having probable AD and 60 community-dwelling volunteers of comparable age, sex distribution, and education. Design Interrater and test-retest reliability, intergroup comparisons between patients with AD and control subjects on the 4 individual tests, and determination of probability of dementia for patients with AD and control subjects using the entire battery of tests. Setting Outpatient care. Main Outcome Measure Comparison of the probability of dementia on the 7 Minute Screen with the criterion standard of clinical diagnosis established by examination and laboratory studies. Secondary Outcome Measures Test-retest and interrater reliability (correlation coefficients), time for administration. Results Mean time of administration was 7 minutes 42 seconds. Mean scores for patients with AD and control subjects on all 4 individual tests were significantly different (for each,P Conclusions The 7 Minute Screen appears highly sensitive to AD and may be useful in helping to make initial distinctions between patients experiencing cognitive changes related to the normal aging process and those experiencing cognitive deficits related to dementing disorders such as AD. It has reasonable interrater and test-retest reliability, can be administered in a brief period, and requires no clinical judgment and minimal training.
420 citations
TL;DR: The results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women.
Abstract: Background Little is known about the effect of sex on age-related changes in brain structure. Methods Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T 1 -weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained. Results Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporo-parietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex. Conclusions Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.
TL;DR: The APOE genotypes explained up to 10% of the variance in age at the onset of dementia and the association between the epsilon4 allele and dementia was strongest in the youngest age category and in those with a family history of dementia.
Abstract: OBJECTIVES: To provide risk estimates of dementia and Alzheimer disease as a function of the apolipoprotein E (APOE) genotypes and to assess the proportion of dementia that is attributable to the APOE genotypes. DESIGN: Case-control study nested in a population-based cohort study with a mean (SD) follow-up of 2.1 (0.9) years. SETTING: General population in Rotterdam, the Netherlands. PARTICIPANTS: A total of 134 patients with incident dementia and a random sample of 997 nondemented control subjects. No participant had dementia at baseline. MAIN OUTCOME MEASURES: Odds ratios for dementia and Alzheimer disease, the fraction of dementia attributable to the APOE epsilon4 allele, and the proportion of the variance in age at the onset of dementia explained by the APOE genotypes.
RESULTS: Persons with the epsilon4/4 genotype had a more than 10-fold higher risk of dementia (odds ratio, 11.2; 95% confidence interval, 3.6-35.2), and subjects with the epsilon3/4 genotype had a 1.7-fold increased risk of dementia (95% confidence interval, 1.0-2.9) as compared with persons with the epsilon3/3 genotype. The proportion of patients with dementia that is attributable to the epsilon4 allele was estimated to be 20%. The APOE genotypes explained up to 10% of the variance in age at the onset of dementia. The association between the epsilon4 allele and dementia was strongest in the youngest age category and in those with a family history of dementia. CONCLUSIONS: The APOE genotype is an important determinant of the risk of dementia. At a population level, however, other factors than the APOE genotype may play an important role in the cause of dementia.
TL;DR: Motor recovery after cortical infarction in the middle cerebral artery territory appears to rely on activation of premotor cortical areas of both cerebral hemispheres, with short-term output from motor cortex likely to be initiated.
Abstract: Objective To study the mechanisms underlying recovery from middle cerebral artery infarction in 7 patients with an average age of 53 years who showed marked recovery of hand function after acute severe hemiparesis caused by their first-ever stroke. Interventions Assessment of motor functions, transcranial magnetic stimulation, somatosensory evoked potentials, magnetic resonance imaging, and positron emission tomographic measurements of regional cerebral blood flow during finger movement activity. Results The infarctions involved the cerebral convexity along the central sulcus from the Sylvian fissure up to the hand area but spared the caudate nucleus, thalamus, middle and posterior portions of the internal capsule, and the dorsal part of the precentral gyrus in each patient. After recovery (and increase in motor function score of 57%,P Conclusions Motor recovery after cortical infarction in the middle cerebral artery territory appears to rely on activation of premotor cortical areas of both cerebral hemispheres. Thereby, short-term output from motor cortex is likely to be initiated.
TL;DR: The rate of change in psychometric performance before clinically detectable cognitive change occurred was not significantly different between those who eventually developed dementia and those who remained stable, except for performance on the Logical Memory subtest of the Wechsler Memory Scale.
Abstract: Objective To examine the earliest cognitive changes associated with the onset of dementia as well as changes associated with normal aging. Design Longitudinal evaluation of participants with annual clinical and psychometric examinations for up to 15½ years. Setting and Participants Elderly volunteers (n=82) enrolled with a Clinical Dementia Rating of 0 (cognitively intact) in longitudinal studies. Interventions None. Main Outcome Measures Clinical Dementia Rating and results of a 1½-hour psychometric battery. Results As estimated with survival analysis, 40% of participants had a Clinical Dementia Rating greater than 0 (cognitive decline) within 12 years of enrollment; 59% of these were judged to have dementia of the Alzheimer type or incipient dementia. Participants with poorer performance on psychometric testing at enrollment were at higher risk for cognitive decline subsequently. The rate of change in psychometric performance before clinically detectable cognitive change occurred was not significantly different between those who eventually developed dementia and those who remained stable, except for performance on the Logical Memory subtest of the Wechsler Memory Scale. When subtle cognitive decline was clinically detected, however, an abrupt deterioration in performance on independently administered psychometric tests was observed. Conclusions Cognitively healthy elderly people maintain stable cognitive performance when measured longitudinally by both careful clinical evaluation and repeated psychometric testing. This stability is maintained unless and until they develop a dementing illness, at which time a sharp decline in performance is observed.
TL;DR: This study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.
Abstract: Background Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. Objectives To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. Methods Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. Main Outcome Measures Sensitivity and positive predictive value (PPV) were chosen as validity measures and the κ statistic as a reliability measure. Results Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. Conclusions The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.
TL;DR: Occlusive disease involving the V1 segment of the vertebral artery is common in patients with posterior circulation ischemia, but is often associated with other potential mechanisms of stroke.
Abstract: Background Previous studies of patients with bilateral intracranial vertebral artery (ICVA) disease were selective and retrospective. Methods We studied risk factors, vascular lesions, symptoms, signs, and outcomes in patients with bilateral ICVA disease among 430 patients in the New England Medical Center Posterior Circulation Registry. Results Forty-two patients had bilateral ICVA occlusive disease (18 had bilateral stenosis; 16, unilateral occlusion and contralateral stenosis; and 8, bilateral occlusion). The most common risk factors were hypertension (32/42 [76%]) and hyperlipidemia (22/42 [52%]). Sixteen patients (38%) had transient ischemic attacks (TIAs) only; 18 (43%), TIAs before stroke. Occlusive vascular disease also involved the basilar artery in 29 patients (69%), the extracranial vertebral arteries in 18 (43%), and the internal carotid arteries in 11 (26%). Only 6 patients had no other major vascular lesion. Cerebellar symptoms were common. Among 30 patients with infarction, 21 (70%) had proximal intracranial territory involvement, and 15 (50%) had distal territory involvement. The location of occlusive lesions in relation to posterior inferior cerebellar artery origins did not significantly influence prognosis. During follow-up, 31 patients had no symptoms or slight disability, 2 had progression, and 7 died. Among 7 patients with poor outcome, 6 also had basilar artery stenosis or occlusion and 5 had proximal and distal intracranial territory infarcts. Conclusions Most patients with bilateral ICVA occlusive disease have hypertension, other major occlusive lesions, and TIAs before stroke. Short- and long-term outcomes are usually favorable, but patients with bilateral ICVA and basilar artery–occlusive lesions often have poor outcomes.
TL;DR: Findings are consistent with the hypothesis that NPs are among the earliest neuropathological lesions in AD, and even very mild or questionable dementia is associated with increased density of neocortical NPs that do not distinguish between clinically questionable vs definite dementia.
Abstract: Background Identification of the neuropathological lesions that are most closely associated with the earliest symptoms of Alzheimer disease (AD) is crucial to the understanding of the disease process and the development of treatment strategies to affect its progress. Do the classical neuropathological lesions of AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration? Design and Outcome Measures We examined the extent of neuritic plaque (NP) formation in 5 neocortical regions and the hippocampus, entorhinal cortex, and amygdala in 66 elderly subjects with no dementia, questionable dementia, or mild dementia as assessed using the Clinical Dementia Rating Scale (CDR). Setting and Patients Postmortem study of nursing home residents. Results Even questionable dementia (CDR, 0.5) was associated with a significant ( P =.04) increase in neocortical NP density. The density of NPs increased further with increasing dementia severity in all brain regions examined. However, subjects with questionable dementia or definite but mild dementia did not differ significantly from each other. Density of NPs was nearly maximal in subjects with moderate dementia (CDR=2.0), suggesting that other neuropathological changes may be responsible for cognitive deficits beyond this level. Dementia severity correlated significantly with the density of NPs in all brain regions examined ( r range, 0.47-0.56; P Conclusions These findings are consistent with the hypothesis that NPs are among the earliest neuropathological lesions in AD. Even very mild or questionable dementia is associated with increased density of neocortical NPs that do not distinguish between clinically questionable vs definite dementia.
TL;DR: Ulastructural examination of Lewy bodies has revealed masses of aggregated 7-to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified.
Abstract: The presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra pars compacta, as well as neuron loss and gliosis, is a diagnostic hallmark of Parkinson disease (PD), but LBs also are seen in other cortical and subcortical neurons of the PD brain. Additionally, LBs also occur in similar populations of neurons in the brains of patients with the classic clinical and pathological features of Alzheimer disease (AD). Furthermore, the presence of numerous cortical intraneuronal LBs, but only rare AD neurofibrillary tangles and senile plaques in the brains of patients with an AD-like dementia, defines a neurodegenerative disorder known as dementia with LBs (DLB). Ultrastructural examination of LBs has revealed masses of aggregated 7-to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified. Indeed, the biological significance of LBs, especially the role that they might play in the degeneration of neurons in LB disorders, is still enigmatic (Figure).
TL;DR: The data support a recommendation that children with cerebral thromboembolism be evaluated for prothrombotic disorders, and there was a predominance of children with anticardiolipin antibody.
Abstract: Background To our knowledge, the contribution of prothrombotic conditions to cerebral thromboembolism has never been prospectively studied in a large series of pediatric patients. Methods The Hospital for Sick Children, Toronto, Ontario, established a program in January 1992 to diagnose and treat children (term newborn to 18 years old) with arterial ischemic stroke or sinovenous thrombosis. The routine evaluation for prothrombotic conditions included plasminogen, antithrombin, protein C, free protein S, activated protein C resistance, IgG and IgM anticardiolipin antibody, and lupus anticoagulant. We analyzed samples taken within 2 years of the event. We report results on patients seen from January 1, 1992, to January 1, 1997. Results Ninety-two patients (47 males and 45 females) entered the program during the study interval. Patients ranged from newborn to 18 years in age. Arterial ischemic stroke occurred in 78% of patients while sinovenous thrombosis occurred in 22%. All were tested for prothrombotic disorders. One or more abnormal results were present in 35 (38%) of the 92 patients. The majority (21/35) had multiple abnormal test results. The abnormal test results were anticardiolipin antibody (33%), plasminogen (9.5%), activated protein C resistance (9%), protein C (7%), antithrombin (12.5%), lupus anticoagulant (8%), and free protein S (11.5%). Male sex predicted the presence of prothrombotic abnormalities (relative risk, 1.7; 95% confidence interval, 1.2-2.5), but stroke type (relative risk, 0.8; 95% confidence interval, 0.7-1.1), age group, and presence of other risk factors did not predict abnormal testing. Conclusions A significant proportion (38%) of children with cerebral thromboembolism had evidence of prothrombotic conditions. In particular, there was a predominance of children with anticardiolipin antibody (33%). These data support a recommendation that children with cerebral thromboembolism be evaluated for prothrombotic disorders.
TL;DR: The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks.
Abstract: Objective To assess the effectiveness of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. Design Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies. Setting Private practice, referral centers, and general community. Patients Migraineurs with moderate or severe headache pain who met International Headache Society diagnostic criteria for migraine with aura or without aura. The most severely disabled segment of migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set. Intervention Two tablets of the nonprescription combination of acetaminophen, aspirin, and caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute migraine attack. Main Outcome Measures Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none. Results Significantly greater reductions in migraine headache pain intensity 1 to 6 hours after dose were seen in patients taking the acetaminophen, aspirin, and caffeine combination than in those taking placebo in each of the 3 studies. Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients ( P P P P ≤.01). Conclusions The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks. This drug combination also has an excellent safety profile and is well tolerated.
TL;DR: The hypothesis that patients with epilepsy who die suddenly and unexpectedly have cardiac pathologic conditions that may be responsible for their deaths is supported.
Abstract: Background Approximately 1 in 1000 patients with epilepsy dies suddenly and unexpectedly with no obvious medical cause. The purpose of this study was to determine if the hearts of such individuals harbor occult cardiac pathology. Design Following a comprehensive protocol, we performed careful pathologic evaluations of the hearts of 7 patients with epilepsy who died suddenly and 13 previously healthy people who died by hanging or a drug overdose. Hearts were studied only when there was no history or gross anatomical evidence of heart disease or the use of adrenergic drugs. Methods Multiple sections of each heart were evaluated independently by 2 cardiac pathologists who were blinded to patient group. Results Pathologic conditions were found in 5 hearts in the group with epilepsy and in none of the hearts in the comparison group. Four of the 7 hearts in the group with epilepsy had evidence of irreversible pathology in the form of perivascular and interstitial fibrosis. These 4 hearts plus a fifth had evidence of reversible pathology in the form of myocyte vacuolization. Lesions occurred predominantly in the subendocardium. Conclusion Our results support the hypothesis that patients with epilepsy who die suddenly and unexpectedly have cardiac pathologic conditions that may be responsible for their deaths.
TL;DR: Both affective symptoms and neuroendocrine abnormalities were related to inflammatory disease activity but not to degree of disability, supporting the hypothesis that these symptoms are causally associated with brain injury.
Abstract: Objective To investigate the association between affective and neuroendocrine abnormalities, commonly observed in multiple sclerosis, with inflammatory disease activity. Design Cross-sectional design. Twenty-three patients with definite relapsing-remitting multiple sclerosis and age- and sex-matched control subjects were investigated. Depression and anxiety were assessed using structured interviews, self-report measures, and Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria. Neurologic impairment was assessed by the Kurtzke Expanded Disability Status Scale and function of hypothalamic-adrenal-pituitary axis was analyzed using a corticotropin-releasing hormone stimulation test after dexamethasone suppression. Inflammatory disease activity was evaluated first by routine and experimental laboratory tests, and second by magnetic resonance assessment of gadolinium uptake of multiple sclerotic plaques. Setting University hospital, a major provider of acute neurologic care. Results Compared with controls, patients with multiple sclerosis had higher scores on depression and anxiety scales and exhibited a failure of suppression of cortisol release after dexamethasone pretreatment. Both affective symptoms and neuroendocrine abnormalities were correlated with cerebrospinal fluid white blood cell counts and presence of gadolinium-enhancing lesions on magnetic resonance images; however, no association with the degree of neurologic impairment was observed. Conclusion Affective and neuroendocrine disorders were related to inflammatory disease activity but not to degree of disability, supporting the hypothesis that these symptoms are causally associated with brain injury.
TL;DR: A significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases was showed, ie, state 2 and state A (the milder states) of ALS.
Abstract: Background In an attempt to better understand and define the progression of amyotrophic lateral sclerosis (ALS), we developed a classification of 5 discrete health states that reflect patients' activities of daily living. These health states were used to determine whether patients with ALS who are treated with riluzole differed from those treated with placebo. Setting Clinics for patients with ALS. Design Placebo-controlled trial of riluzole treatment in 959 patients with ALS. Interventions Treatment with riluzole or placebo. Main Dependent Measures A Cox model was used to assess whether, from the initial randomization to the end of an 18-month follow-up, there was a difference in the times of transition into subsequent health states between patients treated with riluzole and those treated with placebo. Results Our analysis showed a significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases, ie, state 2 and state A (the milder states) of ALS. Conclusion Patients receiving riluzole remained in the milder health states longer ( P
TL;DR: A defect is in guanosine triphosphate cyclohydrolase I, a gene that makes a cofactor for the synthesis of dopamine, which explains why this form of dystonia should be amenable to treatment with levodopa.
Abstract: Any model for the physiology of dystonia must be able to explain how dystonia can be produced in various circumstances. Brain lesions can cause dystonia; responsible sites include the basal ganglia, brainstem, and thalamus, but the most common site is the putamen. Dystonia can be hereditary, and genetic linkage has been found for both generalized and focal dystonia. The only genetic dystonia for which the gene product is known is Segawa disease, a hereditary progressive dystonia with marked diurnal fluctuation. The defect is in guanosine triphosphate cyclohydrolase I, a gene that makes a cofactor for the synthesis of dopamine, which explains why this form of dystonia should be amenable to treatment with levodopa. Another example of dystonia in which a disorder of dopamine pharmacology appears responsible is the dystonia occurring in Parkinson disease, either spontaneously or as a result of treatment. Curiously, the dystonia occurs at both peak and trough dopamine levels.
TL;DR: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex, which may serve as a marker of progressive neocortical disconnection in Alzheimer disease.
Abstract: Background Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres. Objective To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss. Method Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on midsagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes. Results The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score. Conclusions Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neocortical disconnection in Alzheimer disease.
TL;DR: In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain andStructural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.
Abstract: Objective To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. Design Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. Setting Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. Participants Eighty-six HIV-1–positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. Main Outcome Measures Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. Results Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test,P=.02 andP=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+lymphocyte count. Conclusions In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.
TL;DR: In this paper, a single 4-mm isocenter of radiation was focused on the proximal trigeminal nerve just anterior to the pons, which is associated with a low risk of facial paresthesias, an approximate 80% rate of significant pain relief, and a low recurrence rate in patients who initially attain complete relief.
Abstract: Background Trigeminal neuralgia is a disabling pain syndrome responsive to both medical and surgical therapies. Stereotactic radiosurgery using the gamma knife can be used to inactivate a specified volume in the brain by cross firing 201 photon beams. We evaluated pain relief and treatment morbidity after trigeminal neuralgia radiosurgery. Methods All evaluable patients (n=106) had medically or surgically refractory trigeminal neuralgia. A single 4-mm isocenter of radiation was focused on the proximal trigeminal nerve just anterior to the pons. For follow-up an independent physician who was unaware of treatment parameters contacted all patients. Results After radiosurgery, 64 patients (60%) became free of pain and required no medical therapy (excellent result), 18 (17%) had a 50% to 90% reduction (good result) in pain severity or frequency (some still used medications), and 9 (9%) had slight improvement. At last follow-up (median, 18 months; range, 6-48 months), 77% of patients maintained significant relief (good plus excellent results). Only 6 (10%) of 64 patients who initially attained complete relief had some recurrent pain. Radiosurgery dose (70-90 Gy), age, surgical history, or facial sensory loss did not correlate with pain relief. Poorer results were found in patients with multiple sclerosis. Twelve patients developed new or increased facial paresthesias after radiosurgery (10%). No patient developed anesthesia dolorosa. There was no other procedural morbidity. Conclusions Gamma knife radiosurgery is a minimally invasive technique to treat trigeminal neuralgia. It is associated with a low risk of facial paresthesias, an approximate 80% rate of significant pain relief, and a low recurrence rate in patients who initially attain complete relief. Longer-term evaluations are warranted.
TL;DR: Platelets of patients with AD exhibit greater unstimulated activation than those of controls, and it is possible that AD platelet activation may reflect or even contribute to the pathogenesis of the disease.
Abstract: Background In light of recent reports of diminished platelet serotonin concentration and increased plasma serotonin levels in patients with Alzheimer disease (AD), we hypothesized that a state of heightened platelet activation might be present in AD. Objective To compare baseline activation of unstimulated platelets in patients with AD with that in control subjects. Patients and Methods Flow cytometry was used to measure platelet activation in 91 patients with probable AD and 40 age-matched control subjects. Groups were compared for percentage of circulating platelet aggregates, expression of CD62p, formation of leukocyte-platelet complexes, and presence of circulating platelet microparticles, controlling for effects of demographic, clinical, physiological, and logistical factors. Results Multiple analysis of covariance on ranked data revealed a 39.5% increase in percentage of platelet aggregates ( P =.0001), a 59.3% increase in expression of CD62p ( P =.001), and a 53.3% increase in leukocyte-platelet complexes ( P =.0001) in the group with AD but no differences in the number of platelet microparticles, overall platelet count, plasma fibrinogen level, or plasma platelet factor 3. Activation was weakly correlated with sex, but was independent of age, severity of disease, duration of disease, depression, agitation, and family history of dementia. Conclusions Platelets of patients with AD exhibit greater unstimulated activation than those of controls. Potential causes of such activation include possible stimulation of platelets by damaged cerebral endothelial cells or platelet activation induced by membrane abnormalities previously reported to be present in platelets of patients with AD. In light of recent evidence that platelets are the principal source of both amyloid precursor protein and β-amyloid peptide in human blood, it is possible that AD platelet activation may reflect or even contribute to the pathogenesis of the disease.
TL;DR: Although sway amplitude and velocity were consistently increased in patients with bilateral vestibular loss and patients with cerebellar atrophy, none of the posturography measurements reliably distinguished the 2 patient groups.
Abstract: Objective To assess the diagnostic usefulness of posturography in 2 well-defined patient groups with impaired balance. Patients Ten control subjects, 10 patients with bilateral vestibular loss, and 10 patients with cerebellar atrophy. Outcome Measures Amplitude, velocity, and frequency of sway in the anteroposterior and medial-lateral directions on a static platform, on foam, and on a moving platform. Results Both patient groups consistently had increased sway compared with controls, particularly when standing on foam or on a moving platform with eyes closed. Sway amplitude and velocity were increased about the same amount. The Romberg ratio (sway with eyes closed/sway with eyes open) did not reliably differentiate patients from controls or the 2 patient groups from each other. Some patients with cerebellar atrophy exhibited a characteristic body tremor at about 3 Hz in the anteroposterior direction. Conclusions Although sway amplitude and velocity were consistently increased in patients with bilateral vestibular loss and patients with cerebellar atrophy, none of the posturography measurements reliably distinguished the 2 patient groups. The finding of increased frequency of sway in the anteroposterior direction in patients with cerebellar atrophy was of limited value since the tremor was visible at the bedside.
TL;DR: Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.
Abstract: Background To date, to our knowledge, there is no systematic presentation of treatment outcome in large series of patients clinically diagnosed as having corticobasal degeneration. Objective To evaluate the clinical presentation and treatment outcome of patients clinically diagnosed as having corticobasal degeneration. Subjects We gathered case patients seen in 8 major movement disorder clinics during the last 5 years who were diagnosed as having corticobasal ganglionic degeneration. Methods Using a chart review method, we recorded the clinical presentation, medications used, response to medications, and adverse effects. Results A total of 147 case patients were reviewed, 7 were autopsy proven. Parkinsonian features were present in all, other movement disorders in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). Other movement disorders were dystonia in 71% and myoclonus in 55%. Higher cortical dysfunction included dyspraxia (82%), alien limb (42%), cortical sensory loss (33%), and dementia (25%). Ninety-two percent of the case patients received dopaminergic drugs, which resulted in a beneficial effect for 24%. Parkinsonian signs were the elements improving the most and levodopa was the most effective drug. Benzodiazepines, primarily clonazepam, were administered to 47 case patients, which resulted in improvement of myoclonus in 23% and dystonia in 9%. The most frequent disabling adverse effects of drug trials in these case patients were somnolence (n=24), gastrointestinal complaints (n=23), confusion (n=16), dizziness (n=12), hallucinations (n=5), and dry mouth (n=5). Conclusions Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.