Showing papers in "JAMA Neurology in 1999"

Mild Cognitive Impairment: Clinical Characterization and Outcome

Abstract: Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

Diagnostic Criteria for Parkinson Disease

Abstract: The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts have been made to develop explicit diagnostic criteria. We propose a clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD. Three levels of diagnostic confidence are differentiated: Definite, Probable, and Possible. The diagnoses of Possible and Probable PD are based on clinical criteria alone. Neuropathologic confirmation is required for the diagnosis of Definite PD in patients with the clinical diagnosis of Possible or Probable PD. Criteria for histopathologic confirmation of PD are also presented.

Cerebrospinal Fluid β-Amyloid(1-42) in Alzheimer Disease: Differences Between Early- and Late-Onset Alzheimer Disease and Stability During the Course of Disease

Abstract: Objectives To study the diagnostic potential of the 42 amino acid form of β-amyloid (β-amyloid (1-42) ) in cerebrospinal fluid (CSF) as a biochemical marker for Alzheimer disease (AD), the intra-individual biological variation of CSF-β-amyloid (1-42) level in patients with AD, and the possible effects of differential binding between β-amyloid and apolipoprotein E isoforms on CSF-β-amyloid (1-42) levels. Design A 20-month prospective follow-up study. Setting Community population-based sample of consecutive patients with AD referred to the Pitea River Valley Hospital, Pitea, Sweden. Patients Fifty-three patients with AD (mean±SD age, 71.4±7.4 years) diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria and 21 healthy, age-matched (mean±SD age, 68.8±8.0 years) control subjects. Main Outcome Measures Cerebrospinal fluid β-amyloid (1-42) level—analyzed using enzyme-linked immunosorbent assay—and severity of dementia—analyzed using the Mini–Mental State Examination. Results Mean±SD levels of CSF-β-amyloid (1-42) were decreased ( P r =0.90; P (1-42) levels was found. There were no significant correlations between CSF-β-amyloid (1-42) level and duration ( r =−0.16) or severity ( r =−0.02) of dementia. Low levels were also found in patients with mild dementia (Mini–Mental State Examination score, >25). Conclusions The sensitivity of CSF-β-amyloid (1-42) level as a diagnostic marker for AD is high. The intra-individual biological variation in CSF-β-amyloid (1-42) level is low. Low CSF-β-amyloid (1-42) levels are also found in the earlier stages of dementia in patients with AD. These findings suggest that CSF-β-amyloid (1-42) analyses may be of value in the clinical diagnosis of AD, especially in the early course of the disease, when drug therapy may have the greatest potential of being effective but clinical diagnosis is particularly difficult.

Clinical and Pathological Evidence for a Frontal Variant of Alzheimer Disease

Abstract: Objective To evaluate the clinical and pathological features of a subgroup of patients with Alzheimer disease (AD) who exhibited early and disproportionately severe impairments on tests of frontal lobe functioning. We hypothesized that these patients would exhibit a greater degree of either neurofibrillary tangle (NFT) or senile plaque pathology in the frontal lobes than would patients with typical AD. Design and Outcome Measures We examined the neuropsychological profiles and senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in 3 patients with AD who exhibited disproportionate frontal impairments during early stages of dementia (frontal AD) and 3 matched patients with typical AD (typical AD). Results Compared with the typical AD group, the frontal AD group performed significantly worse on 2 tests of frontal lobe functioning and on the Wechsler Adult Intelligence Scale–Revised Block Design test. No significant group differences were found on other tests. Analysis of brain tissue samples demonstrated that, despite comparable entorhinal, temporal, and parietal NFT loads, the frontal AD group showed a significantly higher NFT load in the frontal cortex than the typical AD group. Senile plaque pathology in the frontal and entorhinal cortices did not differentiate the 2 groups. Conclusions We identified a subgroup of patients with pathologically confirmed AD who presented in the early stages of dementia with disproportionate impairments on tests of frontal lobe functioning and had a greater-than-expected degree of NFT pathology in the frontal lobes, suggesting the existence of a frontal variant of AD that has distinctive clinical and pathological features.

Long-term Evaluation of Bilateral Fetal Nigral Transplantation in Parkinson Disease

Abstract: Background Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate control of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyskinesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervation, and improve motor function. In patients with PD, cell survival and clinical benefit have been observed following fetal nigral grafting, but results have been inconsistent. Objective To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias. Patients and Methods Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 612to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off" and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18 F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation. Results Patients have been followed up for a mean ± SD of 20.5 ± 5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly ( P P P t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen. Conclusions Fetal nigral tissue can be transplanted into the postcommissural putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomography. Clinical improvement appears to be related to the survival and function of transplanted fetal tissue.

Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community-based study.

Abstract: Background Hallucinations and delusions are frequent in patients with Parkinson disease (PD) and may have severe clinical consequences for those patients and their caregivers. However, the prevalence and clinical features of these symptoms have not been studied in a representative sample. Objective To study the prevalence and clinical correlates of psychosis in a population-based sample of patients with PD. Method Total ascertainment of patients with PD in a defined geographical area in Norway was attempted through a detailed community study. Clinical evaluation consisted of a neurologic examination and assessments of depression and cognition. Psychosis was assessed with the thought disorder subscale of the Unified Parkinson's Disease Rating Scale. Results A total of 245 patients with PD were identified, 235 (95.9%) of whom participated in this study. Twenty-three patients (9.8%) had hallucinations with insight retained, and another 14 patients (6.0%) had more severe hallucinations or delusions. Psychotic symptoms were associated with age, stage and diagnostic subgroup of PD, severity of depression, and cognitive impairment. Type, duration, and dose of antiparkinson drug therapy did not differ between those patients with PD who had or did not have psychosis. In a polychotomous logistic regression analysis, severity of depression, cognitive impairment, and impairment of activities of daily living were the only significant concomitants of psychosis. Conclusions Hallucinations and delusions are common in patients with PD. More advanced and widespread brain changes seem to increase the risk for developing psychosis in patients with PD receiving levodopa therapy.

Functional MRI-BOLD of visually triggered headache in patients with migraine.

Abstract: Background Spreading depression of Leao has been hypothesized as the basis for the visual aura of the migraine attack, supported by cerebral blood flow measurements of spreading hypoperfusion. The early depolarizing or activation phase of experimental spreading depression, however, is associated with a transient but pronounced cerebral blood flow increase that precedes spreading hypoperfusion. Objective To study this early phase of the migraine attack, we investigated visually triggered attacks of headache and visual symptoms using a red-green checkerboard stimulus in patients with migraine. Interventions We studied occipital cortex activation during visual stimulation by measuring occipital cortex perfusion with functional magnetic resonance imaging–blood oxygenation level-dependent contrast in 10 patients with migraine with aura and 2 patients with migraine without aura and 6 healthy subjects. Results In 6 patients with migraine with aura and 2 patients with migraine without aura, their typical headache with (n=2) or without visual change was visually triggered at 7.3 minutes (mean time) after visual stimulation began. In 5 of these patients, the onset of headache or visual change, or both, was preceded by suppression of initial activation (mean onset time, 4.3 minutes; P Conclusions We conclude that visually triggered headache and visual change in patients with migraine is accompanied by spreading suppression of initial neuronal activation and increased occipital cortex oxygenation. We postulate that this spreading suppression may be associated with initial activation of a migraine attack, independent of whether there are associated aura symptoms. We further postulate that there may be an association between vasodilation accompanying the initial stage of suppression and the induction of headache.

The role of oxidative stress in Alzheimer disease.

Abstract: Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. In the neurodegenerative diseases, oxidative stress has been implicated in amyotrophic lateral sclerosis, Parkinson disease, Huntington disease, and Alzheimer disease (AD). The neurodegenerative disorder receiving the most attention has been AD, in which an increase occurs in oxidation of brain lipids, carbohydrates, proteins, and DNA. Some of the products of oxidation have been found in the major histopathologic alterations in AD: the neurofibrillary tangles (NFTs) and senile plaques (reviewed in Markesbery and Carney 1 and Ceballos-Picot 2 ). These oxidative modifications are closely associated with a subtle inflammatory process in the brain in AD. Oxidative stress refers to a state in which free radicals and their products are in excess of antioxidant defense mechanisms. This imbalance can occur as a result of increased free radical production or a decrease in antioxidant defenses. Free radicals are defined as any atom or molecule that has one or more unpaired electrons in its outer shell. The reduction of molecular oxygen to water is a major source of potent radicals. The initial step in this reaction yields the superoxide radical, which produces hydrogen peroxide by addition of an electron. The reduction of hydrogen peroxide yields the highly reactive hydroxyl radical. These radicals plus singlet oxygen are called reactive oxygen species (ROS). Several reactive nitrogen species, nitric oxide, and peroxynitrite also are important modulators of oxidative stress. These free radicals and others are capable of reacting with lipids, proteins, nucleic acids, and other molecules and altering their structure and function. Oxidative stress can lead to alterations in cells with an accumulation of oxidized products such as aldehydes and isoprostanes from lipid peroxidation, protein carbonyls from protein oxidation, and base ad

Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer Disease: A Clinical Perspective of Data From the Consortium to Establish a Registry for Alzheimer's Disease

Abstract: Objective To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Patients A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. Setting Twenty-one CERAD clinical sites throughout the United States. Results An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. Conclusions Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

Aging and the Occurrence of Dementia: Findings From a Population-Based Cohort With a Large Sample of Nonagenarians

Abstract: Context In spite of numerous studies on the occurrence of dementia, many questions remain, such as the relation between age, aging, and dementing disorders. This question is relevant both for under ...

Prefrontal Gray and White Matter Volumes in Healthy Aging and Alzheimer Disease

Abstract: Objectives To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). Design Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n=14; mean age, 70 years), old healthy elderly (OHE) (n=14; mean age, 90 years), and subjects with AD (n=14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. Results Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. Conclusions In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.

A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity.

Abstract: Background Long-term high-frequency stimulation of the subthalamic nucleus (STN) improves akinesia in Parkinson disease. The neural correlates of STN stimulation are not well understood. Positron emission tomography can be applied to the in vivo study of the mechanisms of deep brain stimulation. Objective To study changes in regional cerebral blood flow as an index of synaptic activity in patients with Parkinson disease with effective STN stimulation on and off during rest and movement. Methods Eight patients with Parkinson disease who had electrodes implanted in the STN underwent 12 measurements of regional cerebral blood flow with water O 15 positron emission tomography at rest and during performance of paced freely selected joystick movements, both with and without STN stimulation (3 scans per experimental condition). Motor performance and reaction and movement times were monitored. Statistical parametric mapping was used to compare changes in regional cerebral blood flow between conditions and differences in activation. Results All patients showed improvement in reaction and movement times during scans with the stimulator on. As predicted, increases in activation of rostral supplementary motor area and premotor cortex ipsilateral to stimulation were observed when stimulation was on during contralateral movement ( P Conclusion Stimulation of the STN reduces the movement-related impairment of frontal motor association areas and the inappropriate motor cortex resting activity in Parkinson disease.

Amantadine for Levodopa-Induced Dyskinesias: A 1-Year Follow-up Study

Abstract: Background In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. Objective To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. Design One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. Setting National Institutes of Health Clinical Center. Patients Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. Interventions Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. Main Outcome Measures Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. Results One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). Conclusion The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

Clinical Correlates of Vascular Parkinsonism

Abstract: Background Parkinsonism may be due to other causes besides Parkinson disease (PD). Vascular parkinsonism (VP) has not been well defined and the clinical correlates of VP have not been clarified. Objectives To seek evidence for or against the role of cerebrovascular disease in parkinsonism, and to identify clinical features that suggest a vascular origin. Design Retrospective chart review of patients with parkinsonism. A vascular rating scale was used to identify 2 patient groups, 1 with strong evidence of cerebrovascular disease (VP), and 1 with idiopathic PD. Clinical features of parkinsonism were then compared between the 2 patient groups. Setting A Movement Disorders Clinic, Baylor College of Medicine, Houston, Tex, a tertiary referral center. Patients Three hundred forty-six patients, 69 with VP and 277 with PD. Results The VP and PD groups were clearly differentiated in terms of evidence of cerebrovascular disease (P Conclusions These differences in clinical features suggest a different pathogenesis of parkinsonism in these 2 patient groups. The strong evidence of cerebrovascular disease in the VP group and the differences in clinical features support the concept of VP as a distinct clinical entity. We conclude that compared with PD, patients with parkinsonism associated with vascular disease are more likely to present with gait difficulty and postural instability rather than tremor, have a history of stroke and risk factors for stroke, and fail to respond to levodopa therapy.

Association of Cervical Artery Dissection With Recent Infection

Abstract: Background: Cervical artery dissection (CAD) is an important cause of ischemic stroke in younger patients. However, its cause is insufficiently understood. Objective: To test the hypothesis that CAD is frequently associated with recent infection. Subjects and Methods: We compared the prevalence of infection during the preceding week in 43 consecutive patients with acute CAD and 58 consecutive patients younger than 50 years with acute cerebral ischemia from other causes (control patients). In subgroups of patients, we correlated infectious status with electron microscopic studies of skin biopsy specimens and investigated pathways potentially linking infection and CAD. Results: Recent infection was more common in patients with CAD (25/43 [58.1%]) than in control patients (19/58 [32.8%]; P = .01). Respiratory tract infection was preponderant in both groups. Recent infection, but not the mechanical factors cough, sneezing, or vomiting, was independently associated with CAD in multivariate analysis. Investigation of serum antibodies against Chlamydia pneumoniae, smooth muscle cells, endothelial cells, collagen types I through IV, and heat shock protein 65 and assessment of serum a1-antitrypsin and HLA did not contribute to the understanding of the pathogenesis of CAD. More patients with pathologic findings in skin biopsy specimens tended to have had a recent infection (13/21 [62%]) than patients without pathologic findings (2/9 [22%]; P = .11). Conclusion: Our results suggest a significant association between recent infection and CAD that is not explained by mechanical factors occurring during infection. Arch Neurol. 1999;56:851-856

The Spectrum of Behavioral Responses to Cholinesterase Inhibitor Therapy in Alzheimer Disease

Abstract: Background Behavioral abnormalities are common in Alzheimer disease (AD); cholinergic treatment reduces the behavioral disturbances of some patients with AD. Characterizing the pretreatment profile of patients who are likely to respond to cholinergic therapy will aid the efficient use of clinical resources. Objective To determine the baseline behavioral profile for 86 patients with AD treated with the cholinesterase inhibitor donepezil hydrochloride. Methods Open-label retrospective study of treatment-related behavioral assessments. Based on previous double-blind placebo-controlled experience using the Neuropsychiatric Inventory (NPI), patients were divided into responder (≥4-point total NPI score decrease, indicating improvement), unchanged (±3-point total NPI score change), or nonresponder (≥4-point total NPI score increase, indicating worsening) groups. The Mini-Mental State Examination assessed cognitive response. Results Behavioral improvement was seen in 35 patients (41%), worsening in 24 (28%), and no change in 27 (31%). Comparison of profiles in behavioral responders vs nonresponders revealed significantly worse delusions ( P =.04), agitation ( P =.04), depression ( P =.006), anxiety ( P =.02), apathy ( P =.003), disinhibition ( P =.02), and irritability ( P P =.003 for nonresponders, P =.004 for responders), agitation ( P =.01), anxiety ( P =.006 for nonresponders, P =.004 for responders), disinhibition ( P =.02 for nonresponders, P =.05 for responders), and irritability ( P =.003 for nonresponders, P =.001 for responders). The behavioral changes were dose dependent. Cognition did not change significantly with donepezil treatment within any group. Conclusions Donepezil has psychotropic properties, and pretreatment behaviors help predict patients' responses to treatment.

Parkinson Disease, the Effect of Levodopa, and the ELLDOPA Trial

Abstract: The introduction of effective doses of levodopa for the treatment of Parkinson disease (PD) 1,2 was a revolutionary step in overcoming symptoms of a progressive neurode-generative disease. This took place a little more than 30 years ago, and still, today, levodopa remains the most effective drug for the reversal of symptoms of PD. 1,2 If there were no associated adverse effects with long-term use, treatment of PD would be a simple matter. But most of the physician's effort in providing optimum care of patients with PD is in trying to overcome all too common adverse effects of levodopa.

Occurrence and Progression of Dementia in a Community Population Aged 75 Years and Older: Relationship of Antihypertensive Medication Use

Abstract: Objective To examine whether antihypertensive medication use can affect the occurrence and progression of dementia. Subjects and Methods In a community cohort of 1810 persons aged 75 years and older, 225 prevalent cases of dementia were detected. Among the 1301 persons without dementia, 224 incident cases of dementia were identified during an average period of 3 years. Among the 225 prevalent cases of dementia, 79 were suitable for the analysis of cognitive decline. Information on drug use was collected for the 2 weeks preceding the baseline interview. Results Subjects taking antihypertensive medication (n=651, 83.9% of whom took diuretics) had a lower prevalence of dementia than those not taking antihypertensive medication ( P P =.03). Furthermore, subjects taking diuretics (n=484) had an adjusted relative risk of 0.7 (95% confidence interval, 0.5-1.0; P =.02) for all dementia, and subjects taking diuretic monotherapy (n=345) had an adjusted relative risk of 0.6 (95% confidence interval, 0.4-0.9; P =.006). The use of other antihypertensive medication (calcium antagonists or β-blockers), however, was related to a reduced risk of Alzheimer disease (adjusted relative risk, 0.6; 95% confidence interval, 0.3-1.2) only in the subpopulation with a higher baseline blood pressure (n=458). Patients with dementia at baseline who were not taking diuretics had a 2-fold faster rate of decline in the score on the Mini-Mental State Examination than those taking diuretics. Conclusion The use of diuretics may protect against dementia in elderly persons.

Vascular Abnormalities in Acute Reflex Sympathetic Dystrophy (CRPS I): Complete Inhibition of Sympathetic Nerve Activity With Recovery

Abstract: Background Reflex sympathetic dystrophy/complex regional pain syndrome type I (RSD/CRPS I) is a painful neuropathic disorder that may develop as a disproportionate consequence of a trauma affecting the limbs without overt nerve injury. Clinical features are spontaneous pain, hyperalgesia, impairment of motor function, swelling, changes in sweating, and vascular abnormalities. Objective To investigate pathophysiological mechanisms of vascular abnormalities in RSD/CRPS I. Design Case study. Setting Autonomic test laboratory at a university hospital. Participants A patient with an early stage of RSD/CRPS I of the upper limb and 2 healthy control subjects. Interventions Cutaneous sympathetic vasoconstrictor innervation was assessed by measuring cutaneous blood flow (laser Doppler flowmetry) and skin temperature (infrared thermometry). To quantify sympathetic vasoconstrictor function, phasic (induced by deep inspiration) and tonic (induced by controlled thermoregulation) sympathetic reflexes were analyzed. Venous norepinephrine levels were determined bilaterally. The same tests were performed in the controls after induction of cutaneous antidromic vasodilation produced by histamine dihydrochloride application. Main Outcome Measure Sympathetic cutaneous vasoconstrictor function in RSD/CRPS I. Results Two weeks after the onset of RSD/CRPS I, skin temperature on the affected side was higher (close to core body temperature) than on the contralateral side at room temperature and during controlled thermoregulation, indicating maximal vasodilation. Phasic and tonic stimulation of cutaneous vasoconstrictor neurons did not induce a decrease of skin blood flow or temperature on the affected side but were normal on the contralateral side. Venous norepinephrine levels were lower on the affected side. Parallel to clinical improvement, loss of vasoconstrictor function completely recovered within weeks. Results of investigations in healthy subjects ruled out the possibility that antidromic vasodilation caused by activation of nociceptive afferents is responsible for the complete depression of sympathetic vasoconstrictor reflexes. Conclusions Demonstrated for the first time is a complete functional loss of cutaneous sympathetic vasoconstrictor activity in an early stage of RSD/CRPS I with recovery. The origin of this autonomic dysfunction is in the central nervous system.

Progression of Parkinsonian Signs in Parkinson Disease

Abstract: Background Current knowledge about the rate of progression of extrapyramidal signs (EPSs) in Parkinson disease (PD) is derived largely from cross-sectional studies comparing subjects at various stages of illness rather than longitudinal studies in which the subjects were followed up over time. Objective To longitudinally study the progression of EPSs in PD by quantifying the rate of change of EPSs and by examining each EPS (rigidity, bradykinesia, tremor, and postural instability) separately. Methods A community-based cohort of 237 patients with PD living in Washington Heights–Inwood in Manhattan, NY, was evaluated at baseline and at yearly intervals. The EPSs were rated using the motor portion of the Unified Parkinson's Disease Rating Scale Motor Examination. Analyses of longitudinal data were performed by applying generalized estimating equations to regression analyses. Results The total EPS score increased at an annual rate of 1.5 points (1.5%), but, among those who died, the total EPS score increased at an annual rate of 3.6 points (3.6%). Bradykinesia, rigidity, and gait and balance subscores worsened at similar annual rates of 2.0% to 3.1%, whereas the tremor subscore did not clearly worsen with time. Patients with a shorter disease duration (≤3 years) may have progressed more rapidly than patients with longer disease duration (annual rate of change, 1.9% vs 1.4%, respectively), although this did not reach statistical significance. A high total EPS score was independently associated with dementia, low Activities of Daily Living score, and long disease duration at baseline. Conclusions In this cohort, the progression of EPSs in PD occurred at a rate of 1.5% per year and at twice that rate among those who died. Bradykinesia, rigidity, and gait and balance impairment worsened at similar rates, whereas tremor did not, suggesting that tremor may be relatively independent of these other cardinal manifestations of PD.

Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.

Abstract: Background The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. Design and Main Outcome Measures We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). Setting and Patients Postmortem study of nursing home residents. Results Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased ( P >.20) relative to the nondemented group in any of the brain regions studied. Significant increases ( P P Conclusions Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

Inheritance of frontotemporal dementia.

Abstract: Background Previous studies of families with frontotemporal dementia (FTD) support an autosomal dominant inheritance pattern, but most studies have described genetic transmission in individual families specifically selected for the presence of multiple affected individuals. Objective To investigate the familial presentation and inheritance of FTD and related disorders among a large group of FTD index cases unselected for family history of dementia. Design and Setting We interviewed family members and reviewed medical records and autopsy reports at a university hospital and a university-affiliated hospital to determine the frequency of familial FTD and the most likely mode of inheritance. Characteristic families with the disorder are described, along with the history, clinical findings, and neuroimaging results in affected members of these families. Patients and Participants The 42 index cases of FTD had a mean age of onset of 56.1 years (range, 40-69 years). Of these patients, 21 (50%) were women. All but one of the patients were white. Participants included male and female spouses and children of the index cases. Results Of 42 FTD cases, 19 (45%) had at least 1 other family member with an FTD spectrum disorder and were considered familial cases. The majority (17 [89%]) of familial FTD cases showed a pattern consistent with dominant inheritance. If depression is excluded, familial cases decrease from 19 (45%) to 17 (40%), of which 15 (88%) showed a dominant transmission pattern. The initial presentations in the nonindex familial cases varied but most frequently consisted of personality and behavioral changes that preceded cognitive impairment (19 [43%]), followed by psychiatric illness (14 [33%]), dementia without behavioral change (5 [11%]), amyotrophic lateral sclerosis (5 [11%]), and parkinsonism (2 [5%]). Two of the affected nonindex cases had dual presenting diagnoses. The average age of onset was 56.1 years and did not differ significantly between familial and nonfamilial cases. Onset of FTD-related symptoms occurred after the age of 65 years in only 4 (10%) of 42 index cases and 3 (5%) of 60 affected relatives. Conclusions Familial FTD is usually inherited in an autosomal dominant pattern. The initial onset is insidious, often consisting of mood and behavioral changes occurring in presenile years that are often erroneously attributed to other nonneurologic causes. Although the precise incidence of FTD in North America is not known, it is one of the most common presenile dementias.

Psychiatric Medication and Abnormal Behavior as Predictors of Progression in Probable Alzheimer Disease

Abstract: Objective To examine whether the use of psychiatric medication and the presence of abnormal behaviors affects the progression of Alzheimer disease. Design Cross-sectional with longitudinal follow-up and the likelihood of arriving at 4 end points: (1) Mini-Mental State Examination score of 9 or lower; (2) Blessed Dementia Rating Scale score of 15 or higher for activities of daily living; (3) nursing home admission; and (4) death, evaluated using a proportional hazard model with 9 variables: psychosis, insomnia, wandering, aggression, psychomotor agitation, depression, and use of antidepressants, antipsychotic agents, or sedatives/hypnotics. Setting Multidisciplinary dementia research clinic. Patients We examined baseline and follow-up behavioral symptoms and the use of psychiatric medication in 179 mildly to moderately impaired patients with probable Alzheimer disease participating in a longitudinal study of dementia. Patients were observed from 2.4 to 172 months (mean duration±SD, 49.5±27.4 months). Results Nine patients (5%) were taking sedatives/hypnotics; 16 (9%), antipsychotic agents; and 22 (12%), antidepressants at study entry. Patients taking antipsychotic agents had lower Mini-Mental State Examination scores and higher Blessed Dementia Rating Scale scores for activities of daily living than patients not taking any medication. Using proportional hazard analysis with time-dependent covariates for individual psychiatric symptoms and medications, we found that the development of psychosis was associated with functional decline (time to Blessed Dementia Rating Scale score of ≥15), institutionalization, aggression, and agitation with functional decline after adjusting for age at study entry, education, Mini-Mental State Examination scores, and Blessed Dementia Rating Scale scores. Use of antipsychotic medication was associated with functional decline, and sedatives/hypnotics with death. Neither the presence of psychiatric symptoms nor use of medication was associated with rate of cognitive decline (time to Mini-Mental State Examination score of ≤9). Conclusions These findings indicate that the use of antipsychotic agents and sedatives can affect the natural course of Alzheimer disease. Psychosis, agitation, and aggression are important predictors of outcome, even when the effects of medication to treat them is taken into account.

Increased Basal Ganglia Iron Levels in Huntington Disease

Abstract: Objective: To quantify in vivo brain ferritin iron levels in patients with Huntington disease (HD) and normal control subjects. Design and Subjects: A magnetic resonance imaging method that can quantify ferritin iron levels with specificity in vivo was employed to study 11 patients with HD and a matched group of 27 normal controls. Three basal ganglia structures (caudate, putamen, and globus pallidus) and 1 comparison region (frontal lobe white matter) were evaluated. Results: Basal ganglia iron levels were significantly increased (P,.002) in patients with HD, and this increase occurred early in the disease process. This was not a generalized phenomenon, as white matter iron levels were lower in patients with HD. Conclusions: The data suggest that increased iron levels may be related to the pattern of neurotoxicity observed in HD. Reducing the oxidative stress associated with increased iron levels may offer novel ways to delay the rate of progression and possibly defer the onset of HD. Arch Neurol. 1999;56:569-574

A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor

Abstract: Background: New medication is needed to treat essential tremor. Preliminary evidence suggests that gabapentin may be effective in the treatment of this disorder. Objective: To study the effects of gabapentin in a comparative, double-blind, crossover, placebo-controlled trial of patients who have essential tremor. Patients and Methods: 16 patients with essential tremor (6 with a new onset and 10 with a 2-week washout period of previous treatment with propranolol hydrochloride) received gabapentin (Neurontin), 400 mg 3 times daily; propranolol hydrochloride, 40 mg 3 times daily; and placebo for 15 days with a 1-week washout period between treatments.

The Heidenhain Variant of Creutzfeldt-Jakob Disease

Abstract: Objective To investigate whether typical neuropathological and radiological findings can be identified in patients with the clinical diagnosis of the Heidenhain variant of Creutzfeldt-Jakob disease (CJD). Design Case study. The clinical symptoms, neuropathological findings, electroencephalograms, magnetic resonance images, and cerebrospinal fluid samples of 14 Heidenhain cases were evaluated. Neuropathological changes were compared with those in a group of 14 patients with ataxia as the leading clinical sign. Setting A university hospital, base of the German National Creutzfeldt-Jakob Disease Surveillance Study. Patients Medical records of 169 neurologically examined patients with prospectively classified and neuropathologically confirmed CJD were analyzed. Main Outcome Measure Difference in neuropathological and radiological findings between patients with the Heidenhain variant and other patients with CJD. Results Of 169 patients with confirmed CJD, 20% showed characteristic clinical findings such as blurred vision, visual field restriction, metamorphopsia, or cortical blindness. Disease course of the Heidenhain group, as compared with the group of all patients with definite CJD, was significantly shorter (5.7 months vs 7.5 months; P =.02, t test). Neuropathological examination of patients with the Heidenhain variant showed most pronounced changes in the occipital lobe but less damage in the cingulate gyrus and basal ganglia compared with 14 patients with CJD who had ataxia as the leading clinical sign. Eleven (92%) of 12 genetically analyzed Heidenhain cases were homozygous for methionine at codon 129 of the prion protein gene ( PRNP ). In 9 of 9 cases, the 14-3-3 protein was present. In 7 (78%) of 9 cases, the level of neuron-specific enolase was elevated, with a concentration above 35 ng/mL. Periodic sharp-wave complexes were observed in 11 (78%) of the 14 cases. In 7 (63%) of 11 patients, magnetic resonance images showed symmetric hyperintensities in the basal ganglia in the T 2 - and proton-weighted sequence. In 4 of 11 cases the T 2 - and proton density–weighted images showed a pronounced signal increase confined to the gray matter of the occipital and visual cortex. Isolated atrophy of the visual cortex was noticeable in 2 of 11 cases. Conclusions The clinical presentation of the Heidenhain variant of CJD was shown to correlate with the neuropathological findings of gliosis and nerve cell loss. In patients with visual disorders of unclear origin and signs of dementia, the differential diagnosis of a Heidenhain variant of CJD must be taken into consideration.

Neuropsychologic status in multiple sclerosis after treatment with glatiramer.

Abstract: Background Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). Objective To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. Methods Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, Results Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. Conclusions Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.

Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors.

Abstract: Background Antiamphiphysin antibodies react with a 128-kd protein found in synaptic vesicles.They were first described in patients with paraneoplastic stiff-man syndrome and breast cancer, but studies suggest that they can also occur in patients with other tumors and neurological disorders. Objective To determine if antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Patients and Methods Of 2800 serum samples tested by routine immunohistochemical procedures on sections of paraformaldehyde-fixed rat brain for the detection of autoantibodies associated with paraneoplastic neurological syndromes, 5 were selected because of labeling suggestive of antiamphiphysin antibodies and subsequently confirmed by the results of Western blot analysis using recombinant amphiphysin protein. Controls consisted of 40 patients with various nonparaneoplastic neurological diseases; 101 patients with cancer but without paraneoplastic neurological syndrome; 9 patients with small cell lung cancer, anti-Hu antibodies, and paraneoplastic neurological syndrome; 3 patients with M 2 -type antimitochondrial antibodies but no neurological disorder; and 30 normal subjects. Results Of the 5 patients with antiamphiphysin antibodies, patient 1 had sensory neuronopathy, encephalomyelitis, and breast cancer; patient 2 had limbic encephalitis, and small cell lung cancer was detected in the mediastinum after 24 months of follow-up; patient 3 had encephalomyelitis and ovarian carcinoma; and patients 4 and 5 had Lambert-Eaton myasthenic syndrome and small cell lung cancer (patient 4 subsequently developed cerebellar degeneration). None of the 5 had stiffness. Two patients (Nos. 2 and 4) had antimitochondrial antibodies. The two patients (Nos. 4 and 5) with Lambert-Eaton myasthenic syndrome had antibodies directed against the voltage-gated calcium channel, and patient 2 subsequently developed anti-Hu antibodies. In the controls, antiamphiphysin antibodies were detected by Western blot analysis in 3 of 8 patients with anti-Hu antibodies, but in none of the other groups. Conclusions These data indicate that antiamphiphysin antibodies are not specific for one type of tumor or one neurological syndrome and can be associated with other neural and nonneural antibodies. The simultaneous association of several antibodies in some patients suggests multimodal autoantibody production.

Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders.

Abstract: The use of magnetism in medicine has a long and colorful history since its legendary discovery in the Western world by the shepherd Magnes. More recent use of magnetism has centered on nuclear magnetic resonance. Magnetic resonance spectroscopy (MRS) provides chemical information on tissue metabolites. Both hydrogen 1 (1H) and phosphorus 31 resonances have been used to study brain tissue, but the magnetic resonance sensitivity for protons is far greater than it is for phosphorus. One of the most important contributions of 1H-MRS to clinical neurology is its ability to quantify neuronal loss and to demonstrate reversible neuronal damage. 1H-magnetic resonance spectroscopy has been found to be a useful research tool in elucidating the pathophysiology underlying certain diseases. This review focuses on the use of proton MRS to study various neurologic diseases, including epilepsy, multiple sclerosis, brain tumors, human immunodeficiency virus 1-associated neurologic disorders, as well as cerebrovascular, neurodegenerative, and metabolic diseases. It highlights the contributions of 1H-MRS to the diagnosis and the monitoring of these neurologic diseases that make it a useful adjunct in patient management.

Peripheral Nerve Function in HIV Infection: Clinical, Electrophysiologic, and Laboratory Findings

Abstract: Objective To determine the effects of immunodeficiency, nutritional status, and concurrent systemic disease on peripheral nerve function in acquired immunodeficiency syndrome. Design Survey of subjects infected with human immunodeficiency virus (HIV), recruited as part of a prospective study of neuromuscular complications of HIV infection. Setting A neuro–acquired immunodeficiency syndrome outpatient clinic in a university medical center. Patients A consecutive sample of 251 HIV-infected individuals. Primary care providers referred subjects to the study for evaluation of neurologic symptoms or for prospective neurologic assessment. Main Outcome Measures Standardized history and neurologic examination, laboratory tests (complete blood cell count, serum albumin level, vitamin B 12 level, and T-lymphocyte subsets), and electrophysiologic testing of sural, tibial, and ulnar nerves. Results The most frequent neurologic diagnosis was distal symmetrical polyneuropathy (DSP) (38%). The most common clinical features were nonpainful paresthesias (71%), abnormalities of pain and temperature perception (71%), and reduced or absent ankle reflexes (66%). Patients with DSP were significantly older ( P =.009), and had lower CD4 lymphocyte cell counts ( P =.004) and lower hemoglobin levels ( P =.004) than those without DSP. Deterioration of values on nerve conduction studies, irrespective of the clinical diagnosis of DSP, was significantly correlated with low CD4 counts, aging, abnormal serum albumin and hemoglobin levels, and weight loss. Most of these factors co-correlated, and, with the exception of age, no single variable significantly accounted for changes in results of nerve conduction studies when the influence of other factors was eliminated. Conclusion The combination of several factors, including age, immunosuppression, nutritional status, and chronic disease, contributes to distal peripheral nerve dysfunction in HIV infection.