Neuroanatomy RSS : Gourt

Permanent Neurology Job in Central Florida Florida with BioPointe

Private neurology practice of three in FL seeking another to join the group. Practice will assist in moving and interview expenses. There is partnership potential as well as malpractice and health insurance

Permanent Neurology Job in Southern MI Michigan with BioPointe

Four board-certified neurologists need to add a fifth due to continued growth of their practice and to facilitate a reduction in hours by the two senior partners when the new doctor joins the group.

Permanent Neurology Job in LA statewide Louisiana with Medical Doctor Associates, Inc.

Exceptional Neurology opportunity. Be a part of one of THE most prestigious neurosurgery groups in the United States! 30 physician neuroscience group looking for extremely well qualified neurologist.

Permanent Neurology Job in AL statewide Alabama with Medical Doctor Associates, Inc.

Tremendous growth requires recruitment of BC/BE Neurologist to meet community needs. Excellent financial package with Sign On Bonus/Loan Repayment. Located in the beautiful Tennessee River Valley, this

Permanent Neurology Job in Southern Alzheimer's Specialist, 260 Days of Sunshine, Big XII University Sports, #5309 Texas with Timeline Recruiting

$220-$250K Make Your Mark! This highly visible recruitment for an Alzheimer's specialist is garnering tremendous support from our neurology department, college of medicine, university and community!

Permanent Neurology Job in Lake Resort Community Missouri with California Physician Opportunities

Seeking the serenity of a lake community but also want the amenities of a city? Enjoy this lake community that offers world class water sports, fishing, golf and shopping. Major cities and Universities

Permanent NEUROLOGY Job in Southern Massachusetts Massachusetts with Enterprise Medical Service

Seeking a board certified/eligible neurologist for a growing multispecialty group. Join another neurologist in a very busy practice. Strictly outpatient practice with NO call. 16 primary care providers

Locum Tenens Neurology Job in Great Location Arizona with Onyx M.D.

Hot job in a hot place. .. sunny Arizona is calling...Neurology coverage is needed at a great facility in southern Arizona. The schedule is Monday through Friday 8am to 5pm in the outpatient setting,

Permanent Neurology Job in Rockhill New York with New England Physician Recruitment Center

Neurologist join group 7 TOP Salaries and Incentives- New Yorks finest group top money-interviewing early ORANGE COUNTY AREA We are looking for a Physician to join large group in very lucrative

Permanent NEUROLOGY Job in Beautiful Panhandle Area of Sunny Florida Florida with Enterprise Medical Service

Excellent Neurology practice opportunity is now available in Florida joining one other Neurologist. Outpatient Practice, many new referrals. Salary guarantee plus full benefits. Located right on the

Permanent NEUROLOGY Job in Excellent Opportunity in Chicago Illinois with Enterprise Medical Service

Excellent PMR and/or NL Neurology opportunity located in Chicago! You will be joining one other physician in a practice that is growing. There are two office locations in the Chicago and N. West Indiana

Permanent NEUROLOGY Job in Edenton, NC North Carolina with Enterprise Medical Service

Excellent new Neurology opportunity is available in North Carolina. Group is looking for 2 BC/BE Neurologists to join their existing team. Call is 1:4, outstanding benefits including loan repayment,

Permanent NEUROLOGY Job in City of Albuquerque New York with Enterprise Medical Service

Outstanding new Neurology opportunity is now available in New Mexico! General Neurology is acceptable. No Fellowship training needed. Neurologist should be able to do Botox injections and EMG testing.

Permanent NEUROLOGY Job in Between Baltimore and DC Maryland with Enterprise Medical Service

Excellent Neurology opportunity is available in Maryland. Only 36 miles from Baltimore and 40 miles to Washington D.C! Solo practitioner would like another Neurologist with interest in EMG, EEG, & Nerve

Permanent NEUROLOGY Job in Beautiful Coastal City Florida with Enterprise Medical Service

Florida Neurology opportunity is available for summer 2009. Multi-specialty group practice, call 1:2, 32 docs in the group. High patient demand for Neurology in this community. 3 year term contract,

Permanent NEUROLOGY Job in 1 Hour from Baltimore, MD Pennsylvania with Enterprise Medical Service

Excellent Neurology opportunity is available in Pennsylvania located with 1 hour of Baltimore, MD. Group of 3 Neurologist are looking for 2 more. Very busy practice, excellent income guarantee and bonus

Permanent NEUROLOGY Job in 1 hour from Birmingham Alabama with Enterprise Medical Service

Neurologist needed for an excellent opportunity located in Alabama within 60miles of Birmingham. Join a single specialty group that consists of 3 Neurologists. Group is seeking a 4th due to community

Permanent NEUROLOGY Job in Biloxi, MS Opportunity Mississippi with Enterprise Medical Service

Excellent Neurology opportunity is available in Mississippi. Solo practice opportunity. New physician will share call with another solo Neurologist in town. Employed opportunity with full benefits.

Permanent NEUROLOGY Job in 30 Miles from Atlanta Georgia with Enterprise Medical Service

Excellent new Neurology opportunity in Georgia, located 30 miles of Atlanta. Client is looking for 3. General or Fellowship trained will be considered. Employed position with full benefits. Contact:

Permanent NEUROLOGY Job in 30 miles from Atlanta Georgia with Enterprise Medical Service

Excellent Neurology opportunity is available in Georgia located within 30 miles of Atlanta. 2 person practice will be losing 1 within 90 days. EMG experience would be a plus. Income guarantee plus

ORIGINAL CONTRIBUTION: Exclusive Breastfeeding and the Risk of Postpartum Relapses in Women With Multiple Sclerosis

Objective To determine if exclusive breastfeeding protects against postpartum relapses of multiple sclerosis (MS) and, if so, whether this protection is related to prolonged lactational amenorrhea.Design We conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age.Setting Kaiser Permanente Northern California and Stanford University.Participants We prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls.Main Outcome Measure Postpartum relapse.Results Of the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01).Conclusions Our findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study.Published online June 8, 2009 (doi:10.1001/archneurol.2009.132).

ORIGINAL CONTRIBUTION: Validity of Self-reported Stroke in Elderly African Americans, Caribbean Hispanics, and Whites

Background The validity of a self-reported stroke remains inconclusive.Objective To validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard.Design, Setting, and Participants Community-based cohort study of nondemented, ethnically diverse elderly persons in northern Manhattan.Methods High-resolution quantitative MRIs were acquired for 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the 2 test. Putative relationships between factors potentially influencing the reporting of stroke, including memory performance, cognitive function, and vascular risk factors, were assessed using logistic regression models. Subsequently, all analyses were repeated, stratified by age, sex, ethnic group, and level of education.Results In analyses of the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4%, and specificity was 78.9%. In analyses stratified by median age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity and specificity, 36.7% and 81.3% vs 27.6% and 26.2%; P = .02). Impaired memory, cognitive skills, or language ability and the presence of hypertension or myocardial infarction were associated with higher rates of false-negative results.Conclusions Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease, and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.Published online May 11, 2009 (doi:10.1001/archneurol.2009.83).

ABOUT THIS JOURNAL: About This Journal

THIS MONTH IN ARCHIVES OF NEUROLOGY: This Month in Archives of Neurology

ANNOUNCEMENT: Full-text Online Access

EDITORIAL: Cerebral Microbleeds: Evidence of Heightened Risk Associated With Aspirin Use

NEUROLOGICAL REVIEW: Deep Brain Stimulation, Neuroethics, and the Minimally Conscious State: Moving Beyond Proof of Principle

NEUROLOGICAL REVIEW: Primary Angiitis of the Central Nervous System

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis of unknown cause. The mean age of onset is 50 years, and men are affected twice as often as women. Headache and encephalopathy are the most frequent initial symptoms. Stroke or focal symptoms develop in less than 20% of patients at the onset of disease and are uncommon in the absence of headache or encephalopathy. Symptoms or signs of vasculitis outside of the central nervous system are rare; serologic markers of inflammation are typically normal. Magnetic resonance imaging of the brain is abnormal in more than 90% of patients, but the pattern of abnormal findings is not specific. Cerebrospinal fluid analysis is also usually abnormal because of modest, nonspecific elevations in total protein level or white blood cell count. Angiography has a low sensitivity and low specificity. Most patients suspected of having PACNS have another disease. The diagnosis of PACNS is established by brain biopsy. The differential diagnosis of PACNS is broad and includes reversal cerebral vasoconstriction. In contrast to patients with PACNS, patients with reversal cerebral vasoconstriction are more often young women who experience a thunderclap headache and have a normal cerebrospinal fluid analysis. Patients with biopsy-proven PACNS are treated with cyclophosphamide and prednisone.

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ORIGINAL CONTRIBUTION: Use of Antithrombotic Drugs and the Presence of Cerebral Microbleeds: The Rotterdam Scan Study

Background Cerebral microbleeds are hemosiderin deposits in the brain that are indicative of microangiopathy. Microbleeds in strictly lobar brain locations have been related to cerebral amyloid angiopathy, a bleeding-prone disease state. Objective To investigate the relation between antithrombotic drug use and the presence of cerebral microbleeds, especially those in strictly lobar locations. Design A population-based, cross-sectional analysis that used magnetic resonance imaging (MRI) to assess the presence and location of microbleeds. Complete information on outpatient use of platelet aggregation inhibitors and anticoagulant drugs before MRI was obtained from automated pharmacy records. Setting The Rotterdam Scan Study, a population-based imaging study in a general elderly community in the Netherlands. Participants A population-based sample of 1062 persons from a longitudinal cohort, 60 years and older, free of dementia, who underwent MRI examinations between August 15, 2005, and November 22, 2006. Main Outcome Measures Presence of cerebral microbleeds on MRI. Results Compared with nonusers of antithrombotic drugs, cerebral microbleeds were more prevalent among users of platelet aggregation inhibitors (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21-2.41). We did not find a significant association for anticoagulant drugs and microbleed presence (OR, 1.49; 95% CI, 0.82-2.71). Strictly lobar microbleeds were more prevalent among aspirin users (adjusted OR compared with nonusers, 2.70; 95% CI, 1.45-5.04) than among persons using carbasalate calcium (adjusted OR, 1.16; 95% CI, 0.66-2.02). This difference was even more pronounced when comparing persons who had used similar dosages of both drugs. Conclusions This cross-sectional study shows that use of platelet aggregation inhibitors is related to the presence of cerebral microbleeds. Furthermore, aspirin and carbasalate calcium use may differently relate to the presence of strictly lobar microbleeds. Published online April 13, 2009 (doi:10.1001/archneurol.2009.42).

ANNOUNCEMENT: Research Letters

ORIGINAL CONTRIBUTION: How Seizure Detection by Continuous Electroencephalographic Monitoring Affects the Prescribing of Antiepileptic Medications

Objectives To assess the effect of continuous electroencephalographic monitoring on the decision to treat seizures in the inpatient setting, particularly in the intensive care unit. Design Retrospective cohort study. Setting Medical and neuroscience intensive care units and neurological wards. Patients Three hundred consecutive nonelective continuous electroencephalographic monitoring studies, performed on 287 individual inpatients over a 27-month period. Main Outcome Measures Epileptiform electroencephalographic abnormalities and changes in antiepileptic drug (AED) therapy based on the electroencephalographic findings. Results The findings from the continuous electroencephalographic monitoring led to a change in AED prescribing in 52% of all studies with initiation of an AED therapy in 14%, modification of AED therapy in 33%, and discontinuation of AED therapy in 5% of all studies. Specifically, the detection of electrographic seizures led to a change in AED therapy in 28% of all studies. Conclusions The findings of continuous electroencephalographic monitoring resulted in a change in AED prescribing during or after half of the studies performed. Most AED changes were made as a result of the detection of electrographic seizures.

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ORIGINAL CONTRIBUTION: Automatisms in Absence Seizures in Children With Idiopathic Generalized Epilepsy

Background Automatisms are well recognized to occur in complex partial seizures; however, their occurrence in generalized epilepsies is not always appreciated. There has been considerable debate regarding the nature, triggers, and timing of automatisms in absence seizures. Objectives To examine the frequency and nature of automatisms in new-onset absence seizures and assess the influence of the state of arousal, provocation, age, and epilepsy syndrome on the presence and type of automatisms. Design Analysis of absence seizures through video electroencephalogram (EEG) recordings. Setting British Columbia's Children's Hospital, Vancouver, British Columbia, Canada. Patients Seventy consecutive children with new-onset untreated absence seizures in idiopathic generalized epilepsy recruited between January 1, 1992, and June 30, 1997. Main Outcome Measures Each seizure was analyzed for the presence and characteristics of automatisms. The influence of the following variables on the presence of automatisms was statistically analyzed: state of arousal (awake, drowsy, asleep), provocation (hyperventilation, photic stimulation), age, and epilepsy syndrome. Results Automatisms occurred in 163 of 405 seizures (40%) in 53 of 70 children (76%). Automatisms were more likely in longer seizures and hyperventilation. Only 23% of spontaneous awake seizures had automatisms. Automatisms were similar for an individual child; however, automatisms were not present in all their seizures. Age, epilepsy syndrome, or state of alertness had no effect on the presence of automatisms. Conclusions Automatisms are frequently seen during childhood absence seizures. The high frequency of automatisms during EEG recordings is predominantly due to the effect of hyperventilation. Their preponderance during longer seizures may relate to opportunity for automatisms to occur. The characteristic pattern of automatisms suggests a reactive phenomenon to internal and external stimuli.

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ORIGINAL CONTRIBUTION: Ganglionic Acetylcholine Receptor Autoantibody: Oncological, Neurological, and Serological Accompaniments

Objective To describe the clinical utility of the nicotinic ganglionic acetylcholine receptor (3-AChR) autoantibody as a marker of neurological autoimmunity and cancer. Design Case-control study. Setting Mayo Clinic, Rochester, Minnesota. Patients A total of 15 000 patients seen at Mayo Clinic (2005-2007) and evaluated on a service basis for paraneoplastic neurological autoimmunity for whom clinical information was obtained retrospectively by medical record review as well as 457 neurologically asymptomatic patients or control subjects of whom 173 were healthy, 245 had lung cancer, and 39 had systemic lupus erythematosus or Sjögren syndrome. Outcome Measures Neurological, oncological, and serological associations of 3-AChR autoantibody seropositivity. Results Of 15 000 patients tested on a service basis, 1% were seropositive (median, 0.12 nmol/L; range, 0.03-18.8 nmol/L; normal, ≤0.02 nmol/L), 55% were male, and the median age was 65 years. Cancer was found (new or by history) in 24 of 78 patients evaluated for cancer while at Mayo Clinic (30%); 43% had adenocarcinoma (more patients had breast cancer than prostate, lung, and gastrointestinal cancers; each of the latter groups had about the same number of patients). Of 12 patients with high antibody values (≥1.00 nmol/L), 83% had pandysautonomia. Of 85 patients with medium antibody values (0.10-0.99 nmol/L), neurological presentations were more diverse and included peripheral neuropathies (36%), dysautonomia (20%, usually limited), and encephalopathy (13%). Of 58 patients with low antibody values (0.03-0.09 nmol/L), 54% had a nonautoimmune neurological disorder or no neurological disorder. Of 245 control patients with lung cancer, 7.8% were seropositive. Only 1 of 212 control patients without cancer (0.5%) was seropositive (P < .001). Conclusion The detection of 3-AChR autoantibody aids the diagnosis of neurological autoimmunity and cancer.

ORIGINAL CONTRIBUTION: Prospective Differentiation of Multiple System Atrophy From Parkinson Disease, With and Without Autonomic Failure

Objective To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD. Methods We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. Results We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. Conclusions The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.

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ORIGINAL CONTRIBUTION: A Long-term Prospective Study of the Natural Course of Sporadic Adult-Onset Lower Motor Neuron Syndromes

Objective To determine the natural course of sporadic adult-onset lower motor neuron syndrome in a long-term prospective study of patients with the syndrome. Design Inception cohort with a follow-up of 72 months. Setting Three university hospitals in the Netherlands (referral centers for neuromuscular diseases). Patients Thirty-two patients were classified as having the following phenotypes according to previously defined criteria: progressive muscular atrophy (PMA; 10 patients), segmental distal muscular atrophy (8 patients), and segmental proximal muscular atrophy (14 patients). A disease duration of at least 4 years was chosen to exclude most patients with amyotrophic lateral sclerosis (ALS). Main Outcome Measures Muscle strength, functional impairment, and respiratory function were assessed at 0, 6, 12, 18, and approximately 72 months. Results The diagnosis had to be changed to ALS in 3 patients (classified at inclusion as PMA in 2 patients and segmental proximal muscular atrophy in 1) owing to the development of upper motor neuron signs in 2 patients and familial ALS in 1. The remaining 8 patients with PMA showed further deterioration, and the other 24 patients remained more or less stable during long-term follow-up. Respiratory insufficiency developed in 6 of the 11 patients with ALS or PMA, 5 of whom died. Conclusions Patients with lower motor neuron syndromes and a disease duration of at least 4 years usually have a favorable prognosis if muscle involvement has a segmental distribution. In patients with a generalized phenotype, progression is relentlessly progressive and eventually leads to death due to respiratory insufficiency.

ORIGINAL CONTRIBUTION: Defining Survival as an Outcome Measure in Amyotrophic Lateral Sclerosis

Objectives To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis. Design and Setting We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with 2 and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points. Patients In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline. Main Outcome Measures Death or combined death, tracheostomy, or permanent assisted ventilation. Results Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone. Conclusions Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

ORIGINAL CONTRIBUTION: Effect of Changes in Fat Availability on Exercise Capacity in McArdle Disease

Background The major fuel for exercising muscle at low exercise intensities is fat. Objective To investigate the role of fat metabolism in McArdle disease (also known as glycogen storage disease type V), an inborn error of muscle glycogenolysis, by manipulating free fatty acid availability for oxidation during exercise. Design Randomized, placebo-controlled, crossover trial. Setting Hospitalized care. Patients Ten patients (8 men and 2 women) with McArdle disease. Interventions Patients cycled at a constant workload corresponding to 70% of their maximum oxygen consumption. In random order and on separate days, patients received nicotinic acid (a known blocker of lipolysis) to decrease the availability of free fatty acids or 20% Intralipid infusion to increase free fatty acid availability during exercise. Results were compared with placebo (isotonic sodium chloride solution infusion) and glucose infusion trials. Main Outcome Measures Exercise tolerance was assessed by heart rate response to exercise during different infusions. Results Free fatty acid levels more than tripled by Intralipid infusion and were halved by nicotinic acid administration. Heart rate was significantly higher during exercise in the Intralipid infusion and nicotinic acid trials compared with the placebo and glucose infusion trials, an effect that was observed before and after the patients had experienced the second wind phenomenon. Conclusions Lipids are an important source of fuel for exercising muscle in McArdle disease, but maximal rates of fat oxidation seem limited and cannot be increased above physiologically normal rates during exercise. This limitation is probably caused by a metabolic bottleneck in the tricarboxylic acid cycle due to impaired glycolytic flux in McArdle disease. Therapies aimed at enhancing fat use in McArdle disease should be combined with interventions targeting expansion of the tricarboxylic acid cycle.

ORIGINAL CONTRIBUTION: Biracial Population Study of Mortality in Mild Cognitive Impairment and Alzheimer Disease

Objective To assess mortality associated with mild cognitive impairment (MCI) and Alzheimer disease (AD) among older African Americans and whites from an urban community. Design Longitudinal population-based observational study. Setting Four adjacent neighborhoods in Chicago, Illinois. Participants Persons deemed free of dementia in a previous wave of data collection (n = 1715) underwent detailed clinical evaluation: 802 had no cognitive impairment (46.8%), 597 had MCI (34.8%), 296 had AD (17.3%), and 20 had other forms of dementia (1.2%). Main Outcome Measure All-cause mortality. Results During as many as 10 years of observation (mean [SD], 4.7 [3.0] years), 634 individuals died (37.0%). Compared with people without cognitive impairment, risk of death was increased by about 50% among those with MCI (hazard ratio [95% confidence interval], 1.48 [1.22-1.80]) and was nearly 3-fold greater among those with AD (2.84 [2.29-3.52]). These effects were seen among African Americans and whites and did not differ by race. Among participants with MCI, risk of death increased with more severe cognitive impairment, and this effect did not vary by race. A similar effect was seen among participants with AD, but it was slightly stronger for African Americans vs whites. In the MCI and AD groups, the association of cognitive impairment with survival was stronger for perceptual speed than for other cognitive functions. Conclusion The presence and severity of MCI and AD are associated with reduced survival among African Americans, and these effects are comparable to those seen among whites.

CORRECTION: Error in Correction to Figure Legend in: Episodic Ataxia Associated With EAAT1 Mutation C186S Affecting Glutamate Reuptake

ORIGINAL CONTRIBUTION: Stability of the Clinical Dementia Rating, 1979-2007

Objective To examine dementia severity as determined by the Clinical Dementia Rating (CDR) over time. Design Secondary analysis of data from longitudinal studies of aging and dementia. Setting Alzheimer’s Disease Research Center, where a variety of clinicians contributed CDR ratings during the study. Participants Adults aged 63 to 83 years with no (CDR 0), very mild (CDR 0.5), or mild (CDR 1) dementia enrolled in the Alzheimer’s Disease Research Center at any time from August 13, 1979, through May 30, 2007. Main Outcome Measures Within each CDR group, changes in scores on standardized psychometric tests with time were examined using multiple linear regression analyses. These tests included the Mini-Mental State Examination, Short Blessed Test, Logical Memory IA-Immediate from the Wechsler Memory Scale–Revised, and Blessed Dementia Scale, and a psychometric composite score. Results A total of 1768 participants met the inclusion criteria. With time, participants were older, more educated, and more likely to be nonwhite and less likely to be men. Statistically significant change in psychometric test performance with time occurred only within the CDR 1 group for Logical Memory and the psychometric composite, but the degree of change was minimal. Conclusion Despite changes in participant characteristics, the CDR demonstrates general stability for assessment of dementia for almost 3 decades.

FROM JAMA: Enough Is Enough: Moving on to Deep Brain Stimulation in Patients With Fluctuating Parkinson Disease

OBSERVATION: Cognitive Functions in a Patient With Parkinson-Dementia Syndrome Undergoing Deep Brain Stimulation

Background Dementia represents one of the most challenging health problems. Despite intense research, available therapies have thus far only achieved modest results. Deep brain stimulation (DBS) is an effective treatment option for some movement disorders and is under study for psychiatric applications. Recently, diencephalic DBS revealed selective effects on memory functions, another facet of subcortical DBS. Objective To report a new DBS strategy for the modification of cognitive functions in a patient with severe Parkinson-dementia syndrome. Design Prospective study with double-blinded sham stimulation period. Setting Departments of Stereotaxy and Functional Neurosurgery and Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. Patient A 71-year-old man with slowly progressive Parkinson-dementia syndrome. Intervention We inserted 2 electrodes into the nucleus basalis of Meynert in addition to electrodes in the subthalamic nucleus. Main Outcome Measure Improvement of cognitive functions. Results Turning on the subthalamic nucleus electrodes improved motor symptoms but left cognitive performance almost unchanged. Turning on electrical stimulation of the nucleus basalis of Meynert resulted in markedly improved cognitive functions. The improvement in attention, concentration, alertness, drive, and spontaneity resulted in the patient's renewed enjoyment of former interests and enhanced social communication. Conclusions Such a broad effect on cognition is consistent with ample experimental evidence revealing that the nucleus basalis of Meynert provides cholinergic innervation to the cortical mantle, complemented by glutaminergic and -aminobutyric acid–transmitting projections from the basal forebrain. These projections provide background tuning facilitating cortical operations. Furthermore, nucleus basalis of Meynert stimulation paired with sensory stimuli can accomplish persistent reorganization of specific processing modules. The improvements in cognitive and behavioral performance in our patient are likely to be related to the effects of stimulating residual cholinergic projections and cell bodies in the nucleus basalis of Meynert.

OBSERVATION: Minimally Conscious State After Ruptured Giant Basilar Aneurysm

Objective To report the clinical and radiologic findings in a case of transient minimally conscious state after rupture and coiling of a giant basilar aneurysm. Design Case report. Setting Neuroscience intensive care unit. Patient A 44-year-old man who developed a transient minimally conscious state in association with perianeurysmal edema in the rostral brainstem and thalamus after rupture and coiling of a giant basilar artery aneurysm. Main Outcome Measure Correlation of clinical and magnetic resonance imaging findings. Results A minimally conscious state and bilaterally symmetric vasogenic edema of the rostral brainstem and thalamus developed 2 days after endovascular aneurysm coiling. The clinical and radiologic abnormalities improved significantly and in parallel during the following 4 weeks. Conclusions Perianeurysmal vasogenic edema in the brainstem and thalamus can develop after rupture and coiling of a giant basilar artery aneurysm. This process can be transient and can produce dramatic alterations in consciousness that later resolve.

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OBSERVATION: Occurrence of Basal Ganglia Germ Cell Tumors Without a Mass

Objective To report a case series in which basal ganglia calcifications without mass effect proved to be germ cell tumors. Design Case series. Setting Tertiary care hospital. Patients Four patients. Interventions Computed tomography, magnetic resonance imaging, positron emission tomography, biopsy, chemotherapy, and radiation therapy. Main Outcome Measures Recognition of clinical syndrome and radiological features. Results All patients had progressive hemiparesis, and 1 patient also had frontal lobe dementia. Imaging demonstrated progressive asymmetric signal abnormality with basal ganglia calcification and associated brainstem atrophy. Fludeoxyglucose F 18–positron emission tomography showed hypometabolism in contrast to malignant glioma. Conclusion Germ cell tumor should be considered in patients with an indolently progressive neurological course, particularly if basal ganglia calcification is present with or without enhancement, asymmetric brain atrophy, or a mass.

OBSERVATION: Propionibacterium acnes Brain Abscess Appearing 10 Years After Neurosurgery

Objective To describe a case of Propionibacterium acnes infection arising 10 years after neurosurgery and to review the literature regarding similar cases and their treatment. Design Case report. Setting Hospital of the University of Pennsylvania. Patient A 70-year-old man with an intracerebral abscess and 2 biopsies culture positive for P acnes 10 years after subdural hematoma evacuation. Intervention Surgical biopsy followed by 6 weeks of intravenous vancomycin. Main Outcome Measures Magnetic resonance imaging, neurologic examination, and microbiology culture results. Results Biopsies obtained from abscesses grew only P acnes. Magnetic resonance imaging and serial neurological examinations showed marked improvement after 6 weeks of intravenous vancomycin. Conclusions Infection by P acnes can complicate neurosurgical procedures as late as 10 years after surgery and therefore should be considered in the evaluation of patients presenting with neurologic signs and symptoms with a history of neurosurgery.

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IMAGES IN NEUROLOGY: Scattered Cerebral Microbleeds Due to Cardiac Myxoma

ANNOUNCEMENT: New Initiatives: Clinical Trials and Videos

IMAGES IN NEUROLOGY: Neurodegeneration With Pantothenate Kinase Syndrome: Retinal and Magnetic Resonance Imaging Findings

CALL FOR PAPERS: Archives Express

IMAGES IN NEUROLOGY: Liposuction in Mind

BOOK REVIEWS: Neuropsychological Neurology: The Neurocognitive Impairments of Neurological Disorders

BOOK REVIEWS: Pocket Guide and Toolkit to DeJong's Neurologic Examination

CORRESPONDENCE: Aggressive Blood Pressure Lowering in Acute Ischemic Stroke

CORRESPONDENCE: Aggressive Blood Pressure Lowering in Acute Ischemic Stroke--Reply

CORRESPONDENCE: Olfactory Disturbance in Parkinson Disease

CORRESPONDENCE: Olfactory Disturbance in Parkinson Disease--Reply

ANNOUNCEMENT: CME for Peer Reviewers

ABOUT THIS JOURNAL: About This Journal

THIS MONTH IN ARCHIVES OF NEUROLOGY: This Month in Archives of Neurology

EDITORIAL: The Expanding Role of Genetics in the Lewy Body Diseases: The Glucocerebrosidase Gene

ANNOUNCEMENT: CME for Peer Reviewers

NEUROLOGICAL REVIEW: The Mirror Neuron System

Mirror neurons are a class of neurons, originally discovered in the premotor cortex of monkeys, that discharge both when individuals perform a given motor act and when they observe others perform that same motor act. Ample evidence demonstrates the existence of a cortical network with the properties of mirror neurons (mirror system) in humans. The human mirror system is involved in understanding others' actions and their intentions behind them, and it underlies mechanisms of observational learning. Herein, we will discuss the clinical implications of the mirror system.

CLINICAL TRIALS: Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease

Objective To compare the long-term outcomes of subjects initially treated with pramipexole dihydrochloride with those of subjects initially treated with levodopa in the Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) trial. Design Up to 2 years of open extended follow-up of the CALM-PD subjects. Setting Academic movement disorders clinics at 22 sites in the United States and Canada. Patients Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability were enrolled between October 1996 and August 1997, a subset of whom consented to extended follow-up until August 2003 (n = 222). Intervention Subjects were randomized to receive initial treatment with either pramipexole (n = 151) or levodopa (n = 150). Investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. Main Outcome Measures The primary outcome variable was the time-weighted average of self-reported disability scores in the "on" and "off" states as measured by the Schwab and England Activities of Daily Living Scale at the final visit. Secondary outcomes included the Unified Parkinson's Disease Rating Scale score, the presence and severity of dopaminergic motor complications, quality-of-life scale scores, Geriatric Depression Scale score, Epworth Sleepiness Scale score, and adverse events. Results After a mean (SD) follow-up of 6.0 (0.2) years, mean (SD) self-reported weighted Schwab and England Activities of Daily Living Scale scores were similar in the initial pramipexole (79.9 [16.2]) and initial levodopa (82.5 [14.6]) groups (P = .19). Dopaminergic motor complications (wearing off, on-off effects, or dyskinesias) were more common in the initial levodopa group (68.4%) than in the initial pramipexole group (50.0%) (P = .002), although disabling dyskinesias were uncommon in both groups. The mean (SD) Epworth Sleepiness Scale score was significantly higher in the initial pramipexole group (11.3 [5.8]) than in the initial levodopa group (8.6 [4.7]) (P < .001). Mean (SD) changes from baseline in the total Unified Parkinson's Disease Rating Scale score did not significantly differ between the initial pramipexole (2.4 [17.4]) and initial levodopa (0.5 [17.1]) groups (P = .11). Conclusions The policies of initial pramipexole and initial levodopa use followed by open-label levodopa use resulted in similar self-reported disability 6 years after randomization. Persistent differences favoring initial pramipexole were seen in the rates of dopaminergic motor complications, with less severe somnolence favoring initial levodopa. Trial Registration clinicaltrials.gov Identifier: NCT00804479 Published online March 9, 2009 (doi:10.1001/archneurol.2009.32).

ORIGINAL CONTRIBUTION: Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease

Background Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD). Objectives To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD. Design Case-control study. Setting Multicenter university-based study. Participants Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects. Main Outcome Measures Disease status and GBA variations. Results Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD. Conclusion Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.

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ORIGINAL CONTRIBUTION: Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies

Background Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders. Objective To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings. Design Case-control study. Setting Academic research. Participants The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases). Main Outcome Measures GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging–Reagan Institute). Results GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45-17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging–Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15-0.79; P=.01) after adjustment for sex, age at death, and APOE4. Conclusion GBA mutations may be associated with pathologically "purer" LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders.

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ORIGINAL CONTRIBUTION: A Single, Early Magnetic Resonance Imaging Study in the Diagnosis of Multiple Sclerosis

Background A diagnosis of multiple sclerosis in patients who present for the first time with a clinically isolated syndrome (CIS) can be established with brain magnetic resonance imaging (MRI) if the MRI demonstrates demyelinating lesions with dissemination in space (DIS) and dissemination in time (DIT). Objective To investigate the diagnostic performance of a single MRI study obtained within the first 3 months after symptom onset in a cohort of patients with a CIS suggestive of multiple sclerosis at presentation. Design Multicenter inception cohort with a follow-up of at least 24 months. Setting Referral hospitals. Patients Patients with CIS onset between April 1, 1995, and September 30, 2004, who fulfilled the following criteria were included: (1) age of 14 to 50 years and (2) clinical follow-up for at least 24 months after CIS onset or until development of clinically definite multiple sclerosis (CDMS), if this occurred within 2 years. Main Outcome Measure All patients underwent 2 comparable brain MRI examinations, the first within 3 months (early) and the second between 3 and 12 months (delayed) after CIS onset. We defined DIS using several existing MRI criteria, and DIT was inferred when there were simultaneous gadolinium-enhancing and nonenhancing lesions on a single MRI. Results Two hundred fifty patients were included in the study. The comparison of the diagnostic performance of various MRI criteria for identifying early converters to CDMS showed similar sensitivity and specificity between early and delayed MRIs. In addition, the use of less stringent criteria for DIS yielded better sensitivity and similar specificity, particularly when assessed in the first weeks after CIS onset. Conclusion A single brain MRI study that demonstrates DIS and shows both gadolinium-enhancing and nonenhancing lesions that suggest DIT is highly specific for predicting the early development of CDMS, even when the MRI is performed within the first 3 months after the onset of a CIS.

ORIGINAL CONTRIBUTION: Progressive Multifocal Leukoencephalopathy and Relapsing-Remitting Multiple Sclerosis: A Comparative Study

Objective To identify clinical and magnetic resonance imaging (MRI) features that distinguish progressive multifocal leukoencephalopathy (PML) from relapsing-remitting multiple sclerosis (RRMS). Design Retrospective medical record review. Setting Two urban teaching hospitals in Detroit, Michigan. Patients Forty-five confirmed PML cases and 100 patients with RRMS. Main Outcome Measures Clinical and MRI features distinguishing PML from RRMS. Results Overall, monosymptomatic presentations were more common in multiple sclerosis (MS) than PML (85% vs 47%; P < .01). However, patients with PML presented more often with hemiparesis (24% vs 5%; P = .001) and altered mentation (19% vs 0%; P < .0001), whereas brainstem (2% vs 18%; P = .007) presentations were more common in patients with RRMS. Spinal cord and optic neuritis presentations were seen in 18% and 33% of patients with RRMS, respectively, but not in patients with PML (m < .0001). Brain MRI scans, available in 35 (78%) PML cases, revealed 7 lesion types. Large, confluent T2-weighted lesions (74% vs 2%; P < .0001) and deep gray matter lesions (31% vs 7%; P < .001) were more frequent in patients with PML than patients with RRMS. Crescentic cerebellar lesions (23% vs 0%; P < .001) were seen only in patients with PML. Gadolinium-enhancing (23%), transcallosal (9%), and periventricular (9%) lesions were noted in patients with PML. Brain magnetization transfer ratio (MTR) was low in both PML and MS lesions. However, normal-appearing brain tissue MTR in PML was higher than normal-appearing brain tissue MTR in RRMS (44.15% vs 41.04%; P = .002), suggesting that PML may be relatively more focal than MS. Conclusions There appear to be differences between the clinical and MRI characteristics of PML and RRMS, which may help distinguish new MS activity from PML. Magnetization transfer ratio studies may provide additional clues in improving early detection of PML in patients with preexisting MS and warrant further investigation.

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ORIGINAL CONTRIBUTION: Diffusely Abnormal White Matter in Chronic Multiple Sclerosis: Imaging and Histopathologic Analysis

Background Diffuse abnormalities in the white matter (WM), ie, the so-called diffusely abnormal WM (DAWM), as observed on magnetic resonance imaging (MRI), may contribute to the development of clinical disability in multiple sclerosis (MS). Underlying pathologic and MRI characteristics of DAWM are largely unknown. Objectives To explore and describe the histopathologic and radiologic characteristics of DAWM in chronic MS. Design An MRI and histopathologic postmortem correlative study. Methods We analyzed 17 formalin-fixed hemispheric brain slices from 10 patients with chronic MS using histopathologic analysis and qualitative and quantitative MRI. A region-of-interest approach was applied to compare radiologically defined DAWM, normal-appearing WM, and focal WM lesions and to correlate quantitative MRI measures with histopathologic findings. Main Outcome Measures The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Increased T1- and T2-relaxation times and decreased fractional anisotropy values were found in DAWM regions of interest, in association with extensive axonal loss and reduced myelin density. Increased T1- and T2-relaxation times were associated with chronic gliosis. Conclusions This study classifies DAWM in chronic MS as an abnormality that is different from normal-appearing WM and focal WM lesions, most likely resulting from the cumulative effects of ongoing inflammation and axonal pathology. As such, DAWM is likely to substantially contribute to disease progression and may prove to be an important new disease marker in clinical trials focusing on the neurodegenerative aspects of MS.

ORIGINAL CONTRIBUTION: Association of Prior Stroke With Cognitive Function and Cognitive Impairment: A Population-Based Study

Background Defining the nature of the contribution of stroke to cognitive impairment remains challenging. Objective To describe associations between stroke history, APOE genotype, and subtypes of mild cognitive impairment (MCI). Methods We randomly selected residents from Olmsted County, Minnesota, aged 70 to 89 years on October 1, 2004, and invited eligible subjects without documented dementia to participate. Participants (n = 2050) were evaluated through an informant interview, a neurological evaluation, and neuropsychological testing. Neuropsychological testing included 9 tests to assess memory, attention, executive function, visuospatial cognition, and language. Subjects were diagnosed by consensus as cognitively normal or as having MCI (either amnestic or nonamnestic) or dementia. A history of stroke was obtained from the subjects and confirmed in their medical records. We computed the odds ratios (ORs) for a clinical diagnosis of MCI or for scoring in the lowest quartile on each cognitive domain. Results There were 1640 cognitively normal subjects and 329 subjects with MCI: 241 with amnestic MCI and 88 with nonamnestic MCI. In fully adjusted models with only subjects without dementia, a history of stroke was associated with a higher OR of nonamnestic MCI (OR, 2.85; 95% confidence interval [CI], 1.61-5.04) than amnestic MCI (OR, 1.77; 95% CI, 1.14-2.74). A history of stroke was also associated with impaired function in each cognitive domain except memory. The association was strongest for attention and executive function (OR, 2.48; 95% CI, 1.73-3.53). APOE 4 genotype was associated only with amnestic MCI and with impaired memory function. Conclusions In this population-based sample of persons without dementia, a history of stroke was particularly associated with nonamnestic MCI and impairment in nonmemory cognition. The APOE 4 genotype was associated with memory impairment and amnestic MCI.

ORIGINAL CONTRIBUTION: The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases {beta}-Amyloid Protein Levels

Objective To assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on apoptosis and β-amyloid protein (Aβ) levels in vitro and in vivo. Subjects Naive mice, H4 human neuroglioma cells, and H4 human neuroglioma cells stably transfected to express full-length amyloid precursor protein. Interventions Human H4 neuroglioma cells stably transfected to express full-length amyloid precursor protein were exposed to 4.1% sevoflurane for 6 hours. Mice received 2.5% sevoflurane for 2 hours. Caspase-3 activation, apoptosis, and Aβ levels were assessed. Results Sevoflurane induced apoptosis and elevated levels of β-site amyloid precursor protein–cleaving enzyme and Aβ in vitro and in vivo. The caspase inhibitor Z-VAD decreased the effects of sevoflurane on apoptosis and Aβ. Sevoflurane-induced caspase-3 activation was attenuated by the -secretase inhibitor L-685,458 and was potentiated by Aβ. These results suggest that sevoflurane induces caspase activation which, in turn, enhances β-site amyloid precursor protein–cleaving enzyme and Aβ levels. Increased Aβ levels then induce further rounds of apoptosis. Conclusions These results suggest that inhalational anesthetic sevoflurane may promote Alzheimer disease neuropathogenesis. If confirmed in human subjects, it may be prudent to caution against the use of sevoflurane as an anesthetic, especially in those suspected of possessing excessive levels of cerebral Aβ.

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ORIGINAL CONTRIBUTION: Preclinical Evidence of Alzheimer Changes: Convergent Cerebrospinal Fluid Biomarker and Fluorodeoxyglucose Positron Emission Tomography Findings

Background Alterations in cerebrospinal fluid (CSF) tau and β-amyloid peptide 1-42 (Aβ42) levels and rates of cerebral glucose metabolism (CMRglu) on fluorodeoxyglucose positron emission tomography (FDG-PET) occur years before clinical symptoms of Alzheimer disease (AD) become manifest, but their relationship remains unclear. Objective To determine whether CSF AD biomarker levels and CMRglu in healthy individuals correlate in brain structures affected early in AD. Design Cohort study. Setting Alzheimer disease research center. Participants Twenty individuals without dementia aged 46 to 83 years. Interventions Lumbar CSF sampling and FDG-PET imaging of CMRglu. The CSF Aβ42, tau, and tau phosphorylated at threonine 181 (ptau181) levels were measured using immunobead-based multiplex assays. Main Outcome Measures Correlations between CMRglu and CSF biomarker levels were analyzed via voxel-based and volume-of-interest approaches. Results Voxel-based analyses demonstrated significant negative correlations between CSF tau and ptau181 levels and CMRglu in the posterior cingulate, precuneus, and parahippocampal regions. In contrast, a limited positive correlation was found between CSF Aβ42 levels and CMRglu in the inferior temporal cortex. Volume-of-interest analyses confirmed negative associations between CSF tau and ptau181 levels and CMRglu in the parietal and medial parietal lobes and a positive association between CSF Aβ42 levels and CMRglu in the parahippocampal gyrus. Conclusions In healthy individuals, higher CSF tau and ptau181 concentrations were associated with more severe hypometabolism in several brain regions affected very early in AD, whereas lower CSF Aβ42 concentrations were associated with hypometabolism only in the medial temporal lobe. This suggests that early tau and Aβ abnormalities may be associated with subtle synaptic changes in brain regions vulnerable to AD. A longitudinal assessment of CSF and FDG-PET biomarkers is needed to determine whether these changes predict cognitive impairment and incipient AD.

ORIGINAL CONTRIBUTION: Cerebrospinal Fluid Biomarkers and Rate of Cognitive Decline in Very Mild Dementia of the Alzheimer Type

Background Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. Objective To determine whether Aβ 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). Design Retrospective analysis of CSF biomarkers and clinical data. Setting An academic Alzheimer disease research center. Participants Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). Main Outcome Measures Baseline CSF levels of Aβ 42, Aβ 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. Results The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ 42 levels, higher tau or ptau181 levels, or high tau: Aβ 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Aβ 42 values and 0.3 for the highest tertile of Aβ 42 values. Conclusions In individuals with very mild DAT, lower CSF Aβ 42 levels, high tau or ptau181 levels, or high tau:Aβ 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

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ORIGINAL CONTRIBUTION: Cortical {alpha}7 Nicotinic Acetylcholine Receptor and {beta}-Amyloid Levels in Early Alzheimer Disease

Objective To examine 7 nicotinic acetylcholine receptor (nAChR) binding and β-amyloid (Aβ) peptide load in superior frontal cortex (SFC) across clinical and neuropathological stages of Alzheimer disease (AD). Design Quantitative measures of 7 nAChR by [3H]methyllycaconitine binding and Aβ concentration by enzyme-linked immunosorbent assay in SFC were compared across subjects with antemortem clinical classification of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem neuropathological diagnoses. Setting Academic medical center. Subjects Twenty-nine elderly retired clergy. Main Outcome Measures Quantitative measures of 7 nAChR binding and Aβ peptide concentration in SFC. Results Higher concentrations of total Aβ peptide in SFC were associated with clinical diagnosis of mild to moderate AD (P = .02), lower Mini-Mental State Examination scores (P = .003), presence of cortical Aβ plaques (P = .02), and likelihood of AD diagnosis by the National Institute on Aging–Reagan criteria (P = .002). Increased 7 nAChR binding was associated with National Institute on Aging–Reagan diagnosis (P = .02) and, albeit weakly, the presence of cortical Aβ plaques (P = .08). There was no correlation between the 2 biochemical measures. Conclusions These observations suggest that during the clinical progression from normal cognition to neurodegenerative disease state, total Aβ peptide concentration increases while 7 nAChRs remain relatively stable in SFC. Regardless of subjects' clinical status, however, elevated 7 nAChR binding is associated with increased Aβ plaque pathology, supporting the hypothesis that cellular expression of these receptors may be upregulated selectively in Aβ plaque–burdened brain areas.

FROM JAMA: Ginkgo biloba Prevention Trials: More Than an Ounce of Prevention Learned

OBSERVATION: Cross-reactive T-Cell Receptors in Tumor and Paraneoplastic Target Tissue

Background According to established criteria, paraneoplastic encephalomyelitis with adrenal neuroblastoma comprises a definite paraneoplastic neurologic syndrome. Objective To detect T-cell clones that cross-react against antigens shared between tumor and nervous system. Design Case study. Setting Academic research. Patient A 22-year-old woman having paraneoplastic encephalomyelitis with adrenal neuroblastoma. Main Outcome Measures We compared the T-cell receptor repertoires expressed in blood, cerebrospinal fluid, and neuroblastoma tumor tissue using complementary determining region 3 (CDR3) spectratyping and clone-specific polymerase chain reaction. Results The T-cell receptor repertoire in cerebrospinal fluid was narrow compared with that in tumor and blood. Four T-cell clones from different tissues had identical T-cell receptor β chains. Remarkably, the chains showed identical amino acid sequences but different nucleotide sequences. Conclusions These T cells represent ontogenetically distinct clones but share functionally identical receptors. They recognize the same antigen in nervous system and tumor tissue and represent an attractive target for selective therapy.

OBSERVATION: Allogeneic Hematopoietic Cell Transplantation for Refractory Myasthenia Gravis

Objective To describe a patient with intractable myasthenia gravis (MG) who was treated with a matched sibling peripheral blood stem cell transplantation. Design Case report. Patient A 17-year-old boy with MG diagnosed at 11 months of age who was previously treated with pyridostigmine, intravenous immunoglobulin, corticosteroids, thymectomies, azathioprine, mycophenolate mofetil, plasmaphereses, rituximab, and high-dose cyclophosphamide. Results The patient underwent a reduced-toxicity conditioning with intravenous busulfan, fludarabine, and alemtuzumab, followed by a peripheral blood stem cell infusion from his HLA-matched sibling. Before transplantation, the patient was receiving frequent plasmaphereses, intravenous immunoglobulin, and pyridostigmine. He had ophthalmoplegia, oropharyngeal and limb muscle involvement, and limited mobility. At 40 months posttransplantation, his oropharyngeal and skeletal muscle weakness has completely resolved, he is not taking any medications for MG, and he is an avid athlete. However, his ophthalmoplegia persists, and his anti–acetylcholine receptor antibody levels remain elevated. Conclusions Following allogeneic hematopoietic stem cell transplantation, the presence of anti–acetylcholine receptor antibodies was not sufficient for inducing symptoms of MG. This confirms that additional immune mechanisms are important in pathogenesis of this disease. Allogeneic transplantation may be a therapeutic option for patients with severe, refractory MG. However, little is known about the long-term efficacy of allogeneic transplantation for this disease, and long-term follow-up is warranted.

OBSERVATION: Hashimoto Encephalopathy and Down Syndrome

Background Hashimoto encephalopathy is a potentially fatal condition associated with a presentation of myoclonus, altered conscious state, strokelike episodes, rapid cognitive decline, and neuropsychiatric symptoms. Both congenital hypothyroidism and acquired hypothyroidism are common in patients with Down syndrome. Objective To describe the presentation of Hashimoto encephalopathy in patients with Down syndrome. Design Clinical case reports. Setting General neurology unit. Patients Two Down syndrome patients diagnosed as having Hashimoto encephalopathy are described. Intervention High-dose oral corticosteroids. Main Outcome Measures Neurologic examination, electroencephalography, and blood analysis results. Results Both patients responded to treatment, with a slow return to their premorbid level of function. Conclusion Hashimoto encephalopathy should be considered in Down syndrome patients with rapidly progressive cognitive decline.

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IMAGES IN NEUROLOGY: Pineal Metastasis From Breast Cancer

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RESEARCH LETTERS: No Association Between SRGAP3/MEGAP Haploinsufficiency and Mental Retardation

CORRESPONDENCE: D. Carleton Gajdusek, MD (1923-2008)

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THIS MONTH IN ARCHIVES OF NEUROLOGY: This Month in Archives of Neurology

CORRECTION: Error in Byline and Author Contributions in: No TARDBP Mutations in a French Canadian Population of Patients With Parkinson Disease

EDITORIAL: Brain Traffic: Subcellular Transport of the Amyloid Precursor Protein

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NEUROLOGICAL REVIEW: Epilepsy and Cognitive Impairments in Alzheimer Disease

Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of β-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that β-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis. Published online February 9, 2009 (doi:10.1001/archneurol.2009.15).

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NEUROLOGICAL REVIEW: Emerging Concepts in the Pathogenesis of Epilepsy and Epileptogenesis

Recent studies of the problem of ictogenesis, or the ways that seizures develop in an already hyperexcitable brain, are leading to paradigm-shifting concepts that may lead to exciting new therapies for seizures. Research on the equally important area of epileptogenesis, or the ways that a normal brain becomes epileptic, is also expanding, but comparable research into translation of laboratory findings into successful clinical interventions for those at high risk needs to be developed.

ORIGINAL CONTRIBUTION: Reduction of SorLA/LR11, a Sorting Protein Limiting {beta}-Amyloid Production, in Alzheimer Disease Cerebrospinal Fluid

Background The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces β-amyloid precursor protein trafficking to secretases, notably BACE1 that generates β-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. Objective T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like β-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. Design Case-control study. Setting Academic research. Participants Patients with AD and control subjects. Main Outcome Measures We evaluated CSF LR11, β-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. Results LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with β-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble β-amyloid precursor protein but not apolipoprotein E levels. Conclusion Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote β-amyloid production or as an index of therapeutic response in late-onset AD.

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ORIGINAL CONTRIBUTION: Diagnostic Value of N-methyl-D-aspartate Receptor Antibodies in Women With New-Onset Epilepsy

Background In women younger than 45 years, a new form of encephalitis associated with ovarian teratoma and presenting with seizures and psychiatric symptoms has been described. Most patients have antibodies to NR1/NR2 heteromers of the N-methyl-d-aspartate receptor (NMDAR). Objective To assess the frequency and significance of antibodies to NMDAR in otherwise unexplained new-onset epilepsies in young women. Design Prospective cohort study. Setting University department of epileptology. Patients From January 1, 2005, to June 30, 2007, we identified 19 female patients aged 15 to 45 years with unexplained new-onset epilepsy. In addition, we studied 61 cerebrospinal fluid–serum sample pairs from patients with other cryptogenic epilepsies and 11 cerebrospinal fluid–serum sample pairs from surgically treated patients with epilepsy with no evident encephalitic abnormalities. Main Outcome Measures Antibodies to NMDAR and characteristics of affected patients. Results Five of the 19 patients had antibodies against NMDAR. These patients had diffuse cerebral dysfunction and seizure origins. Psychiatric symptoms and pleocytosis were significantly associated with this group of patients. The disease course was episodic, in part relapsing-remitting, with full recoveries either spontaneously or after corticosteroid or intravenous immunoglobulin treatments. Only 1 patient had a neoplasm (multiple neuroendocrine tumors that included the ovaries) identified to date. In the control series, one 22-year-old man with a cryptogenic, severely encephalopathic seizure disorder was NMDAR antibody positive, and he also recovered fully. Conclusions Anti-NMDAR encephalitis accounts for a relevant proportion of otherwise unexplained new-onset epilepsies. Patients harboring NMDAR antibodies usually have prominent psychiatric symptoms and pleocytosis, and they may develop hypoventilation. Anti-NMDAR encephalitis is not always paraneoplastic.

ORIGINAL CONTRIBUTION: Deep Brain Stimulation for Primary Generalized Dystonia: Long-term Outcomes

Background Pallidal deep brain stimulation (DBS) is the best therapeutic option for patients with disabling primary generalized dystonia (PGD) that is refractory to medications. However, little is known about its long-term effects. Objective To describe long-term clinical outcomes in patients with PGD who underwent pallidal DBS. Design Case series. Setting University hospital. Patients Thirty consecutive patients with at least 2 years' follow-up after pallidal DBS for intractable PGD. Interventions Pallidal DBS and annual follow-up examinations up to 8 years after DBS implantation. Main Outcome Measures Clinical outcome as measured by changes in the Burke-Fahn-Marsden dystonia scale, incidence and prevalence of adverse events, total electrical energy delivered, and implantable pulse generator longevity. Results Twenty-three patients were followed for 3 years, 13 for 4 years, 9 for 5 years, 5 for 6 years, 5 for 7 years, and 1 for 8 years after DBS. Overall improvement at 1 year was maintained in all at successive yearly examinations. There were no intraoperative complications; hardware-related adverse events were infrequent. Rare stimulation-related adverse events primarily affected speech. Implantable pulse generators were replaced every 24 months on average in patients who received initial stimulation at 130-Hz frequency. No battery was replaced, for up to 48 months, in 20 patients initially stimulated using 60 Hz. Clinical outcome did not depend on high energies of stimulation. Conclusions Pallidal DBS is a safe and effective treatment for PGD, with improvement sustained for up to 8 years in 1 patient. Low energies of stimulation, although they did not affect clinical outcome, were associated with longer battery life.

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ORIGINAL CONTRIBUTION: Regulatory T Cells Are Reduced During Anti-CD25 Antibody Treatment of Multiple Sclerosis

Objective Maintenance therapy with anti-CD25 antibody has emerged as a potentially useful treatment for multiple sclerosis (MS). Constitutive CD25 expression on CD4+CD25+ regulatory T cells (Treg) suggests that anti-CD25 antibody treatment may potentially target a subset of T cells that exhibit immune suppressive properties. We examined changes to CD4+CD25+ Treg in patients with MS receiving maintenance anti-CD25 monoclonal antibody treatment to determine the effect of treatment on Treg and, consequently, on immunological tolerance. Design Peripheral blood and cerebrospinal fluid samples obtained from a before-and-after trial of anti-CD25 antibody monotherapy were examined to compare baseline and treatment differences in CD4+CD25+ Treg. Subjects A total of 15 subjects with MS. One subject was withdrawn owing to an adverse effect. Results Sustained reduction of the frequency of CD4+CD25+ Treg was observed during treatment. Anti-CD25 antibody treatment led to evidence of impaired in vivo Treg proliferation and impaired ex vivo Treg suppression. Inflammatory MS activity was substantially reduced with treatment despite reduction of circulating Treg, and there was no correlation between changes in the frequency of Treg and changes in brain inflammatory activity. However, new-onset inflammatory disease, notably dermatitis, was also observed in a number of subjects during treatment. Conclusion The reduction in Treg did not negatively affect maintenance of central nervous system tolerance during anti-CD25 antibody treatment. The incidence of new-onset inflammatory disease outside of the central nervous system in a subset of patients, however, warrants further studies to examine the possibility of compartmental differences in the capacity to maintain tolerance in the setting of reduced CD4+CD25+ Treg.

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ORIGINAL CONTRIBUTION: Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple Sclerosis

Background Several questions arise concerning the use of the anti-CD25 antibody daclizumab to treat multiple sclerosis (MS). Objectives To answer the following 3 questions related to the efficacy of daclizumab therapy in patients with MS: Is the therapeutic effect of daclizumab dependent on combination with interferon beta? Is a higher dosage of daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to daclizumab? Design An open-label baseline vs treatment phase II clinical trial of daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta–daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of daclizumab was doubled. Setting Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. Patients Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. Intervention Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5). Main Outcome Measures The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta–daclizumab combination therapy, and daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. Results Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and daclizumab therapy was discontinued. Although daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta–daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56bright natural killer cells and decrease in CD8+ T cells) were identified that can differentiate between full and partial daclizumab responders. Conclusions Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta–daclizumab combination therapy or higher dosages of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS. Trial Registration clinicaltrials.gov Identifier: NCT00001934

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ORIGINAL CONTRIBUTION: Long-term Course of Demyelinating Neuropathies Occurring During Tumor Necrosis Factor-{alpha}-Blocker Therapy

Objective To report the long-term follow-up (mean, 41 months; range, 25-55 months) of patients with demyelinating neuropathy occurring after tumor necrosis factor- (TNF-) blocker treatment (infliximab [Remicade], etanercept [Enbrel], and adalimumab [Humira]). Background Demyelinating neuropathy is a rare adverse event of anti–TNF- therapy. Improvement usually occurs after drug interruption and/or in association with usual treatments for demyelinating neuropathies. Design Case report with review of the previously published cases. Setting University hospital in Le Kremlin-Bicêtre, France: tertiary reference center for peripheral neuropathies and national reference center for rare peripheral neuropathies (www.nnerf.fr). Patients Five patients (4 men, mean age, 47 years) who developed a demyelinating neuropathy during anti–TNF- therapy. Main Outcome Measure Development of neuropathy. Results Neuropathy developed early (8 months) after treatment introduction. Various clinical patterns were encountered, including pure sensory neuropathy. Immunomodulating treatments were always required for neuropathy control. Chronic demyelinating neuropathy developed either after change of anti–TNF- drug or spontaneously after treatment discontinuation without any drug reintroduction. Conclusion Influence of anti–TNF- treatment continuation on the long-term course of neuropathy is variable, suggesting that anti–TNF- treatment withdrawal is not always necessary for neuropathy control.

CORRECTION: Error in Figure in: Episodic Ataxia Associated With EAAT1 Mutation C186S Affecting Glutamate Reuptake

ORIGINAL CONTRIBUTION: Diffusion Abnormalities in the Primary Sensorimotor Pathways in Writer's Cramp

Objective To determine whether there are diffusion abnormalities along the fibers connecting sensorimotor regions, including the primary sensorimotor areas and the striatum, in patients with writer's cramp using voxel-based diffusion analysis and fiber tracking. Recent studies have shown structural changes in these regions in writer's cramp. Design Patient and control group comparison. Setting Referral center for movement disorders. Participants Twenty-six right-handed patients with writer's cramp and 26 right-handed healthy control subjects matched for sex and age. Interventions Clinical motor evaluations. Main Outcome Measures Fractional anisotropy changes and results of fiber tracking in writer's cramp. Results Diffusion-tensor imaging revealed increased fractional anisotropy bilaterally in the white matter of the posterior limb of the internal capsule and adjacent structures in the patients with writer's cramp. Fiber tracking demonstrated that fractional anisotropy changes involve fiber tracts connecting the primary sensorimotor areas with subcortical structures. Conclusions Diffusion abnormalities are present in fiber tracts connecting the primary sensorimotor areas with subcortical structures in writer's cramp. These abnormalities strengthen the role of the corticosubcortical pathways in the pathophysiologic mechanisms of writer's cramp.

ORIGINAL CONTRIBUTION: Differentiation of Hereditary Spastic Paraparesis From Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes

Objective To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from primary lateral sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. Design Case series. Setting Tertiary referral center. Patients One hundred four Dutch patients with an adult-onset, sporadic upper motor neuron syndrome of at least 3 years' duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). Results All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. Conclusions In most patients with a sporadic adult-onset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing.

ORIGINAL CONTRIBUTION: Amyotrophic Lateral Sclerosis in Sweden, 1991-2005

Objectives To investigate the temporal trend of amyotrophic lateral sclerosis (ALS) incidence in Sweden between January 1, 1991, and December 31, 2005, and to explore incidence variations according to major demographic factors. Design Population-based study. Setting Academic research. Participants All incident cases of ALS identified through the Swedish Inpatient Register between January 1, 1991, and December 31, 2005. Main Outcome Measure Age-standardized incidence rates were calculated by applying the observed age-specific incidence rates to the age distribution of the Swedish population in 1991. A linear regression model was used to assess the potential trend of the incidence during calendar years. We also followed up the entire population registered in the 1990 Population and Housing Census for incidence of ALS. Relative risk and 95% confidence interval of ALS associated with demographic variables were estimated using Poisson regression models. Results The age-standardized incidence rates increased from 2.32 per 100 000 person-years in 1991-1993 to 2.98 per 100 000 person-years in 2003-2005, representing an annual increase of approximately 2% during the 15 years (P value for trend, .002). The age-specific incidence rates increased in all age groups except those younger than 50 years. The observed increase remained significant when restricting the analysis to individuals born in Sweden (P value for trend, <.001). Compared with individuals born from April through June, those born from October through December were at 11% increased risk of ALS (95% confidence interval, 1.01-1.23). Conclusions The incidence of ALS has been increasing during the last 15 years in Sweden. Further studies are warranted to explore the underlying reasons for this observed trend.

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FROM JAMA: High-Dose B Vitamin Supplementation as a Disease-Modifying Therapy in Alzheimer Disease

OBSERVATION: Tularemic Meningitis in the United States

Background Tularemia is a zoonotic disease caused by Francisella tularensis. Tularemia presents with various clinical illnesses, but meningitis is rare. Objectives To describe a patient who developed typhoidal tularemia with atypical acute meningitis and to review the pathogenesis, clinical and laboratory features, and antibiotic drug treatment of reported cases of tularemic meningitis. Design Case study and literature review. Setting University hospital, tertiary care center. Patient A 21-year-old healthy man who had recently worked as a professional landscaper in the Albuquerque, New Mexico, metropolitan area developed fever, malaise, headache, and a stiff neck. Main Outcome Measures Francisella tularensis cerebrospinal fluid culture, antibiotic sensitivity, transmission source, and outcome. Results The cerebrospinal fluid contained a lymphocytic pleocytosis, negative Gram stain, and F tularensis isolation with chloramphenicol and streptomycin antibiotic sensitivities. Conclusions Although tularemia is uncommon and tularemic meningitis is rare in the United States, attention is drawn to the increasing number of cases in professional landscapers, the atypical cerebrospinal fluid picture, and unusual antibiotic sensitivities.

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OBSERVATION: Cerebral Arteriolar Thromboembolism in Idiopathic Hypereosinophilic Syndrome

Objective To describe imaging findings as well as postmortem brain and cardiac pathology in a patient with fulminant idiopathic hypereosinophilic syndrome. Design Case report. Setting University hospital. Patient A 48-year-old right-handed man with hypereosinophilia, rapidly progressive encephalopathy, and focal neurological deficits who died 22 days after presentation. Main Outcome Measures Physical examination, radiologic, and neuropathologic examination results. Results Imaging of the brain revealed bihemispheric ischemic changes in and beyond the watershed distributions. Pathology review demonstrated mural cardiac thrombus that likely caused cardioembolism as well as diffuse microangiopathy despite resolution of the hypereosinophilia. Conclusions Timely recognition of idiopathic hypereosinophilic syndrome may enable aggressive treatment prior to widespread cardioembolism and degranulation that result in devastating cerebrovascular complications.

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IMAGES IN NEUROLOGY: Angiographic Diagnosis of Primary Central Nervous System Vasculitis With Spinal Cord Involvement

IMAGES IN NEUROLOGY: Bilateral Facial Palsy in Neuroborreliosis

IMAGES IN NEUROLOGY: Devoid of Flow

BOOK REVIEWS: Wolff's Headache and Other Head Pain

CORRESPONDENCE: Parkinsonism: The Hyposmia and Phantosmia Connection

CORRESPONDENCE: Parkinsonism: The Hyposmia and Phantosmia Connection--Reply

CORRESPONDENCE: Can Treatment With Nonsteroidal Anti-inflammatory Drugs Protect From Dementia?

CORRESPONDENCE: Can Treatment With Nonsteroidal Anti-inflammatory Drugs Protect From Dementia?--Reply

CORRESPONDENCE: Tissue Plasminogen Activator Does Not Benefit Most Eligible Patients With Stroke

CORRESPONDENCE: Tissue Plasminogen Activator Does Not Benefit Most Eligible Patients With Stroke--Reply

CORRESPONDENCE: Moderate Alcohol Consumption, Apolipoprotein E, and Neuroprotection

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ABOUT THIS JOURNAL: About This Journal

THIS MONTH IN ARCHIVES OF NEUROLOGY: This Month in Archives of Neurology

NEUROLOGICAL REVIEW: The Role of Metabolic Disorders in Alzheimer Disease and Vascular Dementia: Two Roads Converged

In recent years a rapidly increasing number of studies has focused on the relationship between dementia and metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. Etiological heterogeneity and comorbidity pose challenges for determining relationships among metabolic disorders. The independent and interactive effects of brain vascular injury and classic pathological agents such as β-amyloid have also proved difficult to distinguish in human patients, blurring the lines between Alzheimer disease and vascular dementia. This review highlights recent work aimed at identifying convergent mechanisms such as insulin resistance that may underlie comorbid metabolic disorders and thereby increase dementia risk. Identification of such convergent factors will not only provide important insight into the causes and interdependencies of late-life dementias but will also inspire novel strategies for treating and preventing these disorders.

CORRECTION: Omission of Participating Site Investigators/Coordinators in: Randomized Controlled Trial of Ethyl-Eicosapentaenoic Acid in Huntington Disease: The TREND-HD Study

CLINICAL IMPLICATIONS OF BASIC NEUROSCIENCE RESEARCH: Implications of Amylin Receptor Agonism: Integrated Neurohormonal Mechanisms and Therapeutic Applications

FROM JAMA: Exercised Against Dementia

CORRECTION: Incorrect Year for Reference in: Young-Onset Dementia: Demographic and Etiologic Characteristics of 235 Patients

ORIGINAL CONTRIBUTION: Different Patterns of Cerebral Injury in Dementia With or Without Diabetes

Background Diabetes mellitus (DM) increases the risk of dementia in the elderly. However, its underlying mechanisms, its connection with Alzheimer disease and vascular cognitive impairment, and effects of therapy remain unclear. Objective To test the hypothesis that DM promotes specific neuropathologic processes that contribute to dementia and that these processes may be suppressed by antidiabetic therapy. Design A comprehensive neuropathologic assessment of all cases from a community-based study of incident dementia (Adult Changes in Thought Study) that underwent autopsies (n = 259) and had information on DM status (n = 196). Biochemical analysis was conducted on a subset of these cases with rapidly frozen brain tissue (n = 57). Participants Autopsy cases were divided into 4 groups: no DM/no dementia (DM–/dementia–), DM/no dementia (DM+/dementia–), no DM/dementia (DM–/dementia+), and DM/dementia (DM+/dementia+). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of dementia was assigned through a consensus of experts following biennial cognitive and physical evaluations. Diabetes was diagnosed based on information obtained from participants' extensive medical records. Results In cases without dementia (n = 125), neuropathologic and biochemical end points did not differ significantly by DM status. However, we observed 2 patterns of injury in patients with dementia (n = 71) by their DM status. Individuals without DM but with dementia (DM–/dementia+) had a greater amyloid-β peptide load and increased levels of F2-isoprostanes in the cerebral cortex, while DM+/dementia+ patients had more microvascular infarcts and an increased cortical IL-6 (interleukin 6) concentration. The number of microvascular infarcts was greater in deep cerebral structures in patients with dementia whose diabetes was treated, whereas amyloid plaque load tended to be greater for untreated diabetic patients with dementia. Conclusions These novel characterizations of 2 different patterns of cerebral injury in patients with dementia depending on DM status may have etiologic and therapeutic implications. Published online January 12, 2009 (doi:10.1001/archneurol.2008.579).

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ORIGINAL CONTRIBUTION: The Metabolic Syndrome and Development of Cognitive Impairment Among Older Women

Background Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment. Objective To investigate the association between the metabolic syndrome and its components and incident cognitive impairment in older women. Design We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment, or low global cognitive test score). Setting The study was conducted at 180 clinical centers in 25 countries. Participants A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures. Main Outcome Measures Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment. Results A total of 497 women (10.2%) had the metabolic syndrome and, of these, 36 (7.2%) developed cognitive impairment compared with 181 (of 4398 or 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14-2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23; 95% confidence interval, 1.09-1.39) per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect. Conclusion We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.

ORIGINAL CONTRIBUTION: Total and Regional Adiposity and Cognitive Change in Older Adults: The Health, Aging and Body Composition (ABC) Study

Objectives To investigate whether total and/or regional adiposity measured by anthropometry and radiographic studies influences cognitive decline in older adults and whether this association is explained by hormones and inflammatory factors known to be secreted by adipose tissue. Design Prospective cohort study. Setting Two clinical centers. Participants Three thousand fifty-four elderly individuals enrolled in the Health ABC Study. Adiposity measures included body mass index, waist circumference, sagittal diameter, total fat mass by dual-energy x-ray absorptiometry, and subcutaneous and visceral fat by abdominal computed tomography. We examined the association between baseline body fat measures and change in Modified Mini-Mental State Examination (3MS) score, sequentially adjusting for confounding and mediating variables, including comorbid diseases, adipocytokines, and sex hormones. Main Outcome Measure Scores from the 3MS, administered at the first, third, fifth, and eighth annual clinical examinations. Results All baseline adiposity measures varied significantly by sex. In mixed-effects models, the association between total and regional adiposity and change in 3MS score varied significantly by sex, with the highest adiposity tertile being associated with greater cognitive declines in men (for each adiposity measure, P < .05) but not in women (for interaction, P < .05). Total fat mass was significantly associated with greater change in 3MS scores among men (lowest tertile, –1.6; middle tertile, –2.2; highest tertile, –2.7; P = .006), even after adjusting for mediators. Conclusions Higher levels of all adiposity measures were associated with worsening cognitive function in men after controlling for metabolic disorders, adipocytokines, and sex hormone levels. Conversely, there was no association between adiposity and cognitive change in women.

ANNOUNCEMENT: Research Letters

ORIGINAL CONTRIBUTION: Midlife and Late-Life Obesity and the Risk of Dementia: Cardiovascular Health Study

Background While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting. Objective To evaluate associations between midlife and late-life obesity and risk of dementia. Design Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999). Setting Community-dwelling sample in 4 US sites recruited from Medicare eligibility files. Participants A total of 2798 adults without dementia (mean age, 74.7 years; 59.1% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times. Main Outcome Measures Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria. Results Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI. Conclusion These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.

ORIGINAL CONTRIBUTION: Contribution of Vascular Risk Factors to the Progression in Alzheimer Disease

Background Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). Objective To determine whether prediagnosis vascular risk factors are associated with progression of AD. Design Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. Setting Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure Change in a composite score of cognitive ability from diagnosis onward. Results In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E 4 (APOE-4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. Conclusion Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD.

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ORIGINAL CONTRIBUTION: PGC-1{alpha} Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia

Objectives To explore mechanisms through which altered peroxisome proliferator–activated receptor coactivator 1 (PGC-1) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1 expression in neurons might be developed as a novel therapeutic strategy in AD. Design Case-control. Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases. Results Using genome-wide complementary DNA microarray analysis, we found that PGC-1 messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1 in clinical dementia and found that PGC-1 protein content was negatively associated with both AD-type neuritic plaque pathology and β-amyloid (Aβ)X-42 contents. Moreover, we found that the predicted elevation of amyloidogenic Aβ1-42 and Aβ1-40 peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1 expression. Most importantly, we found that the reconstitution of exogenous PGC-1 expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" -secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression. Conclusion Therapeutic preservation of neuronal PGC-1 expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Aβ peptides.

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ORIGINAL CONTRIBUTION: Fat Metabolism During Exercise in Patients With Mitochondrial Disease

Objective To determine whether patients with defects of the respiratory chain have metabolic adaptations that promote a preferential use of fats or carbohydrates, similar to what is observed in metabolic myopathies affecting glycolysis or fat oxidation. Design Causation and case-control study. Fat metabolism was determined by means of indirect calorimetry and stable isotope technique in patients and healthy subjects. Patients carried various types and loads (mean [SE], 72% [5%]) of mitochondrial DNA (mtDNA) mutations in skeletal muscle. All subjects exercised at the same absolute workload (mean [SE], 65 [10] W), corresponding to 72% (in patients) and 30% (in healthy subjects) of maximum oxygen consumption. Setting Neuromuscular research unit. Participants Ten patients with mtDNA mutations and 10 sex-matched healthy subjects. Main Outcome Measures Fat turnover, plasma concentrations of palmitate and total free fatty acids, glucose mobilization, and total carbohydrate oxidation. Results Fat turnover and plasma concentrations of palmitate and total free fatty acids were similar in patients and healthy subjects at rest and during exercise. In line with the higher relative workload of the patients, glucose mobilization and total carbohydrate oxidation were higher in the patients compared with the healthy subjects. Conclusion During moderate-intensity exercise, the balance between fat and carbohydrate use in patients with mtDNA mutations matches that seen in healthy subjects, indicating that manipulating dietary fat and carbohydrate content is not a feasible therapeutic option to improve exercise intolerance in these disorders.

ORIGINAL CONTRIBUTION: Iron Accumulation in the Substantia Nigra of Patients With Alzheimer Disease and Parkinsonism

Background Preliminary studies have shown an increase in iron accumulation in the substantia nigra but not in the hippocampus in patients with Parkinson disease without dementia and the reverse in patients with Alzheimer disease (AD) and no parkinsonism. Objective To determine whether iron levels (measured as T2 shortening on magnetic resonance images) are greater in the substantia nigra of patients with AD who have parkinsonism than in those with AD alone. Design Case-control study. Setting Albany Medical College, Albany, New York. Participants Fifteen patients with only AD (controls) and 18 with AD as well as parkinsonism, aged 56 to 89 years, and with a total Clinical Dementia Rating of 5.0 to 11.5. Patients were selected according to the purity of their disease; patients with a Unified Parkinson's Disease Rating Scale motor score of 15 or greater were considered to have parkinsonism. Main Outcome Measure Area under the curve for short T2 (30 milliseconds) in patients with only AD vs patients with AD who developed parkinsonism. Results Patients who developed parkinsonism along with their existing dementia had significantly more iron in their substantia nigra than did patients with AD alone (P = .03, 2-sample t test). Conclusions Iron accumulation may be a predictor of parkinsonism. The development of parkinsonism during the course of AD appears to be associated with the accumulation of iron, which in turn may contribute to the pathogenesis of neurologic decline.

CALL FOR PAPERS: Archives Express

ORIGINAL CONTRIBUTION: Measuring Demyelination and Remyelination in Acute Multiple Sclerosis Lesion Voxels

Objective To validate the use of the magnetization transfer ratio (MTR) as a practical imaging marker of demyelination and remyelination in acute multiple sclerosis lesions. Design Case study. Setting University hospital multiple sclerosis clinic. Patients Six patients with relapsing-remitting multiple sclerosis and acute gadolinium-enhancing lesions were studied serially using a quantitative magnetization transfer examination. Main Outcome Measures Changes in the water content and macromolecular content, a marker of myelin content that, unlike MTR, is not affected by changes in water content (edema) associated with acute inflammation, and changes in MTR of lesions. Results Both the macromolecular content and MTR were lower than normal in acute lesions and recovered over several months. The decrease in macromolecular content relative to contralateral normal-appearing white matter was greater than the decrease in MTR (0.46 vs 0.75 at the time of gadolinium enhancement), likely because edema in the acute lesion increased the T1 relaxation time of water and attenuated the decrease in MTR. Nevertheless, there was still a strong correlation between changes in the relative MTR and macromolecular content (R2 = 0.70; P < .001). Conclusion Our data support the use of MTR as a practical marker of demyelination and remyelination, even in acute lesions where decreases in MTR are attenuated because of the effects of edema.

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ORIGINAL CONTRIBUTION: Cerebrospinal Fluid {beta}-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain

Background There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and β-amyloid 42 (Aβ42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. Objective To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. Design Cross-sectional study to correlate levels of CSF Aβ42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. Setting Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. Main Outcome Measures Levels of CSF Aβ42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Aβ, hyperphosphorylated tau, and -synuclein. Results Cerebrospinal fluid Aβ42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Aβ42 level correlated inversely with total Aβ load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Aβ42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Aβ42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. Conclusions Cerebrospinal fluid Aβ42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Aβ42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.

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OBSERVATION: Muscle Phosphoglycerate Mutase Deficiency Revisited

Background Phosphoglycerate mutase (PGAM) deficiency (glycogen storage disease type X) has been reported in 12 patients of whom 9 were African American. Objective To describe 2 patients, 1 of Pakistani and 1 of Italian ethnic origin, with typical clinical and biochemical changes of glycogen storage disease type X and novel mutations in the gene encoding the muscle subunit of PGAM (PGAM2). Design Clinical, pathological, biochemical, and molecular analyses. Setting Tertiary care university hospitals and academic institutions. Patients A 37-year-old Danish man of Pakistani origin who had exercise-related cramps and myoglobinuria and a 65-year-old Italian man who had exercise intolerance and myalgia but no pigmenturia and had undergone long-term statin therapy. Main Outcome Measures Clinical course and biochemical and molecular features. Results Biochemical evidence showed severe isolated PGAM deficiency, and molecular studies revealed 2 novel homozygous mutations, a nonsense mutation and a single nucleotide deletion. Pathological studies of muscle showed mild glycogen accumulation but prominent tubular aggregates in both patients. Conclusions We found that glycogen storage disease type X is not confined to the African American population, is often associated with sarcoplasmic reticulum (SR) proliferation, and is genetically heterogeneous.

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OBSERVATION: A New Mitochondrial Transfer RNAPro Gene Mutation Associated With Myoclonic Epilepsy With Ragged-Red Fibers and Other Neurological Features

Background Pathogenic mutations of the human mitochondrial genome are associated with well-characterized, progressive neurological syndromes, with mutations in the transfer RNA genes being particularly prominent. Objective To describe a novel mitochondrial transfer RNAPro gene mutation in a woman with a myoclonic epilepsy with ragged-red fibers–like disease. Design, Setting, and Patient Case report of a 49-year-old woman presenting with a myoclonic epilepsy with ragged-red fibers–like disease comprising myoclonic jerks, cerebellar ataxia, and proximal muscle weakness. Results Histochemical analysis of a muscle biopsy revealed numerous cytochrome-c oxidase–deficient, ragged-red fibers, while biochemical studies indicated decreased activity of respiratory chain complex I. Molecular investigation of mitochondrial DNA revealed a new heteroplasmic mutation in the TC stem of the mitochondrial transfer RNAPro gene that segregated with cytochrome-c oxidase deficiency in single muscle fibers. Conclusions Our case serves to illustrate the ever-evolving phenotypic spectrum of mitochondrial DNA disease and the importance of performing comprehensive mitochondrial genetic studies in the absence of common mitochondrial DNA mutations.

OBSERVATION: Peripheral Autoimmune Neuropathy Assessed Using Corneal In Vivo Confocal Microscopy

Background Corneal nerves can be examined using in vivo confocal microscopy (IVCM). This new technique permits sequential observation of the corneal subbasal nerve plexus and detects early signs of diabetic peripheral neuropathy. Objective To describe a patient with autoimmune peripheral neuropathy followed up using corneal IVCM. Design Case report. Setting Clinic of neurology, Geneva, Switzerland. Patient A 56-year-old man with peripheral neuropathy diagnosed as anti–myelin-associated glycoprotein neuropathy. His symptoms initially worsened despite the administration of intravenous immunoglobulins and plasma exchange. Evolution was eventually favorable after rituximab and corticosteroids were given. At 1-year follow-up, clinical recovery was almost complete, and the patient was stable according to the results of clinical and electrophysiologic assessments. Main Outcome Measure Corneal nerve measurement by IVCM. Results Examination of corneal nerves using IVCM at 2 different times during the patient's clinical evolution (peak disease and recovery phase) demonstrated histologic signs that correlated with the results of clinical and electrophysiologic assessments. Conclusion This observation supports the hypothesis that corneal IVCM could also be helpful for the early detection or follow-up of autoimmune peripheral neuropathy.

IMAGES IN NEUROLOGY: Atypical Presentation of Primary Central Nervous System Lymphoma

IMAGES IN NEUROLOGY: Diffuse Leptomeningeal Astrocytoma in a Patient With Infantile Epilepsy

IMAGES IN NEUROLOGY: Would You Perform Thrombolysis in This Acute Ischemic Stroke Patient?

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COMMENTARY IN NEUROLOGY: We Should Use Magnetic Resonance Imaging to Classify and Monitor the Course of Multiple Sclerosis

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BOOK REVIEWS: The Legacy of Tracy J. Putnam and H. Houston Merritt: Modern Neurology in the United States

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CORRESPONDENCE: National Football League Experiences With Return to Play After Concussion

CORRESPONDENCE: Convolutions of the Silent Sports Concussion: A Neuropsychologist's Response to the Dark Ages of Rule-Based Return-to-Play Decisions

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