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Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease [Original Contribution]

Background The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant.Objective To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD.Design, Setting, and Participants Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects.Main Outcome Measures Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial.Results The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by -tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with -tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with -tocopherol.Conclusions Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.Published online October 12, 2009 (doi:10.1001/archneurol.2009.247).

Autoimmune Targets of Heart and Skeletal Muscles in Myasthenia Gravis [Original Contribution]

Objective To investigate the clinical, histological, and immunological features of patients with myasthenia gravis (MG) who also developed myocarditis and/or myositis.Design Observational and retrospective case series.Setting Keio University, Hanamaki General Hospital, Kanazawa University, Nagasaki University, and Juntendo University.Patients A cohort of 8 patients with MG with clinically defined inflammatory myopathies.Interventions Clinical and histological features were described. Serological analyses included MG-related antistriational autoantibodies (those to titin, ryanodine receptor, muscular voltage-gated potassium channel Kv1.4) and myositis-specific autoantibodies.Results Of 924 patients with MG, 8 (0.9%) had inflammatory myopathies. The mean (SD) onset age of MG was 55.3 (10.3) years. All patients showed severe symptoms with bulbar involvement; 5 patients had myasthenic crisis and 4 had invasive thymoma. Myocarditis was found in 3 patients and myositis in 6. Myocarditis, developing 13 to 211 months after the MG onset, was characterized by heart failure and arrhythmias. Myositis, developing before or at the same time as MG, affected limb and paraspinal muscles. Histological findings of skeletal muscles showed CD8+ lymphocyte infiltration. Seven patients had 1 of these antistriational autoantibodies but not myositis-specific autoantibodies. Immunomodulatory therapy was required for all patients and was effective for both MG and inflammatory myopathies, although 1 patient died.Conclusions Heart and skeletal muscles are autoimmune targets in some patients with MG. This autoimmunity has a broad clinical spectrum with antistriational autoantibodies.Published online September 14, 2009 (doi:10.1001/archneurol.2009.229).

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Immunotherapy for Multiple Sclerosis: The Curious Case of Interferon Beta [Editorial]

Physiologic Alterations in Ataxia: Channeling Changes Into Novel Therapies [Neurological Review]

The ataxias constitute a heterogeneous group of diseases in which cerebellar dysfunction typically underlies the major neurologic manifestations. It is increasingly clear that ataxia can result directly from mutations in ion channels or from perturbations in ion channel physiology in the absence of a primary channel defect. Neuronal dysfunction stemming from perturbed channel activity likely explains some motor deficits in episodic and degenerative ataxias. Understanding these pathophysiologic changes may reveal novel therapeutic targets for symptomatic treatment of ataxia.

Essential Tremors: A Family of Neurodegenerative Disorders? [Neurological Review]

Essential tremor (ET) is the most common pathologic tremor in humans. The traditional view of ET, as a monosymptomatic condition, is being replaced by an appreciation of the spectrum of clinical features, with both motor and nonmotor elements. These features are not distributed homogeneously across patients. In addition, postmortem studies are now demonstrating distinct structural changes in ET. There is growing evidence that ET may be a family of diseases rather than a single entity. Furthermore, this aging-associated, progressive disorder is associated with neuronal loss and postmortem changes that occur in traditional neurodegenerative disorders.

Promising Strategies for the Prevention of Dementia [Neurological Review]

The incidence and prevalence of dementia are expected to increase several-fold in the coming decades. Given that the current pharmaceutical treatment of dementia can only modestly improve symptoms, risk factor modification remains the cornerstone for dementia prevention. Some of the most promising strategies for the prevention of dementia include vascular risk factor control, cognitive activity, physical activity, social engagement, diet, and recognition of depression. In observational studies, vascular risk factors—including diabetes, hypertension, dyslipidemia, and obesity—are fairly consistently associated with increased risk of dementia. In addition, people with depression are at high risk for cognitive impairment. Population studies have reported that intake of antioxidants or polyunsaturated fatty acids may be associated with a reduced incidence of dementia, and it has been reported that people who are cognitively, socially, and physically active have a reduced risk of cognitive impairment. However, results from randomized trials of risk factor modification have been mixed. Most promising, interventions of cognitive and physical activity improve cognitive performance and slow cognitive decline. Future studies should continue to examine the implication of risk factor modification in controlled trials, with particular focus on whether several simultaneous interventions may have additive or multiplicative effects.

Enhancement of Chemokine Expression by Interferon Beta Therapy in Patients With Multiple Sclerosis [Original Contribution]

Background Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed. Objective To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting. Design The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples. Setting Outpatient units in Germany. Patients Untreated and interferon beta–treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study. Main Outcome Measures Gene expression and serum chemokine protein levels. Results CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta–treated, NAB-negative MS patients. In contrast, gene expression in interferon beta–treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta–treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta–treated, NAB-positive MS patients. Conclusions We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta. Published online August 10, 2009 (doi:10.1001/archneurol.2009.138).

Prediction by Modeling That Epilepsy May Be Caused by Very Small Functional Changes in Ion Channels [Original Contribution]

Objective To use computer simulation to perform a "genetic sensitivity" analysis to predict which genes are best positioned to increase risk as well as to predict functionally how variants in these genes might increase network excitability. Methods A previously published, biophysically realistic model of the dentate gyrus that included mossy fiber sprouting between granule cells was used to model putative environmental changes associated with temporal lobe epilepsy. Properties of voltage-gated ion channels, either 1 at a time or in combinations, were varied systematically to determine their effect on network excitability. Results We found that the network is most sensitive to changes in steady-state voltage dependence of activation and relatively insensitive to changes in inactivation. Changes in sodium channels had the greatest effect on excitability, followed by changes in fast-delayed rectifier potassium channels and then N-type calcium channels. We also investigated the effects of simultaneous small changes in several ion channels, modeling a complex genetic background expected for common epilepsies. A combination of 2 or 3 simultaneous voltage shifts in steady-state activation as small as 2 mV could produce large changes in network excitability. Conclusion Statistical power calculations indicate that changes this small are effectively undetectable with current experimental practices, thus posing new challenges for the functional analysis and validation of epilepsy genes.

Seizure Relapse and Development of Drug Resistance Following Long-term Seizure Remission [Original Contribution]

Objective To quantify and identify predictive risk factors for seizure relapse and development of drug resistance in patients who achieved long-term (>1 year) antiepileptic drug–induced seizure remission. Design Prospective cohort study. Setting Epilepsy Center, Rambam Medical Center. Patients Two hundred fifty-six consecutive patients who entered long-term (>1 year) antiepileptic drug–induced seizure remission were followed up prospectively for 2 years or more. Main Outcome Measures Seizure relapse and development of drug-resistant epilepsy. Results Five years after entering seizure remission, 40.2% of patients experienced seizure relapse and 25.3% of patients developed drug-resistant epilepsy. The Kaplan-Meier curves could be fitted by monoexponential functions, with a maximal seizure relapse rate of 43.6%, maximal drug-resistance rate of 27.4%, and half-decay constant of 21.5 months for both curves. Treatment history served as a significant independent prognostic risk factor for both seizure relapse and development of drug resistance. The preremission seizure frequency and duration of epilepsy were also identified as significant prognostic risk factors in the univariant analysis but failed to reach statistical significance in the multivariate analysis. Conclusion Seizure relapse commonly occurs in patients following long-term seizure remission. Treatment history and duration of epilepsy are predictive risk factors for both seizure relapse and development of drug resistance.

Codistribution of Amyloid {beta} Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype [Original Contribution]

Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation. Objective To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration. Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype. Setting Alzheimer disease research center. Participants Two generations of a family. Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family. Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children. Conclusions To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aβ deposition.

Ten-Year Change in Plasma Amyloid {beta} Levels and Late-Life Cognitive Decline [Original Contribution]

Background Plasma levels of amyloid β peptide (Aβ) are potential biomarkers of early cognitive impairment and decline and of Alzheimer disease risk. Objective To relate midlife plasma Aβ measures and 10-year change in plasma Aβ measures since midlife to late-life cognitive decline. Design Prospective study of a population-based sample. Setting Academic research. Participants Plasma Aβ40 and Aβ42 levels were measured in 481 Nurses' Health Study participants in late midlife (mean age, 63.6 years) and again 10 years later (mean age, 74.6 years). Cognitive testing also began 10 years after the initial blood draw. Participants completed 3 repeated telephone-based assessments (mean span, 4.1 years). Multivariable linear mixed-effects models were used to estimate relations of midlife plasma Aβ40 to Aβ42 ratios and Aβ42 levels to late-life cognitive decline, as well as relations of 10-year change in Aβ40 to Aβ42 ratios and Aβ42 levels to cognitive decline. Main Outcome Measures The 3 primary outcomes were the Telephone Interview for Cognitive Status (TICS) findings, a global score averaging the results of all tests (TICS, immediate and delayed verbal recall, category fluency, and attention), and a verbal memory score averaging the results of 4 tests of verbal recall. Results Higher midlife plasma Aβ40 to Aβ42 ratios were associated with worse late-life decline on the global score (P = .04 for trend). Furthermore, increase in Aβ40 to Aβ42 ratios since midlife predicted greater decline in the global score (P = .03 for trend) and in the TICS (P = .02 for trend). There was no association of cognitive decline with midlife plasma Aβ42 levels alone or with change in Aβ42 levels since midlife. Conclusion In this large community-dwelling sample, higher plasma Aβ40 to Aβ42 ratios in late midlife and increases in Aβ40 to Aβ42 ratios 10 years later were significantly associated with greater decline in global cognition at late life.

Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease [Original Contribution]

Background Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. Objective To model the cognitive decline in preclinical Alzheimer disease. Design Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. Setting Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. Participants One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. Main Outcome Measures Inflection point in longitudinal cognitive performance. Results The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. Conclusions There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.

Implication of Sex and SORL1 Variants in Italian Patients With Alzheimer Disease [Original Contribution]

Objective To investigate the association of genetic variants in sortilin-related receptor (SORL1), which has been proposed as an important genetic contributor to late-onset Alzheimer disease (LOAD). Design We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a case-control association study. Participants The sample included 708 Italian subjects: 251 unrelated, sporadic patients with LOAD, 99 sporadic patients with early-onset Alzheimer disease (AD), and 358 healthy controls. Main Outcome Measures We analyzed the 13 SNPs in the SORL1 gene that had been studied in previous reports using case-control methods and included sex, apolipoprotein E (APOE) genotype, and age at AD onset as covariates. Results The SNPs 4 (rs661057), 7 (rs12364988), and 10 (rs641120) were significantly associated with LOAD compared with controls. We found an association between these 3 variants and sex, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. Of interest, the association of these SNPs with LOAD was confined to APOE 4 noncarriers. Several haplotypic associations at the 5' end of SORL1 were found, including the previously associated CGC haplotype at SNPs 8 through 10. Conclusions Our results confirm the association of SORL1 with AD and show a possible effect of female sex, suggesting that this gene may be a promising susceptibility factor for LOAD. Further studies to detect pathogenic variants and further elucidate the effect of SORL1 on the development of AD are necessary.

Association of Intronic Variants of the BTBD9 Gene With Tourette Syndrome [Original Contribution]

Objective To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. Design Case-control association study. Setting Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. Main Outcome Measures Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. Results The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (2 = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (2 = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. Conclusion Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Error in Table in: Progress and Challenges in RNA Interference Therapy for Huntington Disease [Correction]

Association of Ideomotor Apraxia With Frontal Gray Matter Volume Loss in Corticobasal Syndrome [Original Contribution]

Objective To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS). Design Case-control and cross-sectional study. Participants Forty-eight patients with CBS and 14 control subjects. Intervention Administration of the Test of Oral and Limb Apraxia. Main Outcome Measures Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS. Results Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis. Conclusions In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.

Sensations Evoked in Patients With Amputation From Watching an Individual Whose Corresponding Intact Limb Is Being Touched [Observation]

Background After amputation of a limb, the majority of patients experience phantom sensations, such as phantom pain. Such patients provide an opportunity for the exploration of the perceptual correlates of recently discovered "mirror neurons," which fire not only when individuals move their own limb but when they watch the movements of the corresponding limb of another person. Similar neurons exist in the secondary somatosensory cortex for touch: they fire when the individual is touched or simply watches another person be touched. While these neurons cannot by themselves discriminate between the two, the mind is aware of the difference between feeling and watching; one does not confuse empathy with actual experience. Objective To investigate whether patients with amputation experience the sensations of another person in their own phantom limb during the mere observation of someone else being touched, owing to removal of the inhibition of the mirror neuron system that would have occurred had the limb been intact. Design Case report. Setting University campus, academic setting. Patients Four patients with upper-limb amputation. Main Outcome Measures The subjective reports of patients. Results We report that 4 individuals with arm amputation, the mere watching of the intact hand of another being touched evokes vivid, precisely localized sensations in their own phantom hands. Conclusions We suggest these evoked sensations are owing to removal of neural signals from the hand that would have ordinarily inhibited the response of the mirror neurons and prevented their activity from reaching the threshold of conscious awareness.

Polymyoclonus, Laryngospasm, and Cerebellar Ataxia Associated With Adenocarcinoma and Multiple Neural Cation Channel Autoantibodies [Observation]

Objective To describe and provide audiovisual documentation of a syndrome of polymyoclonus, laryngospasm, and cerebellar ataxia associated with adenocarcinoma and multiple neural cation channel autoantibodies. Design Case report with video. Setting University hospitals. Patient A 69-year-old woman presented with subacute onset of whole-body tremulousness and laryngospasm attributed to gastroesophageal reflux. Results Further evaluation revealed polymyoclonus, cerebellar ataxia, and laryngospasm suspicious of an underlying malignant neoplasm. Surface electromyography of multiple limb muscles confirmed the presence of polymyoclonus. The patient was seropositive for P/Q-type voltage-gated calcium channel antibody; subsequently, whole-body fluorine 18 fluorodeoxyglucose positron emission tomography and cervical lymph node biopsy revealed widespread metastatic adenocarcinoma. Follow-up serologic evaluation revealed calcium channel antibodies (P/Q type and N type) and potassium channel antibody. Conclusions We highlight the importance of recognizing polymyoclonus. To our knowledge, this is also the first description of a syndrome of polymyoclonus, laryngospasm, and ataxia associated with adenocarcinoma and these cation channel antibodies.

Stroke Incidentally Identified Using Improved Positron Emission Tomography for Microglial Activation [Images in Neurology]

Neurocysticercosis: Still Life in the Brain [Images in Neurology]

Multiple Brain Abscesses Associated With Tongue Piercing [Images in Neurology]

A Giant Spinal Cord Cavity [Images in Neurology]

Headache and Facial Pain: What Do I Do Now? [Book Reviews]

Humoral Pattern II Multiple Sclerosis Pathology Not Associated With Neuromyelitis Optica IgG [Research Letters]

Notice of Incomplete Referencing [Correspondence]

Notice of Incomplete Referencing--Reply [Correspondence]

Unreported Financial Disclosure [Correspondence]

Unreported Financial Disclosure--Reply [Correspondence]