| In Focus |
in focus: spotlight on the august 31 issue.
- Gross, Robert, MD, PhD. Pages: 757
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| Editorials |
insulin resistance, type 2 diabetes, and ad: cerebrovascular disease or neurodegeneration? (e-pub ahead of print).
- Luchsinger, Jose, MD, MPH. Pages: 758-759
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nonconvulsive status epilepticus and brain damage: further evidence, more questions.
- Young, G., Bryan MD, FRCPC, Claassen, Jan, MD, PhD. Pages: 760-761
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the four seasons of multiple sclerosis.
- Cross, Anne, Parks, Becky. Pages: 762-763
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| Articles |
insulin resistance is associated with the pathology of alzheimer disease: the hisayama study (e-pub ahead of print).
- Matsuzaki, T., Sasaki, K., MD, PhD, Tanizaki, Y., MD, PhD, Hata, J., MD, PhD, Fujimi, K., MD, PhD, Matsui, Y., MD, PhD, Sekita, A., Suzuki, S.O., MD, PhD, Kanba, S., MD, PhD, Kiyohara, Y., MD, PhD, Iwaki, T., MD, PhD. Pages: 764-770
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Objective: We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD.Methods: This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses.Results: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE [epsilon]4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.Conclusion: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE [epsilon]4.(C)2010AAN Enterprises, Inc.
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mrs in presymptomatic mapt mutation carriers: a potential biomarker for tau-mediated pathology.
- Kantarci, K., MD, MS, Boeve, B.F., Wszolek, Z.K., Rademakers, R., Whitwell, J.L., Baker, M.C., Senjem, M.L., Samikoglu, A.R., Knopman, D.S., Petersen, R.C., MD, PhD, Jack, C.R.. Pages: 771-778
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Objective: To determine the proton magnetic resonance spectroscopy (1H MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study.Methods: Patients with MAPT mutations (N279K, V337M, R406W, IVS9-10G>T, P301L) from 5 different families (n = 24) underwent MRI and single voxel 1H MRS from the posterior cingulate gyrus inferior precuneus at 3 T. Ten of the patients were symptomatic with median Clinical Dementia Rating sum of boxes score (CDR-SOB) of 6.5 and 14 patients were presymptomatic with CDR-SOB of 0. Age- and sex-matched controls (n = 24) were recruited.Results: Symptomatic MAPT mutation carriers were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a possible marker for glial activity, decreased NAA/mI, and hippocampal atrophy (p < 0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p < 0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/Cr (R2 = 0. 22; p = 0.021) and hippocampal volumes (R2 = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers.Conclusion: 1H MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the 1H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. 1H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.(C)2010AAN Enterprises, Inc.
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secular changes in cognitive predictors of dementia and mortality in 70-year-olds.
- Sacuiu, S., MD, PhD, Gustafson, D., MS, PhD, Sjogren, M., MD, PhD, Guo, X., MD, PhD, Ostling, S., MD, PhD, Johansson, B., Skoog, I., MD, PhD. Pages: 779-785
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Background: Successive elderly birth cohorts improved in cognitive performance during the 20th century. It is not clear whether this influences cognitive predictors of dementia and mortality.Objective: In 2 longitudinal population studies, representing 2 cohorts of 70-year-olds examined 30 years apart, we investigated the relation between baseline cognitive function and 5-year occurrence of dementia and mortality.Methods: Two representative cohorts of 70-year-olds initially free from dementia born in 1901-1902 (cohort 1901-1902: n = 381) and 1930 (cohort 1930: n = 551) from Gothenburg, Sweden, were examined in 1971-1972 and 2000-2001 and after 5 years for the outcome of dementia and death. Recent memory was evaluated during psychiatric examinations, and nonmemory domains using psychometric tests.Results: At age 70, cohort 1930 performed better on psychometric tests, and had fewer recent memory problems compared to cohort 1901-1902. During 5-year follow-up, 5.0% in cohort 1901-1902 and 4.4% in cohort 1930 (p = 0.742) developed dementia, and 15.7% in cohort 1901-1902 and 4.4% in cohort 1930 died (p < 0.001). Recent memory was associated with incident dementia in both cohorts. Low scores in nonmemory tests were associated with incident dementia in cohort 1901-1902, but not in cohort 1930. Recent memory problems and lower scores in nonmemory tests were associated with 5-year mortality in cohort 1901-1902, but not in cohort 1930.Conclusions: Secular changes in cognitive performance may influence cognitive predictors of dementia and mortality, despite similar incidence of dementia. The findings should be taken cautiously due to differences between cohorts in refusal rates, quality of education, and dementia recognition in medical records.(C)2010AAN Enterprises, Inc.
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change in risk of alzheimer disease over time.
- Hebert, L.E., Bienias, J.L., Aggarwal, N.T., Wilson, R.S., Bennett, D.A., Shah, R.C., Evans, D.A.. Pages: 786-791
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Objective: To assess whether the risk of incidence of Alzheimer disease (AD) varies over time. The increase in numbers of people at the oldest ages in the population will bring an increase in the number of people with AD. Projections of the size of the increase assume the risk of AD is constant.Methods: All persons age 65 or older in a biracial, geographically defined area were invited to participate in a home interview every 3 years. From the approximately 10,000 participants, stratified random samples were selected for detailed clinical evaluation. At each cycle, individuals determined free of AD in a previous cycle, either by examination or by high score on cognitive function tests, were sampled in the subsequent cycle for evaluation for incident AD. The evaluations for disease were structured and uniform across time. These analyses include 1,695 subjects evaluated for incident disease from 1997 through 2008.Results: AD developed in 360 participants. Change over time in risk of incident disease was assessed in logistic regression analyses including evaluation date and controlling for age, gender, education, race, interval from disease-free designation to evaluation for incident disease, and sample design. The time variable (in years) was not significant (odds ratio = 0.970, 95% confidence interval = 0.902 to 1.044).Conclusions: The null relation of evaluation date to disease incidence suggests no recent change in risk of AD over time, and supports this assumption for projections of AD.(C)2010AAN Enterprises, Inc.
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nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy.
- Vespa, P.M., MD, FCCM, McArthur, D.L., Xu, Y., Eliseo, M., Etchepare, M., BSN, RN, Dinov, I., Alger, J., Glenn, T.P., Hovda, D.. Pages: 792-798
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Objective: To determine if posttraumatic nonconvulsive electrographic seizures result in long-term brain atrophy.Methods: Prospective continuous EEG (cEEG) monitoring was done in 140 patients with moderate to severe traumatic brain injury (TBI) and in-depth study of 16 selected patients was done using serial volumetric MRI acutely and at 6 months after TBI. Fluorodeoxyglucose PET was done in the acute stage in 14/16 patients. These data were retrospectively analyzed after collection of data for 7 years.Results: cEEG detected seizures in 32/140 (23%) of the entire cohort. In the selected imaging subgroup, 6 patients with seizures were compared with a cohort of 10 age- and GCS-matched patients with TBI without seizures. In this subgroup, the seizures were repetitive and constituted status epilepticus in 4/6 patients. Patients with seizures had greater hippocampal atrophy as compared to those without seizures (21 +/- 9 vs 12 +/- 6%, p = 0.017). Hippocampi ipsilateral to the electrographic seizure focus demonstrated a greater degree of volumetric atrophy as compared with nonseizure hippocampi (28 +/- 5 vs 13 +/- 9%, p = 0.007). A single patient had an ictal PET scan which demonstrated increased hippocampal glucose uptake.Conclusion: Acute posttraumatic nonconvulsive seizures occur frequently after TBI and, in a selected subgroup, appear to be associated with disproportionate long-term hippocampal atrophy. These data suggest anatomic damage is potentially elicited by nonconvulsive seizures in the acute postinjury setting.(C)2010AAN Enterprises, Inc.
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seasonal prevalence of ms disease activity (podcast).
- Meier, D.S., Balashov, K.E., Healy, B., Weiner, H.L., Guttmann, C.R.G.. Pages: 799-806
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Objective: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity.Methods: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects.Results: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier.Conclusion: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.(C)2010AAN Enterprises, Inc.
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frameshift and novel mutations in fus in familial amyotrophic lateral sclerosis and als/dementia (e-pub ahead of print).
- Yan, J., MD, PhD, Deng, H.-X., MD, PhD, Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J.G., Shi, Y., Ahmeti, K.B., Brooks, B., Engel, W.K., Siddique, T.. Pages: 807-814
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Objective: Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).Methods: All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.Results: We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.Conclusions: FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and ~4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.(C)2010AAN Enterprises, Inc.
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novel missense and truncating mutations in fus/tls in familial als (e-pub ahead of print).
- Waibel, S., Neumann, M., Rabe, M., Meyer, T., Ludolph, A.C.. Pages: 815-817
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Background: Mutations in the FUS/TLS gene have been associated with familial amyotrophic lateral sclerosis (FALS).Methods: We analyzed the presence and frequency of C-terminal FUS/TLS mutations in a German amyotrophic lateral sclerosis (ALS) cohort, including 133 patients with sporadic ALS (SALS) and 58 patients with FALS by sequence analysis of exons 13-15.Results: We identified 2 novel heterozygous FUS/TLS mutations in 4 German ALS families including the novel missense mutation K510R and the truncating mutation R495X. The truncating mutation was associated with an aggressive disease course whereas the K510R mutation showed a mild phenotype with disease duration ranging from 6 to 8 years. No mutation was detected in 133 patients with SALS.Conclusions: Mutations in FUS/TLS account for 7% (4 of 58) of FALS in our German cohort.(C)2010AAN Enterprises, Inc.
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correlates of outcome and response to ivig in 88 patients with multifocal motor neuropathy (cme).
- Cats, E.A., van der Pol, W.-L., MD, PhD, Piepers, S., MD, PhD, Franssen, H., MD, PhD, Jacobs, B.C., MD, PhD, van den Berg-Vos, R.M., MD, PhD, Kuks, J.B., MD, PhD, van Doorn, P.A., MD, PhD, van Engelen, B.G., MD, PhD, Verschuuren, J.J., MD, PhD, Wokke, J.H., MD, PhD, Veldink, J.H., MD, PhD, van den Berg, L.H., MD, PhD. Pages: 818-825
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Objective: Identification and examination of all patients with multifocal motor neuropathy (MMN) in the Netherlands to document the clinical spectrum and response to IV immunoglobulin (IVIg) and to determine correlates of outcome.Methods: A national cross-sectional descriptive study was performed. Ninety-seven patients were identified; 88 participated. Logistic regression analysis was used to study determinants of outcome.Results: Age at onset was younger in men than in women (38 vs 45 years, p = 0.05). Onset of weakness was in distal arm (61%) or distal leg (34%), and occasionally in the upper arm (5%). Initial diagnosis was motor neuron disease in one-third of patients. Brisk, but not pathologic, reflexes in weakened muscles were found in 8%. Conduction blocks were most frequently detected in the ulnar (80%) and median (77%) nerves, but occasionally only between Erb and axilla (6%), or in the musculocutaneous nerve (1%). Ninety-four percent responded to IVIg therapy: nonresponders had longer disease duration before the first treatment (p = 0.03). Seventy-six percent received IVIg maintenance treatment at the time of this study (median duration 6 years; range 0-17): the median dose increased over the years from 12 to 17 g per week (p < 0.01). Independent determinants of more severe weakness and disability were axon loss (p < 0.001; p < 0.0001) and longer disease duration without IVIg (p = 0.03; p = 0.07).Conclusion: The results of this study may help aid recognition the clinical picture of MMN. Early IVIg treatment may help to postpone axonal degeneration and permanent deficits.Classification of evidence: This study provides Class IV evidence that IVIg improves muscle strength of patients with MMN and disability (defined as an increase of >=1 Medical Research Council grade in at least 2 muscle groups without decrease in other muscle groups) in 94% (95% confidence interval, 86.8%-97.4%) of patients.(C)2010AAN Enterprises, Inc.
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docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial (loe classification).
- Paker, A.M., MD, MPH, Sunness, J.S., Brereton, N.H., MS, RD, Speedie, L.J., Albanna, L., Dharmaraj, S., MD, PhD, Moser, A.B., Jones, R.O., Raymond, G.V.. Pages: 826-830
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Objectives: Peroxisome assembly disorders are genetic disorders characterized by biochemical abnormalities, including low docosahexaenoic acid (DHA). The objective was to assess whether treatment with DHA supplementation would improve biochemical abnormalities, visual function, and growth in affected individuals.Methods: This was a randomized, double-blind, placebo-controlled trial conducted at a single center. Treatment groups received supplements of DHA (100 mg/kg per day). The primary outcome measures were the change from baseline in the visual function and physical growth during the 1 year follow-up period.Results: Fifty individuals were enrolled and randomized. Two were subsequently excluded from study analysis when it was determined that they had a single enzyme disorder of peroxisomal [beta] oxidation. Thirty-four returned for follow-up. Nine patients died during the trial of their disorder, and 5 others were lost to follow-up. DHA supplementation was well tolerated. There was no difference in the outcomes between the treated and untreated groups in biochemical function, electroretinogram, or growth. Improvements were seen in both groups in certain individuals.Conclusions: DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders.Classification of evidence: This interventional study provides Class II evidence that DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders during an average of 1 year of follow-up in patients aged 1 to 144 months.(C)2010AAN Enterprises, Inc.
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| Clinical/Scientific Notes |
immune reconstitution inflammatory syndrome after withdrawal of natalizumab? (cme).
- Lenhard, T., Biller, A., Mueller, W., Metz, I., Schonberger, J., Wildemann, B.. Pages: 831-833
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| NeuroImages |
spot sign and live-imaged dramatic intracerebral hematoma expansion.
- Bermejo, P., Garcia, J., Perez-Fernandez, S., Arenillas, J.F., MD, PhD. Pages: 834
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| Video NeuroImages |
dystonic drop foot gait in a patient with manganism (video).
- Janssens, Jules, Vandenberghe, Wim, MD, PhD. Pages: 835
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| Resident & Fellow Section |
teaching video neuroimages: involuntary muscle contractions in hoffman syndrome (video).
- Loomis, Caitlin, Bird, Shawn, Levine, Joshua. Pages: 836
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teaching neuroimages: villaret syndrome.
- de Beer, Frank, Post, Bart, MD, PhD. Pages: e43
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| Correspondence |
what is the risk of permanent disability from a multiple sclerosis relapse?
- Ingram, Gillian, Hirst, Claire, Robertson, Neil. Pages: 837-838
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| Correction |
2010 annual meeting program.
Pages: 839
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| Departments: Book Review |
atlas of clinical sleep medicine.
- Cornelius, Jason. Pages: 840
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| Departments: Calendar |
calendar.
Pages: 841-842
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| Future Issues |
in the next issue of neurology(r): volume 75, number 10, september 7, 2010.
Pages: A26
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