Methods: We used a pre- and post-test design with an educational intervention in between using neurology residents at the University of Iowa as subjects. Each test had 40 questions of research methodology. The educational intervention consisted of a biweekly, structured, topic-centered, research methodology-oriented elective seminar following a year-long predefined curriculum. An exit survey was offered to gather resident’s perceptions about the course.

Results: While a majority of residents agreed that the intervention enhanced their knowledge of research methodology, only 23% attended more than 40% of the sessions. There was no difference between pretest and post-test scores (p = 0.40).

Conclusions: Our experience suggests that, in order to accomplish the Accreditation Council for Graduate Medical Education goals regarding increasing competency of residents in knowledge about research methodology, a major restructuring in the neurology residency curriculum with more intense formal training would be necessary.

Methods: We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects.

Results: Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls.

Conclusion: These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Methods: Indirect immunofluorescence screening of sera from 130,000 patients performed on a service basis for markers of paraneoplastic neurologic autoimmunity identified 80 patients whose IgG bound to the synapse-rich molecular layer of mouse cerebellar cortex in a pattern consistent with VGKC immunoreactivity. Antibody specificity was confirmed in all cases by immunoprecipitation of detergent-solubilized brain synaptic proteins complexed with ¹²⁵I-alpha-dendrotoxin.

Results: Clinical information was available for 72 patients: 51% women, median age at symptom onset 65 years, and median follow-up period 14 months. Neurologic manifestations were acute to subacute in onset in 71% and multifocal in 46%; 71% had cognitive impairment, 58% seizures, 33% dysautonomia, 29% myoclonus, 26% dyssomnia, 25% peripheral nerve dysfunction, 21% extrapyramidal dysfunction, and 19% brainstem/cranial nerve dysfunction. Creutzfeldt-Jakob disease was a common misdiagnosis (14%). Neoplasms encountered (confirmed histologically in 33%) included 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies. Hyponatremia was documented in 36%, other organ-specific autoantibodies in 49%, and a co-existing autoimmune disorder in 33% (including thyroiditis 21%, type 1 diabetes mellitus 11%). Benefit was reported for 34 of 38 patients (89%) receiving immunotherapy and was marked in 50%.

Conclusions: The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized. Evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders.

Methods: We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls.

Results: Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (<70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2, 95% CI 4.6–71.7, p < 0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5–0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects.

Conclusions: In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges.

Methods: This study uses functional MRI to investigate blood oxygenation level dependent changes in the parietal lobe in a high-risk sample of 18 asymptomatic offspring of autopsy-confirmed AD cases, compared to 15 matched controls. The cognitive activation paradigm was a mental rotation task, which requires individuals to rotate three-dimensional cube stimuli to judge their similarity.

Results: We found no differences in either reaction time or performance accuracy between groups. However, the at-risk individuals showed increases in activation in the right superior parietal lobule (BA 7), the right insula (BA 13), the right middle frontal gyrus (BA 10), and the right inferior frontal gyrus (BA 47).

Conclusions: We present evidence for a compensatory mechanism for those at increased risk for Alzheimer disease (AD). This study examines and confirms parietal changes with increased risk for late-onset AD, despite normal cognitive performance. Added to the previous findings from this group, these results demonstrate the sensitivity of functional imaging measures to brain changes that are not yet reflected in cognitive performance, which may ultimately serve as an important indicator of disease.

Background: Obesity is a risk factor for headache "chronification." Adiponectin (ADP) is an adipocytokine secreted primarily by adipose tissue. ADP and its oligomers (high-molecular-weight [HMW], middle-molecular-weight [MMW], and low-molecular-weight [LMW] ADP) have been shown to modulate several inflammatory pathways that have also been shown to be associated with migraine pathophysiology.

Methods: Age- and body mass index (BMI)-matched women participants were enrolled. Anthropometric measures (including waist-to-hip ratio [WHR] and BMI) were measured in all participants. Serum total ADP (T-ADP) levels and its oligomers were measured in EMs during headache-free periods and CDH sufferers at baseline level of pain, as compared with healthy control subjects using ELISA.

Results: Although total body obesity as estimated by BMI showed no significant association between participants, visceral obesity as estimated by WHR was significantly associated with CDH as compared with EMs and controls. WHR was also inversely related to both T-ADP (p = 0.008) and HMW-ADP (p = 0.002). After adjusting for WHR, serum T-ADP levels were higher in CDH sufferers (10.1 ± 4.0) than in both EMs (8.6 ± 3.5) and controls (7.5 ± 2.4) (p = 0.024). In addition, HMW-ADP was higher in CDH (6.1 ± 2.8) as compared with EMs (4.2 ± 1.7) and controls (3.9 ± 1.5) (p = 0.003). MMW-ADP was also higher in CDH (2.0 ± 1.2) as compared with EMs (1.5 ± 0.7) and controls (1.1 ± 0.4) (p = 0.009).

Conclusion: Serum adiponectin levels are increased in women chronic daily headache (CDH) sufferers. In addition, visceral obesity, as measured by waist-to-hip ratio, is a risk factor for CDH in women.

Methods: We studied 2,051 participants age 65+ years at 27 AD Centers who died and underwent autopsy. All took the Mini-Mental State Examination (MMSE) within 2 years before death. Braak & Braak stage, neuritic plaque density, and Consortium to Establish a Registry for Alzheimer’s Disease and National Institute on Aging (NIA)/Reagan diagnostic classifications quantified AD neuropathologic severity. Multivariate analyses modeled MMSE in relation to education and neuropathologic severity, adjusting for age at death, Lewy body pathology, and vascular dementia.

Results: Higher education was associated with higher MMSE scores when AD neuropathology was absent or mild. But with more advanced neuropathology, differences in MMSE scores among education levels were attenuated. For example, among patients without AD by NIA/Reagan criteria, fitted MMSE scores ranged from 19.6 for patients with less than high school education to 25.9 with education beyond high school. But among patients with neuropathologically advanced AD, the range of scores by education was only 7.1 to 8.6.

Conclusions: We found no evidence of larger education-related differences in cognitive function when Alzheimer disease (AD) neuropathology was more advanced. Higher Mini-Mental State Examination scores among more educated persons with mild or no AD may reflect better test-taking skills or cognitive reserve, but these advantages may ultimately be overwhelmed by AD neuropathology.

Methods: We studied 46 subjects with aMCI who progressed to AD (labeled aMCI-P), 46 CN, and 23 aMCI-S. All subjects must have had three or more serial MRI scans. Rates of brain shrinkage and ventricular expansion were measured across all available serial MRI scans in each subject. Change in volumes relative to the point at which subjects progressed to a clinical diagnosis of AD (the index date) was modeled in aMCI-P. Change in volumes relative to age was modeled in all three clinical groups.

Results: In aMCI-P the change in pre to post index rate (i.e., acceleration) of ventricular expansion was 1.7 cm³/year, and acceleration in brain shrinkage was 5.3 cm³/year. Brain volume declined and ventricular volume increased in all three groups with age. Volume changes decelerated with increasing age in aMCI-P, and to a lesser extent in aMCI-S, but were linear in the matched CN. Among all subjects with aMCI, rates of atrophy were greater in apolipoprotein E 4 carriers than noncarriers.

Conclusions: Rates of atrophy accelerate as individuals progress from amnestic mild cognitive impairment (aMCI) to typical late onset Alzheimer disease (AD). Rates of atrophy are greater in younger than older subjects with aMCI who progressed to AD and subjects with aMCI who did not progress. We did not find that atrophy rates varied with age in 70- to 90-year-old cognitively normal subjects.

Methods: Levels of nitric oxide, nitrate, and 3-nitrotyrosine (3-NT)–modified proteins were measured in the CSF of 46 patients with HIV infection stratified according to their neurocognitive status and history of IV drug use (IVD). The 3-NT–modified proteins were isolated and identified by tandem mass spectrometry, and the functional consequence of 3-NT modification of l-prostaglandin D synthase (l-PGDS), the most abundant protein, was determined.

Results: 3-NT–modified proteins were significantly elevated in patients with HIV infection who had progressive neurocognitive decline over the next 6 months and in patients with a history of IVD. Thirteen different proteins with 3-NT modification were identified in the CSF of these patients. l-PGDS was the most abundant. 3-NT modification of this protein resulted in loss of its enzymatic activity.

Conclusions: There is increased nitrosative stress in CSF of HIV-infected patients with active dementia and in patients with a history of IV drug use, measurement of which may serve as a surrogate marker for these patients. Nitrosative stress may also have important functional consequences and may impact the pathogenesis of HIV-associated neurocognitive disorders.

Background: Two ERP components, the P600 and N400, are sensitive to abnormal episodic/declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity.

Methods: Patients with amnestic MCI (n = 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD converters (within 3 years) vs nonconverters, using split-plot analyses of variance.

Results: A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F = 9.9, p = 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood.

Conclusions: Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.

Method: We compared 4+ and 4– individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members.

Results: Compared with 4– individuals, 4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, 4 carriers had higher general cognitive ability than 4– individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability.

Conclusions: Small, but significant, APOE-4-related memory deficits appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.

Methods: A total of 1,435 persons without dementia aged 75+ from the Kungsholmen Project were evaluated for occurrence of dementia over 9 years. A total of 1,070 cognitively unimpaired subjects were also followed using amnestic mild cognitive impairment (aMCI) and other cognitive impairment, no dementia (OCIND) definitions. To correct the observed incidence rates for attrition due to death, cognitive status for subjects lost due to death was imputed using information on previous cognitive and health status. Observed and corrected incidence rates (IR) and 95% CIs were calculated with the person-years method, using Poisson distribution.

Results: Incidence rates per 1,000 person-years were as follows: dementia IR = 70.4 (64.0 to 77.4); aMCI observed IR = 11.4 (8.6 to 15.1), corrected IR = 13.7 (10.3 to 18.2); OCIND observed IR = 33.8 (28.7 to 39.8), corrected IR = 42.1 (36.5 to 48.6). Both aMCI and OCIND incidence increased with advancing age. Observed incidence of aMCI and OCIND together was similar to that of dementia at age 75 to 79 but lower at more advanced ages. However, the cognitive impairment incidence after age 79 increased substantially when the estimates were corrected for attrition due to death during follow-up.

Conclusions: Non-dementia cognitive impairment is common and often underestimated in population studies that do not adjust for attrition.

Methods: Data are from a prospective population-based cohort of 749 Italian subjects aged 65 and older who, in 1999/2000, were cognitively normal at an extensive assessment for clinically overt and preclinical dementia and, in 2003/2004, underwent follow-up for incident dementia. Baseline physical activity was measured as energy expenditure on activities of different intensity (walking, stair climbing, moderate activities, vigorous activities, and total physical activity).

Results: Over 3.9 ± 0.7 years of follow-up there were 86 incident dementia cases (54 AD, 27 VaD). After adjustment for sociodemographic and genetic confounders, VaD risk was significantly lower for the upper tertiles of walking (hazard ratio [HR] 0.27, 95% CI 0.12 to 0.63), moderate (HR 0.29, 95% CI 0.12 to 0.66), and total physical activity (HR 0.24, 95% 0.11 to 0.56) compared to the corresponding lowest tertile. The association persisted after accounting for vascular risk factors and overall health status. After adjustment for sociodemographic and genetic confounders, AD risk was not associated with measures of physical activity and results did not change after further adjustment for vascular risk factors and overall health and functional status.

Conclusions: In this cohort, physical activity is associated with a lower risk of vascular dementia but not of Alzheimer disease. Further research is needed about the biologic mechanisms operating between physical activity and cognition.

Methods: Participants were 929 older Catholic clergy (68.7% women, mean baseline age 74.9 years, education 18.2 years, Mini-Mental State Examination 28.5) free of dementia, enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of AD. All agreed to brain autopsy at time of death and underwent annual structured clinical evaluations, allowing for classification of AD and assessment of cognition (based on 19 neuropsychological tests). Statins were identified by direct medication inspection. Neuropathologic data were available on 262 participants. All macroscopic chronic cerebral infarctions were recorded. A measure of global AD pathology was derived from silver stain, and separate measures of amyloid and tangles were based on immunohistochemistry. We examined the relation of statins to incident AD using Cox proportional hazards, change in cognition using mixed effects models, and pathologic indices using logistic and linear regression.

Results: Statin use at baseline (12.8%) was not associated with incident AD (191 persons, up to 12 follow-up years), change in global cognition, or five separate cognitive domains (all p values > 0.20). Statin use any time prior to death (17.9%) was not related to global AD pathology. Persons taking statins were less likely to have amyloid (p = 0.02). However, among those with amyloid, there was no relation of statins to amyloid load. Statins were not related to tangles or infarction.

Conclusions: Overall, statins were not related to incident Alzheimer disease (AD) or change in cognition, or continuous measures of AD pathology or infarction.

Methods: Participants (n = 1,036) included individuals with an assessment of intelligence based on Armed Services testing in early adulthood. In late adulthood, these individuals completed the modified Telephone Interview for Cognitive Status (TICS-m) and occupational history as part of an epidemiologic study of aging and dementia. Occupational history was coded to produce a matrix of job characteristics. Based on factor analysis, job characteristics were interpreted as reflecting general intellectual demands (GI), human interaction and communication (HC), physical activity (PA), and visual attention (VA).

Results: Based on regression analysis of TICS-m score covarying for age, intelligence, and years of education, higher levels of GI and HC were independently associated with higher TICS-m performance, whereas higher PA was independently associated with lower performance. There was an interaction of GI and intelligence, indicating that individuals at the lower range of intellectual aptitude in early adulthood derived greater cognitive benefit from intellectually demanding work.

Conclusions: Intellectually demanding work was associated with greater benefit to cognitive performance in later life independent of related factors like education and intelligence. The fact that individuals with lower intellectual aptitude demonstrated a stronger positive association between work and higher cognitive performance during retirement suggests that behavior may enhance intellectual reserve, perhaps even years after peak intellectual activity.

Methods: Randomized, placebo-controlled, double-blind, 42-month pilot study with 118 cognitively intact subjects randomized to standardized GBE or placebo. Kaplan-Meier estimation, Cox proportional hazard, and random-effects models were used to compare the risk of progression from Clinical Dementia Rating (CDR) = 0 to CDR = 0.5 and decline in episodic memory function between GBE and placebo groups.

Results: In the intention-to-treat analysis, there was no reduced risk of progression to CDR = 0.5 (log-rank test, p = 0.06) among the GBE group. There was no less of a decline in memory function among the GBE group (p = 0.05). In the secondary analysis, where we controlled the medication adherence level, the GBE group had a lower risk of progression from CDR = 0 to CDR = 0.5 (HR = 0.33, p = 0.02), and a smaller decline in memory scores (p = 0.04). There were more ischemic strokes and TIAs in the GBE group (p = 0.01).

Conclusions: In unadjusted analyses, Ginkgo biloba extract (GBE) neither altered the risk of progression from normal to Clinical Dementia Rating (CDR) = 0.5, nor protected against a decline in memory function. Secondary analysis taking into account medication adherence showed a protective effect of GBE on the progression to CDR = 0.5 and memory decline. Results of larger prevention trials taking into account medication adherence may clarify the effectiveness of GBE. More stroke and TIA cases observed among the GBE group requires further study to confirm.

Methods: A total of 2,798 subjects were followed as part of the Cardiovascular Health Cognition Study for an average of 5.4 years; 480 developed dementia. Knee height was measured 3 years prior to and arm span 4 years after the study’s baseline. Cox proportional hazard models were used to examine their association with subsequent risk of dementia, AD, and VaD.

Results: Among women, greater knee height and arm span were associated with lower risks of dementia (knee height: HR per 1-inch increase 0.84; 95% CI 0.74–0.96; arm span: HR per 1-inch increase 0.93; 95% CI 0.88–0.98) and AD (knee height: HR per 1-inch increase 0.78; 95% CI 0.65–0.93; arm span: HR per 1-inch increase 0.90; 95% CI 0.85–0.96). Women in the lowest quartile of arm span had ~1.5 times greater risk of dementia (HR 1.45; 95% CI 1.03–2.05) and AD (HR 1.70; 95% CI 1.10–2.62) than other women. Among men, only arm span was associated with lower risks of dementia (HR per 1-inch increase 0.94; 95% CI 0.89–1.00) and AD (HR per 1-inch increase 0.92; 95% CI 0.84–1.00). For each gender, knee height was not associated with VaD, while arm span was associated with a nonsignificant lower risk of VaD.

Conclusions: Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk.

Background: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations.

Methods: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (Aβ₄₂). Patients also were assessed with a brief neuropsychological battery.

Results: CSF total tau level and the ratio of CSF total tau to Aβ₄₂ (tau/Aβ₄₂) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/Aβ₄₂ ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD.

Conclusions: The ratio of CSF tau/Aβ₄₂ is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Methods: We recruited 65 patients with Alzheimer disease (mean ± SD age 70 ± 8 y, 58% women, Mini-Mental State Examination [MMSE] 22 ± 5), scanned with an average interval of 1.7 ± 0.6 years. Whole-brain atrophy rates were used as outcome measure. Baseline normalized brain volume, hippocampal volume, and whole-brain atrophy rates were measured using three-dimensional T1-weighted imaging. The influence of age, sex, apolipoprotein E genotype (APOE), baseline MMSE, baseline hippocampal volume, and baseline normalized brain volume on whole-brain atrophy rates was assessed using linear regression.

Results: The mean whole-brain atrophy rate was –1.9 ± 0.9% per year. In the multivariate model, younger age (β [SE] = 0.03 [0.01]; p = 0.04), absence of APOE 4 (β [SE] = 0.61 [0.28]; p = 0.03), and a low MMSE (β [SE] = 0.11 [0.03]; p < 0.001) were associated with a higher whole-brain atrophy rate. Furthermore, a relatively spared hippocampus predicted faster decline for patients with a smaller baseline brain volume (p = 0.09), and with a lower MMSE (p = 0.07). Finally, a smaller brain volume was associated with a higher rate of atrophy in younger patients (p = 0.03).

Conclusions: Our results suggest it is possible to characterize a subgroup of patients with Alzheimer disease (AD) who are at risk of faster loss of brain volume. Patients with more generalized, rather than focal hippocampal atrophy, who often have an onset before the age of 65, and are APOE 4 negative, seem to be at risk of faster whole-brain atrophy rates than the more commonly seen patients with AD, who are older, are APOE 4 positive, and have pronounced hippocampal atrophy.

Methods: Individuals were recruited from two longitudinal cohort studies—the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)—and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of 4 status in each sample.

Results: The presence of at least one 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses.

Conclusion: APOE 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.

Methods: Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls.

Results: Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity.

Conclusions: The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.

Methods: We investigated the effect of treatment of hypertension on cognition with the angiotensin-receptor-blocker, candesartan, in a placebo-controlled, double-blind, randomized controlled trial at one center participating in the Study on Cognition and Prognosis in the Elderly. A total of 257 older adults with hypertension (mean age 76 years, blood pressure 165 ± 8/88 ± 7 mm Hg) were recruited from general practice and treated with 8–16 mg candesartan or placebo once daily, for a mean follow-up period of 44 months. Additional antihypertensive therapy was permitted in both groups to achieve treatment targets. Cognitive function was measured using the Cognitive Drug Research computerized assessment battery, trail-making tests, and verbal fluency. Data from annual assessments were used to calculate individual coefficients of decline by regressing composite test scores over time for five cognitive domains.

Results: The blood pressure difference between groups at study close was 8/3 mm Hg. The candesartan group showed less decline in attention (0.004 vs –0.036, p = 0.04) and episodic memory (0.14 vs –0.22, p = 0.04) compared to placebo, a similar trend for speed of cognition (–2.3 vs –17.4, p = 0.15), but no differences in working memory (0.0014 vs 0.0010, p = 0.90) or executive function (–0.0031 vs –0.0023, p = 0.95). Effect sizes were in the small-to-moderate range.

Conclusions: The potential for blood pressure–lowering with angiotensin-receptor-blockers to reduce the rate of decline of specific areas of cognitive function in older patients with hypertension warrants further investigation to determine clinical efficacy.

Objective: To report the efficacy and tolerance of GK radiosurgery in MTLE after a follow-up > 5 years.

Methods: Patients with a follow-up > 5 years presenting with MTLE and treated with a marginal dose of 24 Gy were included in the study.

Results: Fifteen patients were included. Eight were treated on the left side, and 7 were treated on the right. The mean follow-up was 8 years (range 6–10 years). At the last follow-up, 9 of 16 patients (60%) were considered seizure free (Engel Class I) (4/16 in Class IA, 5/16 in Class IB). Seizure cessation occurred with a mean delay of 12 months (± 3) after GK radiosurgery, often preceded by a period of increasing aura or seizure occurrence (6/15 patients). The mean delay of appearance of the first neuroradiologic changes was 12 months (± 4). Nine patients (60%) experienced mild headache and were placed on corticosteroid treatment for a short period. All patients who were initially seizure free experienced a relapse of isolated aura (10/15, 66%) or complex partial seizures (10/15, 66%) during antiepileptic drug tapering. Restoration of treatment resulted in good control of seizures.

Conclusion: Gamma knife radiosurgery is an effective and safe treatment for mesial temporal lobe epilepsy. Results are maintained over time with no additional side effects. Long-term results compare well with those of conventional surgery.

Methods: We determined the plasma Aβ1-40 and Aβ1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998–1999 and repeated the measurements in 2002–2003. The mean age of the subjects at baseline was 79.3 ± 3.6 years. We examined the association between Aβ levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts.

Results: In an unadjusted prospective model in normal subjects, both Aβ1-40 and Aβ1-42 levels in 1998–1999 were associated with incident AD (n = 55) in 2002–2003 (longitudinal analysis). In the fully adjusted multivariate model, neither Aβ1-42 nor Aβ1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for Aβ1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002–2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD.

Conclusions: Plasma Aβ levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, Aβ-40 and Aβ1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of Aβ do not seem to be useful biomarkers for AD.

Methods: Cases were veterans aged 55 years and older with incident AD using the US Veterans Affairs Health Care system. Matched controls were drawn from the same population. NSAID exposure was categorized into seven time periods: no use, ≤1 year, >1 but ≤2 years, and so on. Using conditional logistic regression, adjusted for race and comorbidities, we tested the association between AD development and the use of 1) any NSAID, 2) any NSAID excluding nonacetylated salicylates, 3) each NSAID class, 4) each individual NSAID, and 5) Aβ_1-42-suppressing NSAIDs.

Results: We identified 49,349 cases and 196,850 controls. Compared with no NSAID use, the adjusted odds ratios for AD among NSAID users decreased from 0.98 for ≤1 year of use (95% CI 0.95–1.00) to 0.76 for >5 years of use (0.68–0.85). For users of ibuprofen, it decreased from 1.03 (1.00–1.06) to 0.56 (0.42–0.75). Effects of other NSAID classes and individual NSAIDs were inconsistent. There was no difference between a group of Aβ_1-42-suppressing NSAIDs and others.

Discussion: Long-term nonsteroidal anti-inflammatory drug (NSAID) use was protective against Alzheimer disease. Findings were clearest for ibuprofen. Aβ_1-42-suppressing NSAIDs did not differ from others.

Methods: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined.

Results: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations.

Conclusion: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Methods: Using a population-based, cohort design, baseline cigarette smoking habits were assessed in 3,348 participants in an epidemiologic study in Spain, among whom 77 developed incident ET.

Results: There were 3,348 participants, among whom 397 (11.9%) were smokers at baseline. Five (6.5%) of 77 incident ET cases had been smokers at baseline, compared with 392 (12.0%) of 3,271 controls (p = 0.14). Baseline pack-years were lower in incident ET cases than in controls (9.2 ± 17.7 vs 15.7 ± 28.4, p = 0.002). Participants were stratified into baseline pack-year tertiles, and few incident ET cases were in the highest tertile (4 [5.2%] cases vs 431 [13.2%] controls, p = 0.039). In Cox proportional hazards models, the highest baseline pack-year tertile was associated with lower risk of incident ET; those in the highest pack-year tertile were one-third as likely to develop ET when compared with nonsmokers (relative risk [RR] 0.37, 95% CI 0.14–1.03, p = 0.057 [unadjusted model] and RR 0.29, 95% CI 0.09–0.90, p = 0.03 [adjusted model]).

Conclusions: We demonstrated an association between baseline heavy cigarette smoking and lower risk of incident essential tremor. The biologic basis for this association requires future investigation.

Methods: We assessed a random sample of 112 of the more than 1,000 current NINDS-sponsored clinical research studies to determine which could involve community physicians in enrollment or follow-up. Scoring factors were based on the premise that participation is feasible for noninvasive studies with simple screening, and follow-up criteria and visit frequency consistent with usual care. Scored studies included 26 Phase III, 31 Phase I/II, and 55 nonclinical trials.

Results: Overall, 41% of the sampled research studies were considered conducive to community physician participation that exceeds referral only; 21% with participation in all study activities and 20% with ability to provide some follow-up. Specialized neuropsychological or neurologic scale testing was judged to exclude community physician participation in 16% of studies.

Conclusion: Many National Institute of Neurological Disorders and Stroke studies are available in which community-based physicians could participate. Involving community physicians may increase efficiency of completing clinical research and encourage application of research findings in community practices.

Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and spasticity. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I–IV).

Results: The highest quality literature available for the respective indications was as follows: adult spasticity (14 Class I studies); spastic equinus and adductor spasticity in pediatric cerebral palsy (six Class I studies).

Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of spasticity in adults and children (Level A).

Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I–IV).

Results: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies).

Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I–IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context.

Results: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies).

Recommendations: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians’ practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.