Methods: We performed extensive characterization by array-based copy number assessment (aCGH), HIPK2 copy number analysis, and BRAF rearrangement and mutation analysis in a set of 79 PAs, including 9 tumors from patients with neurofibromatosis type 1 (NF1).

Results: We identified 1 of 3 previously identified BRAF rearrangements in 42/70 sporadic PAs. An additional 2 tumors with no rearrangement also exhibited BRAF mutation, including a novel 3-base insertion. As predicted from the genomic organization at this locus, 22/36 tumors with BRAF rearrangement also exhibited corresponding HIPK2 amplification. However, 14/36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification and 6/20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12/70 PAs lacked detectable BRAF or HIPK2 alterations. Importantly, none of the 9 PA tumors from NF1 patients exhibited BRAF rearrangement or mutation.

Conclusions: BRAF rearrangement represents the most common genetic alteration in sporadic, but not neurofibromatosis type 1-associated, pilocytic astrocytomas (PAs). These findings implicate BRAF in the pathogenesis of these common low-grade astrocytomas in children, and suggest that PAs arise either from NF1 inactivation or BRAF gain of function.

Methods: A case-control study of handwriting samples from children with and without autism spectrum disorders (ASD) was performed using the Minnesota Handwriting Assessment. Samples were scored on an individual letter basis in 5 categories: legibility, form, alignment, size, and spacing. Subjects were also tested on the Wechsler Intelligence Scale for Children–IV and the Physical and Neurological Examination for Subtle (Motor) Signs.

Results: We found that children with ASD do indeed show overall worse performance on a handwriting task than do age- and intelligence-matched controls. More specifically, children with ASD show worse quality of forming letters but do not show differences in their ability to correctly size, align, and space their letters. Within the ASD group, motor skills were significantly predictive of handwriting performance, whereas age, gender, IQ, and visuospatial abilities were not.

Conclusions: We addressed how different elements of handwriting contribute to impairments observed in children with autism. Our results suggest that training targeting letter formation, in combination with general training of fine motor control, may be the best direction for improving handwriting performance in children with autism.

Methods: The placebo arms of 2 clinical trials were analyzed. One cohort consisted of 548 patients with relapsing-remitting (RR) MS enrolled in a 14-month, randomized, double-blind, placebo-controlled trial of oral glatiramer acetate. The second cohort consisted of 358 patients with secondary progressive (SP) MS still experiencing relapses enrolled in a 3-year, randomized, double-blind, placebo-controlled trial of interferon beta-1b.

Results: At baseline, T2LV was associated with disease duration (p < 0.001), age at MS onset (p < 0.001), and disability (p < 0.001). The relationship between baseline T2LV and Expanded Disability Status Scale (EDSS) was not significantly different between patients with RRMS and SPMS. At a multivariate analysis, T2LV change was associated with the number of on-trial relapses (p < 0.001) and age at MS onset (p = 0.02). The correlations of T2LV change with baseline EDSS and EDSS changes were not significant.

Conclusions: We showed that the plateauing relationship between T2 lesion volume and disability in multiple sclerosis is not always present and is likely due to the reduced frequency of "inflammatory" events in the most common form of secondary progressive multiple sclerosis.

Methods: Women in the Nurses’ Health Study (n = 121,700) and Nurses’ Health Study II (n = 116,671) provided information on weight at age 18 and weight and height at baseline, from which body mass index was derived. Women also selected silhouettes representing their body size at ages 5, 10, and 20. Over the total 40 years of follow-up in both cohorts combined, we confirmed 593 cases of MS. Cox proportional hazards models, adjusting for age, latitude of residence, ethnicity, and cigarette smoking, were used to estimate the rate ratios and 95% confidence intervals (CI).

Results: Obesity at age 18 (body mass index ≥30 kg/m²) was associated with a greater than twofold increased risk of MS (multivariate relative risk_pooled = 2.25, 95% CI: 1.50-3.37, p trend <0.001). After adjusting for body size at age 20, having a large body size at ages 5 or 10 was not associated with risk of MS, whereas a large body size at age 20 was associated with a 96% increased risk of MS (95% CI: 1.33-2.89, p trend = 0.009). No significant association was found between adult body mass and MS risk.

Conclusions: Obese adolescents have an increased risk of developing multiple sclerosis (MS). Although the mechanisms of this association remain uncertain, this result suggests that prevention of adolescent obesity may contribute to reduced MS risk.

25(OH)D = 25-hydroxyvitamin D; BMI = body mass index; CI = confidence interval; MS = multiple sclerosis; NHS = Nurses’ Health Study; NHSII = Nurses’ Health Study II; RR = relative risk.

Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.

Results: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV– patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/µL at PML diagnosis compared to 67% in those with CD4 >200/µL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.

Conclusions: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

CE = contrast enhancement; CI = confidence interval; CTL = cytotoxic T-lymphocytes; HR = hazard ratio; IQR = interquartile range; IRIS = immune reconstitution inflammatory syndrome; JCV = JC virus; PBMC = peripheral blood mononuclear cells; PML = progressive multifocal leukoencephalopathy.

Methods: Thirty-two years of longitudinal body weight, BMI, waist circumference, and waist-to-hip ratio (WHR) data, from the Prospective Population Study of Women in Sweden, were related to dementia. A representative sample of 1,462 nondemented women was followed from 1968 at ages 38-60 years, and subsequently in 1974, 1980, 1992, and 2000, using neuropsychiatric, anthropometric, clinical, and other measurements. Cox proportional hazards regression models estimated incident dementia risk by baseline factors. Logistic regression models including measures at each examination were related to dementia among surviving participants 32 years later.

Results: While Cox models showed no association between baseline anthropometric factors and dementia risk, logistic models showed that a midlife WHR greater than 0.80 increased risk for dementia approximately twofold (odds ratio 2.22, 95% confidence interval 1.00-4.94, p = 0.049) among surviving participants. Evidence for reverse causality was observed for body weight, BMI, and waist circumference in years preceding dementia diagnosis.

Conclusions: Among survivors to age 70, high midlife waist-to-hip ratio may increase odds of dementia. Traditional Cox models do not evidence this relationship. Changing anthropometric parameters in years preceding dementia onset indicate the dynamic nature of this seemingly simple relationship. There are midlife and late-life implications for dementia prevention, and analytical considerations related to identifying risk factors for dementia.

ADCVD = AD with cerebrovascular disease; BMI = body mass index; DBP = diastolic blood pressure; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; HAAS = Honolulu Asia Aging Study; PPSW = Prospective Population Study of Women; SBP = systolic blood pressure; SES = socioeconomic status; VaD = vascular dementia; WHR = waist-to-hip ratio.

Methods: A subset of 20 nondemented older adults was drawn from the Einstein Aging Study, a community-based sample from the Bronx, NY. Pain was measured on 3 time scales: 1) acute pain right now (pain severity); 2) pain over the past 4 weeks (Short Form–36 Bodily Pain); 3) chronic pain over the past 3 months (Total Pain Index). Hippocampal data included volume data normalized to midsagittal area and N-acetylaspartate to creatine ratios (NAA/Cr).

Results: Smaller hippocampal volume was associated with higher ratings on the Short Form–36 Bodily Pain (r_s = 0.52, p = 0.02) and a nonsignificant trend was noted for higher ratings of acute pain severity (r_s = –0.44, p = 0.06). Lower levels of hippocampal NAA/Cr were associated with higher acute pain severity (r_s = –0.45, p = 0.05). Individuals with chronic pain had a nonsignificant trend for smaller hippocampal volumes (t = 2.00, p = 0.06) and lower levels of hippocampal NAA/Cr (t = 1.71, p = 0.10).

Conclusions: Older adults who report more severe acute or chronic pain have smaller hippocampal volumes and lower levels of hippocampal N-acetylaspartate/creatine, a marker of neuronal integrity. Future studies should consider the role of the hippocampus and other brain structures in the development and experience of pain in healthy elderly and individuals with Alzheimer disease.

Methods: Voxel-based morphometry (VBM) was used to assess atrophy in 14 PCA, 10 LPA, and 16 EO-AD patients compared to 65 healthy controls. Genetic analysis for APOE was conducted in 30 patients and 44 controls. Four patients came to autopsy. An additional 14 were studied with the beta-amyloid specific PET with tracer ¹¹C-labeled Pittsburgh Compound-B (PIB).

Results: VBM results demonstrated that, compared to controls, each patient group showed a large area of overlapping atrophy in bilateral parietal, occipital, precuneus, posterior cingulate, posterior temporal, and hippocampal regions. Surrounding this common area, group-specific atrophy was found in small, symptom-specific regions for each group: the right ventral-occipital and superior parietal regions in PCA, the left middle and superior temporal gyri in LPA, and the prefrontal cortex in EO-AD. APOE 4 frequency was higher in all patient groups compared to controls. Four PCA, 5 LPA, and 8 EO-AD patients showed evidence of cortical amyloid at pathology (n = 3) or on PIB-PET (n = 14).

Conclusions: Logopenic progressive aphasia and posterior cortical atrophy showed largely overlapping anatomic and biologic features with early age at onset of Alzheimer disease, suggesting that these clinical syndromes represent the spectrum of clinical manifestation of the nontypical form of Alzheimer disease that presents at an early age.

AD = Alzheimer disease; CBD = corticobasal degeneration; EO-AD = early age at onset of Alzheimer disease; LPA = logopenic progressive aphasia; MAC = Memory and Aging Center; PCA = posterior cortical atrophy; PIB = Pittsburgh Compound-B; PPA = primary progressive aphasia; UCSF = University of California San Francisco; VBM = voxel-based morphometry.

Methods: Forty-eight individuals (75% of the contacted sample) agreed to participate in the current study and were instructed to complete electronic interviews using a personal digital assistant 5 times per day over a 1-week period.

Results: More than 80% of programmed assessments were completed by the sample, and no evidence was found for fatigue effects. Expected patterns of associations were observed among daily life variables, and data collected through ambulatory monitoring were significantly correlated with standard clinic-based measures of similar constructs.

Conclusion: Support was found for the feasibility and validity of computerized ambulatory monitoring with stroke patients. The application of these novel methods with stroke patients should provide complementary information that is inaccessible to standard hospital-based assessments and permit increased understanding of the significance of clinical results and test scores for daily life experience.

DSM-IV-R = Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised; EMA = ecologic momentary assessment; ESM = experience sampling method; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; MMSE = Mini-Mental State Examination; PDA = personal digital assistant; SE = standard error.

Methods: Data were collected in 12 centers across 10 countries in America, Asia, and Europe. In addition to the NMSS, the following measures were applied: Scales for Outcomes in Parkinson’s Disease (SCOPA)-Motor, SCOPA-Psychiatric Complications (SCOPA-PC), SCOPA-Cognition, Hoehn and Yahr Staging (HY), Clinical Impression of Severity Index for Parkinson’s Disease (CISI-PD), SCOPA-Autonomic, Parkinson’s Disease Sleep Scale (PDSS), Parkinson’s Disease Questionnaire–39 items (PDQ-39), and EuroQol–5 dimensions (EQ-5D). NMSS acceptability, reliability, validity, and precision were analyzed.

Results: Four hundred eleven patients with PD, 61.3% men, were recruited. The mean age was 64.5 ± 9.9 years, and mean disease duration was 8.1 ± 5.7 years. The NMSS score was 57.1 ± 44.0 points. The scale was free of floor or ceiling effects. For domains, the Cronbach coefficient ranged from 0.44 to 0.85. The intraclass correlation coefficient (0.90 for the total score, 0.67–0.91 for domains) and Lin concordance coefficient (0.88) suggested satisfactory reproducibility. The NMSS total score correlated significantly with SCOPA-Autonomic, PDQ-39, and EQ-5D (r_S = 0.57–0.70). Association was close between NMSS domains and the corresponding SCOPA–Autonomic domains (r_S = 0.51–0.65) and also with scales measuring related constructs (PDSS, SCOPA-PC) (all p < 0.0001). The NMSS total score was higher for women (p < 0.02) and for increasing disease duration, HY, and CISI-PD severity level (p < 0.001). The SEM was 13.91 for total score and 1.71 to 4.73 for domains.

Conclusion: The Non-Motor Symptoms Scale is an acceptable, reproducible, valid, and precise assessment instrument for nonmotor symptoms in Parkinson disease.