Neurology November 2012 Volume 79 Issue 19

Objectives: Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.Methods: We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).Results: Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups ([chi]2(1) = 19.3; p = 1.1 x 10-5), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.Conclusions: GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.GLOSSARY: AD: Alzheimer diseaseADC: Alzheimer disease centerADNCs: Alzheimer disease neuropathologic changesCI: confidence intervalDLB: dementia with Lewy bodiesLBD: Lewy body diseaseLBDNCs: Lewy body disease neuropathologic changesOR: odds ratioPD: Parkinson diseasePDD: Parkinson disease with dementiapDLB: pure dementia with Lewy bodies(C)2012 American Academy of Neurology

Objectives: APOE is related to cholesterol transport and clearance and brain white matter (WM) properties involving myelin, of which cholesterol is a major component. Diffusion tensor imaging enables in vivo investigations of brain WM, and could increase our understanding of the pathways leading to Alzheimer disease. The main objective was to investigate the association between APOE and diffusion tensor imaging-derived indices of WM microstructure.Methods: Healthy participants were assessed on a range of neuropsychological measures, genotyped, and underwent MRI. A total of 203 volunteers (aged 21.1-69.9 years, mean = 47.6, SD = 14.9) with APOE genotypes [epsilon]2/[epsilon]3 (n = 30), [epsilon]3/[epsilon]3 (n = 113), and [epsilon]3/[epsilon]4 (n = 60) were included.Results: There were widespread increases in mean and radial diffusion in carriers of the [epsilon]3/[epsilon]4 alleles compared with [epsilon]3/[epsilon]3 with medium to strong effect sizes (Cohen's d = 0.77-0.79). No interactions between genotype and age were observed, indicating relatively stable differences from early adulthood. The results were independent of presence of dementia in close family. We also observed increased mean and radial diffusion and decreased fractional anisotropy in carriers of the [epsilon]2/[epsilon]3 alleles compared with [epsilon]3/[epsilon]3 carriers. No significant differences were found between [epsilon]2/[epsilon]3 and [epsilon]3/[epsilon]4.Conclusions: APOE affects microstructural properties of the brain WM from early adulthood, but the specific allelic effects do not directly reflect the associated risk of developing Alzheimer disease. The role of APOE in cholesterol transport, the high density of cholesterol in myelin, and the specific effects on radial diffusivity support a putative functional role of APOE in modulating myelin-related processes in the brain.GLOSSARY: AD: Alzheimer diseaseAxD: axial diffusionDTI: diffusion tensor imagingFA: fractional anisotropyFMRIB: Oxford Centre for Functional MRI of the BrainGLM: general linear modelMD: mean diffusionRD: radial diffusionROI: region of interestTBSS: tract-based spatial statisticsWM: white matter(C)2012 American Academy of Neurology

Objectives: To identify the most accurate clinical predictors of fitness to drive (FTDr) in Huntington disease (HD).Methods: This cross-sectional study included 60 active drivers: 30 patients with manifest HD (8 women) and 30 age- and gender-matched healthy controls. Mean (SD) age of the HD group was 50 (12) years and median (Q1-Q3) disease duration was 24 (12-48) months. A clinical battery consisting of a driving history questionnaire, the cognitive section of the Unified Huntington's Disease Rating Scale (UHDRS), Trail Making Test, and Mini-Mental State Examination, as well as a driving simulator evaluation, were administered to all participants. Additionally, the subjects with HD completed the motor, behavioral, and Total Functional Capacity sections of the UHDRS and underwent an official FTDr evaluation comprising visual, neuropsychological, and on-road tests. The blinded neurologist's appraisal of FTDr and the 3 most predictive clinical tests were compared with the official pass/fail FTDr decision.Results: The patients with HD performed worse on all tests of the clinical battery and driving simulator than the healthy controls. Fifteen patients with HD (50) failed the FTDr evaluation. The blinded neurologist correctly classified 21 patients (70%). The Symbol Digit Modalities Test, Stroop word reading, and Trail Making Test B provided the best model (R2 = 0.49) to predict FTDr, correctly classifying 26 patients (87%).Conclusions: Half of active drivers with HD fail a driving evaluation and pose a potential hazard on the road. Our results suggest that those at risk can be accurately identified using a clinical screening tool.GLOSSARY: AD: Alzheimer diseaseCARA: Center for Evaluation of FTDr and Car AdaptationsCDR: Clinical Dementia RatingCI: confidence intervalDA: divided attentionFTDr: fitness to driveHD: Huntington disease[kappa]w: weighted [kappa]LVFT: Letter Verbal Fluency TaskPD: Parkinson diseaseSDMT: Symbol Digit Modalities TestTFC: Total Functional CapacityTMT: Trail Making TestUHDRS: Unified Huntington's Disease Rating Scale(C)2012 American Academy of Neurology

Objective: There is concern that do-not-resuscitate (DNR) orders may lead to stroke patients receiving less aggressive treatment and poorer care. Our objectives were to assess the relationship between DNR orders and quality of stroke care among veterans.Methods: A cohort of 3,965 acute ischemic stroke patients admitted to 131 Veterans Health Administration (VHA) facilities in fiscal year 2007 underwent chart abstraction. DNR codes were identified through electronic orders or by documentation of "no code," "no cardiopulmonary resuscitation," or "no resuscitation." Quality of care was measured using 14 inpatient ischemic stroke quality indicators. The association between DNR orders and quality indicators was examined using multivariable logistic regression.Results: Among 3,965 ischemic stroke patients, 535 (13.5%) had DNR code status, 71% of whom had orders first documented within 1 day of admission. Overall, 4.9% of patients died in-hospital or were discharged to hospice; these outcomes were substantially higher in patients with DNR orders (29.7%), particularly if they were not documented until >=2 days after admission (47.1%). Patients with DNR orders were significantly older, had more comorbidities, and had greater stroke severity. Following adjustment there were few significant associations between DNR status and the 14 quality indicators, with the exception of lower odds of early ambulation (odds ratio = 0.58, 95% confidence interval = 0.41-0.81) in DNR patients.Conclusions: DNR orders were associated with limited differences in the select quality indicators investigated, which suggests that DNR orders did not impact quality of care. However, whether DNR orders influence treatment decisions that more directly affect survival remains to be determined.GLOSSARY: AF: atrial fibrillationAPACHE III: modified Acute Physiology and Chronic Health EvaluationCMO: comfort measures onlyDNR: do-not-resuscitateFY: fiscal yearHD: hospital dayNIHSS: NIH Stroke ScaleOQP: Office of Quality and PerformanceQI: quality indicatortPA: tissue plasminogen activatorVHA: Veterans Health Administration(C)2012 American Academy of Neurology