Neurology October 2012 Volume 79 Issue 15

Objective: Intake of fruits and vegetables and levels of serum carotenoids have been associated with decreased risk of stroke, but the results have been inconsistent. The aim of the present study was to examine whether serum concentrations of major carotenoids, [alpha]-tocopherol and retinol, are related to any stroke and ischemic stroke in men.Methods: The study population consisted of 1,031 Finnish men aged 46-65 years in the Kuopio Ischaemic Heart Disease Risk Factor cohort. Serum concentrations of carotenoids retinol and [alpha]-tocopherol were measured by high-performance liquid chromatography. The association between the serum concentrations of lycopene [alpha]-carotene, [beta]-carotene, [alpha]-tocopherol, and retinol and the risk of strokes was studied by using Cox proportional hazards models.Results: A total of 67 strokes occurred, and 50 of these were ischemic strokes during a median of 12.1 follow-up years. After adjustment for age, examination year, BMI, systolic blood pressure, smoking, serum low-density lipoprotein cholesterol, diabetes, and history of stroke, men in the highest quartile of serum lycopene concentrations had 59% and 55% lower risks of ischemic stroke and any stroke, compared with men in the lowest quartile (hazard ratio [HR] = 0.45, 95% confidence interval [CI] 0.25-0.95, p = 0.036 for any stroke and HR = 0.41; 95% CI 0.17-0.97, p = 0.042 for ischemic stroke). [alpha]-Carotene, [beta]-carotene, [alpha]-tocopherol, and retinol were not related to the risk of strokes.Conclusions: This prospective study shows that high serum concentrations of lycopene, as a marker of intake of tomatoes and tomato-based products, decrease the risk of any stroke and ischemic stroke in men.GLOSSARY: BMI: body mass indexCI: confidence intervalFINMONICA: Finnish part of Monitoring of Trends and Determinants in Cardiovascular DiseasesHPLC: high-performance liquid chromatographyHR: hazard ratioICD-9: International Classification of Diseases, 9th revisionKIHD: Kuopio Ischaemic Heart Disease Risk FactorLDL: low-density lipoproteinROS: reactive oxygen speciesSBP: systolic blood pressure(C)2012 American Academy of Neurology

Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB).Methods: Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined.Results: We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region.Conclusions: SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS.GLOSSARY: AD: Alzheimer diseaseALS: amyotrophic lateral sclerosisFTLD: frontotemporal lobar degenerationHD: Huntington diseasePD: Parkinson diseasePDB: Paget disease of boneSQSTM1: sequestosome 1 gene(C)2012 American Academy of Neurology

Objectives: Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.Methods: A total of 483 cognitively normal (CN) individuals, aged 70-92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)-PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70-79 and 80-89) to identify 100 participants with PiB >1.4 or >1.5.Results: A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ~0.6-0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE [epsilon]4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70-79 and 33% in those aged 80-89.Conclusions: Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.GLOSSARY: AD: Alzheimer diseaseAUROC: area under the receiver operating characteristic curveAVLT: Auditory Verbal Learning TestBNT: Boston Naming TestCI: confidence intervalCN: cognitively normalIQR: interquartile rangeMCSA: Mayo Clinic Study of AgingMMSE: Mini-Mental State ExaminationNPV: negative predictive valueOR: odds ratioPiB: Pittsburgh compound BPPV: positive predictive valueROI: region of interestTMT: Trail Making TestWAIS-R: Wechsler Adult Intelligence Scale-RevisedWMS-R: Wechsler Memory Scale-Revised.(C)2012 American Academy of Neurology

Objective: This study was undertaken to investigate the association of auditory threshold with cognitive decline and dementia.Methods: The 1,057 surviving men of the Caerphilly cohort with audiometric data at baseline were followed for 17 years for cognitive outcomes. Pure-tone unaided audiometric threshold was assessed at 0.5, 1, 2, and 4 KHz at baseline and after 9 years. Incident dementia was assessed according to DSM-IV criteria, including standard criteria for vascular dementia and for Alzheimer disease. Cognitive decline was assessed by repeat administration of a cognitive test battery.Results: Mean age-adjusted auditory threshold across both time points was associated with incident dementia and cognitive decline. After adjustment for premorbid cognitive function, the association with dementia was retained (odds ratio0.5 KHz = 2.67; 95% confidence interval, 1.38-5.18; p = 0.004). Stronger associations with cognitive decline were found for tests administered by interview than for those administered by computer.Conclusions: This study has found an association of auditory threshold with dementia and cognitive decline over a 17-year period. The mechanisms underlying this association are unclear and may include a prodromal effect of dementia on auditory threshold, an effect of auditory threshold on cognitive assessment, an effect of auditory threshold on cognitive loss, or a shared etiologic pathway between both.GLOSSARY: AH4: Alice Heim test, part 1CaPS: Caerphilly Prospective StudyCIND: cognitive impairment not dementiadBA: unaided pure-tone binaural thresholdDSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th editionMMSE: Mini-Mental State ExaminationNART: National Adult Reading TestNINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders AssociationNINCDS-AIREN: National Institute of Neurological and Communicative Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en NeurosciencesPTA: pure-tone average threshold.(C)2012 American Academy of Neurology

Objectives and Methods: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011.Results: Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 +/- 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).Conclusions: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.GLOSSARY: 3MSE: Modified Mini-Mental State ExaminationAD: Alzheimer diseaseBVRT: Benton Visual Retention TestCES-D: Center for Epidemiology Studies Depression ScaleCHS-CS: Cardiovascular Health Study-Cognition StudyCN: cognitively normalDQ: Dementia QuestionnaireDSST: Digit Symbol Substitution TestIADLs: instrumental activities of daily livingIQ CODE: Informant Questionnaire for Cognitive Decline in the ElderlyMCI: mild cognitive impairmentpy: person-years(C)2012 American Academy of Neurology

Objective: Neuroleptics and neuroleptic-like drugs are known to induce parkinsonism, which may reveal underlying Parkinson disease (PD) in some cases. We assessed the long-term risk of developing PD after past exposure to these drugs, in a 15-year prospective population-based elderly cohort study.Methods: We used the Cox proportional hazards model to assess the relation between past exposure to neuroleptics and the risk of developing incident PD. All incident cases of parkinsonism were identified by standardized procedure and validated by a committee of experts.Results: Of 2,991 subjects followed, 117 developed parkinsonism and 43 developed probable PD during follow-up, of whom 22.2% and 32.6%, respectively, had been exposed to neuroleptics, compared to 16.6% for subjects without parkinsonism. About a third of subjects presented transient parkinsonism during drug exposure. After adjustment for gender and past occupation, past exposure to neuroleptics was associated with incident PD (relative risk, 3.16; 95% confidence interval [CI], 1.65-6.04). The relative risk was 3.65 (95% CI, 1.41-9.45) for benzamides and 2.59 (95% CI, 1.23-5.43) for phenothiazines. The population-attributable fraction of the risk for developing PD was 8.2% for benzamides and 12.2% for phenothiazines.Conclusions: In a French elderly cohort, the risk of probable PD was increased by 3.2-fold after exposure to neuroleptics. This finding suggests the necessity of limiting the use of such drugs in elderly people.GLOSSARY: CI: confidence intervalDIP: drug-induced parkinsonismPAF: population attributable fractionPD: Parkinson diseaseRR: relative riskUKPDSBB: United Kingdom PD Society Brain Bank(C)2012 American Academy of Neurology