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1.  Calibration and validation of an innovative approach for estimating general cognitive performance 
Neuroepidemiology  2014;42(3):144-153.
To evaluate a new approach for creating a composite measure of cognitive function, we calibrated a measure of general cognitive performance from existing neuropsychological batteries.
We applied our approach in an epidemiologic study and scaled the composite to a nationally representative sample of older adults. Criterion validity was evaluated against standard clinical diagnoses. Convergent validity was evaluated against the Mini-Mental State Examination (MMSE).
The general cognitive performance factor was scaled to have a mean=50 and SD=10 in a nationally representative sample of older adults. A cut-point of approximately 45, corresponding with an MMSE of 23/24, optimally discriminated participants with and without dementia (sensitivity=0.94; specificity=0.90; AUC=0.97). The general cognitive performance factor was internally consistent (Cronbach's alpha=0.91) and provided reliable measures of functional ability across a wide range of cognitive functioning. It demonstrated minimal floor and ceiling effects, which is an improvement over most individual cognitive tests.
The cognitive composite is a highly reliable measure, with minimal floor and ceiling effects. We calibrated it using a nationally representative sample of adults over age 70 in the US and established diagnostically relevant cut-points. Our methods can be used to harmonize neuropsychological test results across diverse settings and studies.
PMCID: PMC3988278  PMID: 24481241
dementia; cognitive function; measurement; factor analysis; harmonization; calibration
2.  Physical activity and cognition in the Northern Manhattan Study 
Neuroepidemiology  2013;42(2):100-106.
To test the hypothesis that leisure time PA is associated with cognitive status.
We assessed cognition using the Mini-Mental Status Examination (MMSE) at enrollment, and using the modified Telephone Interview for Cognitive Status (TICS-m) administered annually since 2001 in the Northern Manhattan Study. Baseline measures of leisure-time PA were collected via in-person questionnaires. Total PA was categorized in three groups based on the metabolic equivalent (MET) score, a composite of total reported intensity and time. We used linear regression models to examine the association of PA with MMSE, and generalized estimating equations for change in TICS-m over time.
There were 3298 stroke-free participants with MMSE data (mean MMSE 26.0±3.8) and 2279 with TICS-m scores available. Compared to no PA, those with the upper quartile ofMET-score had greater baseline MMSE scores (adjusted β=0.4,p=0.01) but no association with change in TICS-m over time. There were interactions (p<0.05) between PA and both insurance and education; compared to no PA those in the upper quartile of MET-score had a greater MMSE score only among those with Medicaid/no insurance (adjusted β =0.83,p=0.0005) and those who did not complete high school (adjusted β=0.68, p=0.001).
Increased levels of physical activity were associated with better baseline MMSE, particularly among those with socioeconomic disadvantages, but not with cognitive decline.
PMCID: PMC3942085  PMID: 24335048
physical activity; cognition; dementia
3.  “Essential Tremor” or “the Essential Tremors”: Is This One Disease or a Family of Diseases? 
Neuroepidemiology  2013;42(2):81-89.
There is accumulating evidence that entity referred to as “essential tremor” (ET) is not a single disease. It may be a family of diseases better referred to as “the essential tremors”. This review will summarize the following evidence: (1) the presence of etiological heterogeneity, (2) the heterogeneity of findings in postmortem studies, thus suggesting several diseases, (3) recent discussion that age of onset may be an important marker of disease heterogeneity, (4) clinical expansion of the concept of “ET” in recent years to include a broader range of tremor phenomenology, other motor features (gait ataxia), other involuntary movements (dystonia), and non-motor features (cognitive problems, psychiatric problems), some of which could be primary, (5) heterogeneity of pharmacological response profile and clinical progression, (6) association of ET with Parkinson's disease, Alzheimer's disease and possibly progressive supranuclear palsy, with the possibility that some ET patients are more predisposed to develop one of these.
PMCID: PMC3945103  PMID: 24335621
essential tremor; disease; classification; pathology; genetics; clinical; heterogeneity; neurodegeneration
4.  Yes, It is Time to Reconsider How We Rate Cognitive Impairments in HIV Disease 
Neuroepidemiology  2013;41(0):10.1159/000355128.
PMCID: PMC3872990  PMID: 24157577
5.  Is it time to rethink how neuropsychological tests are used to diagnose mild forms of HIV-associated neurocognitive disorders? Impact of false-positive rates on prevalence and power 
Neuroepidemiology  2013;41(0):208-216.
Between 0–48% of normal HIV-uninfected individuals score below threshold neuropsychological test scores for HIV-associated neurocognitive disorders (HAND), or are false-positives. There has been little effort to understand the effect of varied interpretations of research criteria for HAND on false-positive frequencies, prevalence and analytic estimates.
The proportion of normal individuals scoring below Z-score thresholds drawn from research criteria for HAND, or false-positive frequencies, was estimated in a normal Kenyan population and a simulated normal population using varied interpretations of research criteria for HAND. We calculated the impact of false-positive frequencies on prevalence estimates and statistical power.
False-positive frequencies of 2–74% were observed for Asymptomatic Neurocognitive Impairment/Mild Neurocognitive Disorder and 0–8% for HIV-associated Dementia. False-positive frequencies depended on definition of an abnormal cognitive domain, Z-score thresholds, and neuropsychological battery size. Misclassification led to clinically important overestimation of prevalence and dramatic decreases in power.
Minimizing false-positive frequencies is critical to decrease bias in prevalence estimates and minimize reductions in power in studies of association, particularly for mild forms of HAND. We recommend changing the Z-score threshold to ≤−1.5 for mild impairment, limiting analysis to 3–5 cognitive domains, and using the average Z-score to define an abnormal domain.
PMCID: PMC4019399  PMID: 24157541
Africa; HIV; dementia; prevalence; power
6.  When Do Essential Tremor Patients Develop Head Tremor? Influences of Age and Duration and Evidence of a Biological Clock 
Neuroepidemiology  2013;41(2):10.1159/000351698.
Essential tremor (ET) is a chronic, progressive neurological disease. Head (neck) tremor may eventually develop in as many as 30-60% of patients, yet it is unclear why. Is its appearance merely a function of advancing disease duration? Alternatively, is patient age a primary factor? The latter would argue for the presence of a biological clock that is important for the expression of this clinical feature of ET.
363 ET patients were enrolled in a cross-sectional, clinical-epidemiological study. Each ET patient underwent a 20-minute videotaped neurological examination which included an assessment of the presence/absence of head tremor.
Head tremor was present on examination in 140 (38.6%) patients. Young patients, even with longer duration tremor, rarely had head tremor: 2/27 (7.4%) patients <40 years old with tremor duration ≥10 years had head tremor vs. 121/283 (42.8%) older patients (>60 years old) with tremor duration ≥10 years (p<0.001). In a multivariate logistic regression analysis, while head tremor was associated with age (p<0.001), it was not independently associated with tremor duration (p=0.26); interestingly it was associated with gender in that model (p<0.001). With the exception of one patient, head tremor did not begin before age 36.
Data suggest that the appearance of head tremor in ET depends on a biological factor that is intrinsic to the patient (i.e., age), and is not a clear consequence of advancing disease duration.
PMCID: PMC3808254  PMID: 23860504
essential tremor; clinical; epidemiology; biology; pathophysiology; duration; age; head tremor
7.  What do parents have to do with my cognitive reserve? Life-course perspectives on twelve-year cognitive decline 
Neuroepidemiology  2013;41(2):10.1159/000350723.
To examine the cognitive reserve hypothesis by comparing the contribution of early childhood and life-course factors related to cognitive functioning in a nationally representative sample of older Americans.
We examined a prospective, nationally probability cohort study (Health and Retirement Study HRS; 1998-2010) of older adults (N=8,833) in the contiguous 48 United States. The main cognitive functioning outcome was a 35-point composite of memory (recall), mental status, and working memory tests. The main predictors were childhood socioeconomic position (SEP) and health, and individual-level adult achievement and health.
Individual-level achievement indicators (i.e., education, income, and wealth) were positively and significantly associated with baseline cognitive function, while adult health was negatively associated with cognitive function. Controlling for individual-level adult achievement and other model covariates, childhood health presented a relatively small negative, but statistically significant association with initial cognitive function. Neither individual achievement nor childhood SEP was statistically linked to decline over time.
Cognitive reserve purportedly acquired through learning and mental stimulation across the life-course was associated with higher initial global cognitive functioning over the twelve-year period in this nationally representative study of older Americans. We found little supporting evidence that childhood economic conditions were negatively associated with cognitive function and change, particularly when individual-level achievement is considered.
PMCID: PMC3811933  PMID: 23860477
cognitive reserve; older adults; life-course; development
8.  The timing of tremor: A biological clock in essential tremor? 
Neuroepidemiology  2013;41(2):10.1159/000353212.
PMCID: PMC3831026  PMID: 23860565
9.  Global Epidemiology of Amyotrophic Lateral Sclerosis: a Systematic Review of the Published Literature 
Neuroepidemiology  2013;41(2):118-130.
Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources.
To provide a comprehensive and critical review of the epidemiologic literature on ALS.
MEDLINE and EMBASE (1995–2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods, and incidence and/or prevalence rates. Medians and inter-quartile ranges (IQRs) were calculated, and ALS case estimates derived using 2010 population estimates.
In all, 37 articles met inclusion criteria. In Europe, the median (IQR) incidence rate (/100,000 population) was 2.08 (1.47–2.43), corresponding to an estimated 15,355 (10,852–17,938) cases. Median (IQR) prevalence (/100,000 population) was 5.40 (4.06–7.89), or 39,863 (29,971–58,244) prevalent cases.
Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics, such as age, and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.
PMCID: PMC4049265  PMID: 23860588
Amyotrophic lateral sclerosis; Case ascertainment; Demographics; Diagnostic criteria; Epidemiology; Incidence; Prevalence; Temporal- and age-related trends
10.  Prevalence of Cognitive Impairment No Dementia in a Rural Area of Northern China 
Neuroepidemiology  2014;42(4):197-203.
Few data are available on the prevalence of cognitive impairment no dementia (CIND) in rural China. The aim of this study was to estimate the prevalence of CIND in individuals aged 60 years and older in a large rural community, and to analyze the associated risk factors.
A two-phase, door-to-door epidemiological study was used for residents aged 60 years and older in Ji County, a rural county near Tianjin in Northern China. In phase 1 of the study, the Mini-Mental State Examination and Clinical Dementia Rating were administered for screening purposes. In phase 2, the subjects who screened positive were further examined by neurologists. A total of 5,744 individuals underwent the home visit interview, where demographic variables and comorbidities were recorded; 5,550 individuals completed the two phases. CIND was diagnosed by the Aging, Demographics and Memory Study on CIND criteria. The odds ratio (OR) for each risk factor was calculated by logistic regression analysis.
The prevalence of CIND among those aged 60 years and older was 23.3%. The prevalence of CIND was lower among those with a higher level of education or social involvement. CIND was more prevalent in fe males, older individuals, those with a past history of stroke, and those living without a partner. Significant risk factors were found by multivariate analyses: past history of stroke (OR = 1.889; 95% CI: 1.437–2.483); being female (OR = 1.546; 95% CI: 1.305–1.832); and having no partner (divorced, widowed or single; OR = 1.250; 95% CI: 1.042–1.499). In turn, level of education (OR = 0.560; 95% CI: 0.460–0.681) and engagement in social activities (OR = 0.339; 95% CI: 0.258–0.404) were protective factors.
This is the first large-scale community-based epidemiological study assessing the prevalence of cognitive loss in the rural Chinese population. The total prevalence of CIND observed was 23.3%, which was higher than in other studies in Western and Asian countries. Living without a partner, female gender and previous stroke increased the risk of CIND, whereas a higher level of education and engagement in social activities reduced the risk of CIND.
PMCID: PMC4074439  PMID: 24751796
Cognitive impairment no dementia; China; Prevalence
11.  Adiposity and Cognitive Decline in the Cardiovascular Health Study 
Neuroepidemiology  2013;40(4):274-281.
Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis (BIA), body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.
Cognitive performance was assessed with the modified Mini Mental State Examination (3MS), the Digit Symbol Substitution Test (DSST), and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.
The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.
Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by pre-existing conditions.
PMCID: PMC4044822  PMID: 23445925
adiposity; fat mass; bioelectrical impedance; body mass index; waist circumference; cognition
12.  Age of Onset: Can We Rely on Essential Tremor Patients to Report This? Data from a Prospective, Longitudinal Study 
Neuroepidemiology  2012;40(2):93-98.
Essential tremor (ET) is among the most prevalent neurological diseases. Age of onset, a key variable in neuroepidemiological and genetic research, is chiefly assessed by self-report rather than medical record review; the latter may be of little use. As a researcher, one wonders about the quality of this self-report. Is age of onset something which can be reproducibly self-reported by patients? There are few published data to aid researchers.
Age of onset was self-reported at two time points (baseline and follow-up) in 86 ET cases in a longitudinal epidemiological study in New York.
The mean follow-up interval was 5.7 ± 2.5 (maximum = 14) years. Overall, agreement between the baseline and follow-up reports was high (ρ = 0.85, p < 0.001). Yet the difference (age of onset baseline − age of onset follow-up) ranged widely (from −47 to 32 years), and in one fifth of cases was ≥10 years. Greater agreement was associated with several clinical factors including age, medication use, embarrassment, depressive symptoms, cognitive test score and disease duration.
Differences in reported age of onset in ET may vary widely, and in up to one fifth of patients may be substantial. Investigators should approach these self-reports with caution.
PMCID: PMC4035216  PMID: 23095658
Essential tremor; Epidemiology; Age of onset; Clinical factors; Genetics
13.  Familial Aggregation of Cranial Tremor in Familial Essential Tremor 
Neuroepidemiology  2013;41(1):48-53.
Essential tremor (ET) is often familial and phenotypic features may be shared within families. Cranial (neck, voice, jaw) tremor is an important feature of ET. We examined whether cranial tremor aggregates in ET families, after controlling for other factors (age, tremor severity and duration).
Among ET probands and relatives enrolled in a genetic study at Columbia University (95 subjects in 28 families), we assessed the degree to which occurrence of cranial tremor in the proband predicted occurrence of cranial tremor in affected relatives.
Forty-five (47.4%) subjects had cranial tremor on neurological examination (probands 66.7%, relatives 39.7%). Among 28 families, 23 (82.1%) contained individuals with and individuals without cranial tremor, indicating a high degree of within-family heterogeneity. In comparison to subjects without cranial tremor, those with cranial tremor had higher total tremor scores (p<0.001), were older (p=0.003), and had tremor of longer duration (p=0.01). In logistic regression models, the odds of cranial tremor in a relative was not related to occurrence of cranial tremor in the proband (p>0.24).
Cranial tremor did not aggregate in families with ET; the major predictor of this disease feature was tremor severity rather than presence of cranial tremor in another family member.
PMCID: PMC3770156  PMID: 23712245
essential tremor; genetics; familial; clinical; cranial tremor; head tremor
14.  APOE and Change in Episodic Memory in Blacks and Whites 
Neuroepidemiology  2013;40(3):211-219.
APOE ε4 is related to faster decline in episodic memory in Whites but the relation is unknown in Blacks. The purpose of this study was to determine whether ε4 has a selective effect on decline in episodic memory in Blacks.
Data are from two cohort studies with similar design. The sample consisted of 1,211 participants (28.4% Black, mean age = 78.6 (sd=7.4), education = 14.7 (sd=3.1)) without dementia at baseline, who underwent annual clinical evaluations for up to six years. Summary measures of five cognitive abililites were derived from 18 neuropsychological tests.
In mixed models that controlled for age, sex, education, and race, possession of ε4 (present in 32.9% of Blacks; 21.0% of Whites, p<.001) was related to faster decline in episodic memory and four other cognitive abilities (all p’s <.01). In separate models that examined the interaction of race and ε4 on decline, there was no significant difference between Blacks and Whites in the effect of ε4 on decline in episodic memory, perceptual speed, or visuospatial ability. By contrast, the effect of ε4 differed for semantic memory and working memory. Results were similar after adjusting for vascular conditions.
The results suggest that APOE ε4 is related to a faster rate of decline in episodic memory in Blacks similar to Whites. In addition, there were racial differences in the effect of ε4 in other cognitive abilities such that the ε4 allele was related to faster decline in semantic memory and working memory for Whites but not for Blacks.
PMCID: PMC3645297  PMID: 23364031
15.  Predicting Age of Onset in Familial Essential Tremor: How Much Does Age of Onset Run in Families? 
Neuroepidemiology  2013;40(4):269-273.
The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence it is unclear whether information about age of onset in one family member can be used to predict the age of onset in others.
ET probands and relatives were enrolled in a genetic study at Columbia University.
Data from 26 probands and 52 relatives were analyzed. The probands’ age of onset correlated significantly with their relatives’ age of onset (r=0.50, p=0.001). In 57.7% of cases, the relative’s age of onset was within 10 years of the proband’s onset (i.e., a 20 year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset ≥20 years, (p<0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband.
In families containing multiple individuals with ET, age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset.
PMCID: PMC3718305  PMID: 23363932
essential tremor; genetics; familial; clinical; age of onset
16.  Interleukin 6 Plasma Concentration Associates with Cognitive Decline: The Northern Manhattan Study 
Neuroepidemiology  2013;40(4):253-259.
Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic white and black people who often have a greater prevalence of vascular risk factors and are at elevated risk of dementia. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free race/ethnically diverse community-based sample from Northern Manhattan.
We used mixed effects models to measure the effect of IL-6 on change in performance on the Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors.
There were 1224 participants with IL-6 levels (median 1.5 pg/mL, interquartile range (IQR) 0.83 – 2.57 pg/mL) and TICS-m data available (mean=31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person- and a median 3.0 years of follow-up (IQR 1.1 – 4.0). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β= −0.17 points per year, p=0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (P for interaction <0.001). There was no interaction by race-ethnicity, vascular risk factors, C-reactive protein (CRP), APOE4 allele status, or the metabolic syndrome among non-diabetics.
Interleukin 6 associated with cognitive decline among older participants in this race/ethnically diverse sample independent of other vascular risk factors and CRP.
PMCID: PMC3725587  PMID: 23364322
cognitive decline; cohort studies; Interleukin-6; inflammation
17.  Poor Decision Making is Associated with an Increased Risk of Mortality Among Community-Dwelling Older Persons without Dementia 
Neuroepidemiology  2013;40(4):247-252.
Decision making is thought to be an important determinant of health and well-being across the lifespan, but little is known about the association of decision making with mortality.
Participants were 675 older persons without dementia from the Rush Memory and Aging Project, a longitudinal cohort study of aging. Baseline assessments of decision making were used to predict the risk of mortality during up to 4 years of follow-up.
The mean score on the decision making measure at baseline was 7.1 (SD=2.9, range: 0-12), with lower scores indicating poorer decision making. During up to 4 years of follow-up (mean=1.7 years), 40 (6% of 675) persons died. In a proportional hazards model adjusted for age, sex, and education, the risk of mortality increased by about 20% for each additional decision making error (HR=1.19, 95% CI 1.07, 1.32, p=0.002). Thus, a person who performed poorly on the measure of decision making (score=3, 10th percentile) was about four times more likely to die compared to a person who performed well (score=11, 90th percentile). Further, the association of decision making with mortality persisted after adjustment for the level of cognitive function.
Poor decision making is associated with an increased risk of mortality in old age even after accounting for cognitive function.
PMCID: PMC3760500  PMID: 23364306
18.  Carotid Artery Stenosis as a Cause of Stroke 
Neuroepidemiology  2012;40(1):36-41.
Population-based studies have estimated that ≈15% of ischemic strokes are caused by large vessel cerebrovascular disease. We determined the types of large vessel atherosclerosis responsible for ischemic strokes in a population-based stroke study.
Patients with first-ever or recurrent ischemic stroke in the Greater Cincinnati area were identified during 2005 at all local hospitals. Study physicians assigned ischemic stroke subtypes. Overall event rates and incidence rates for first-ever events were calculated and age, race, and sex-adjusted to the 2000 US population.
There were 2204 ischemic strokes, including 365 strokes of large vessel subtype (16.6% of all ischemic strokes). Extracranial internal carotid artery stenosis was associated with 8.0% of all ischemic strokes, while extracranial internal carotid artery occlusion and intracranial atherosclerosis were each associated with 3.5% of strokes. The annual rate of first-ever and recurrent stroke attributed to extracranial internal carotid stenosis was 13.4 (11.4–15.4) per 100,000 persons. We conservatively estimate that ≈ 41,000 strokes may be attributed to extracranial internal carotid artery stenosis annually in the United States.
Large vessel atherosclerosis is an important cause of stroke, with extracranial internal carotid artery stenosis significantly more common than extracranial internal carotid artery occlusion or intracranial atherosclerotic disease.
PMCID: PMC3626492  PMID: 23075828
carotid stenosis; carotid atherosclerosis; intracranial atherosclerosis; stroke; stroke etiology; epidemiology; carotid occlusion
19.  Antiphospholipid Antibodies, Brain Infarcts, and Cognitive and Motor Decline in Aging (ABICMA): Design of a Community-based, Longitudinal, Clinical-pathological Study 
Neuroepidemiology  2012;40(2):73-84.
The overall goal of the Antiphospholipid antibodies, Brain Infarcts, and Cognitive and Motor decline in Aging study (ABICMA) is to test the hypothesis that antiphospholipid antibodies (aPL) are associated with an increased risk of pathologically-proven brain infarcts and related to cognitive and motor decline in aging. Putative biologic mechanisms underlying the association of aPL with infarcts and the relation of aPL with clinical outcomes of cognitive and motor impairment, including vascular and other processes, will be examined. The design of this longitudinal, clinical-pathologic study involves quantifying four aPL assays, and relating these to brain infarcts, and to cognitive and motor decline. Vascular mechanisms assessed using ante-mortem magnetic resonance neuroimaging and postmortem neuropathology, as well as non-vascular mechanisms of inflammation and blood-brain barrier permeability alterations will be examined as plausible mediators of the relation of aPL to cognitive and motor impairment. We will take advantage of ante-mortem biologic specimens (longitudinally-collected sera and plasma from which aPL, annexins, C-reactive protein, and matrix metalloproteinases will be quantified), and clinical, neuroimaging, and postmortem neuropathologic data from about 800 older, community-dwelling women and men who have agreed to brain autopsy at time of death, participating in one of two ongoing studies of aging: the Religious Orders Study and the Memory and Aging Project.
PMCID: PMC3638838  PMID: 23095514
20.  Association between physical activity and risk of stroke subtypes: The Atherosclerosis Risk in Communities (ARIC) Study 
Neuroepidemiology  2012;40(2):109-116.
The relationship between stroke subtypes and physical activity is unclear.
Using data from 13,069 men and women aged 45-64 years who participated in the Atherosclerosis Risk in Communities (ARIC) Study, physical activity was assessed by self-report using the Baecke questionnaire at baseline (1987-1989). The American Heart Association’s (AHA) ideal cardiovascular health guidelines served as basis for the calculation of three physical activity categories: poor, intermediate, and ideal. Stroke and its subtypes were ascertained from physician review of medical records. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models.
During a median follow-up of 18.8 years, a total of 648 incident ischemic strokes occurred. Significant inverse associations were found between physical activity categories and total, total ischemic, and nonlacunar stroke in adjusted models (age, sex, race-center, education, cigarette-years). Compared with poor physical activity, the adjusted HR (95% CI) for ideal physical activity were 0.78 (0.62, 0.97) for total, 0.76 (0.59, 0.96) for total ischemic, 0.85 (0.51, 1.40) for lacunar, 0.77 (0.47, 1.27) for cardioembolic, and 0.71 (0.51, 0.99) for nonlacunar stroke. Additional adjustments for waist-to-hip ratio, systolic blood pressure, antihypertensive medication, diabetes, left ventricular hypertrophy and laboratory parameters attenuated the HR. Further sex- and race-specific analysis revealed that the association was predominantly observed among males and among African-Americans.
These data suggest a tendency toward a reduced risk of total, total ischemic, and nonlacunar stroke with higher levels of physical activity.
PMCID: PMC3641888  PMID: 23095721
cerebrovascular disease; stroke subtypes; exercise; epidemiology; prevention
22.  Cognition and Incident Dementia Hospitalization: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
Neuroepidemiology  2012;40(2):117-124.
Cognitive decline is a defining feature of dementia. We sought to determine if a single baseline cognitive test score or change in test score over time is more strongly associated with risk of dementia hospitalization. We also sought to compare short- and long-term dementia risk.
Prospective cohort study of 9,399 individuals from the Atherosclerosis Risk in Communities (ARIC) Study (median 10 years follow-up). Cognition was assessed at two time points (6 years apart) using three tests: Delayed Word Recall (DWRT), Digit Symbol Substitution (DSST), and Word Fluency (WFT). Dementia hospitalizations were determined using ICD-9 codes.
Baseline cognitive test scores were associated with both short-term and long-term risk of dementia. The association of 6-year change in cognitive test score with dementia risk was stronger than that of individual test scores at a single visit (change from highest to lowest tertile, DWRT: HR=6.45 (1.80, 23.08), DSST: HR=10.94 (3.07, 38.97)).
In this community-based population, 6-year changes in cognitive scores were more strongly associated with risk of incident dementia hospitalization than baseline scores, although single DWRT and DSST scores at were predictive. Our findings support the contention that cognitive changes may precede clinical dementia by a decade or more.
PMCID: PMC3642775  PMID: 23095770
Cognition; Dementia; Hospitalizations; Cognitive Function; Cognitive Decline
23.  A Systematic Review of Randomized, Double-Blind, Placebo-Controlled Trials Examining the Clinical Efficacy of Vitamin D in Multiple Sclerosis 
Neuroepidemiology  2012;40(3):147-153.
An association between multiple sclerosis (MS) prevalence as well as MS mortality and vitamin D nutrition has led to the hypothesis that high levels of vitamin D could be beneficial for MS. The purpose of this systematic review is to establish whether there is evidence for or against vitamin D in the treatment of MS.
Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the clinical effect of vitamin D on MS in human participants. Data were extracted in a standardized manner and methodological quality was assessed by the Jadad score.
Five trials were located meeting the selection criteria. Of the five trials, four showed no effect of vitamin D on any outcome, and one showed a significant effect, namely upon reduction in the number of T1 enhancing lesions on brain magnetic resonance imaging. Three studies commented on adverse effects of vitamin D, with gastrointestinal adverse effects being the most frequently reported. The literature is limited by small study sizes (studies size ranged from 23 to 68 patients) and heterogeneity of dosing, form of vitamin D tested (vitamin D3 in four trials, and vitamin D2 in one), and outcome clinical measures. Therefore, a meta-analysis was not performed.
The evidence for vitamin D as a treatment for MS is inconclusive. Larger studies are warranted to assess the effect of vitamin D on clinical outcomes in patients with MS. We further encourage researchers to also test the effect of vitamin D on the health-related quality of life experienced by patients and their families.
PMCID: PMC3649517  PMID: 23257784
Multiple sclerosis; treatment; systematic review; vitamin D
24.  Cross-sectional association between polyfluoroalkyl chemicals and cognitive limitation in the National Health and Nutrition Examination Survey (NHANES) 
Neuroepidemiology  2012;40(2):125-132.
Our limited understanding of how polyflouoroalkyl chemicals (PFCs) may impact human health suggests the potential for a protective impact on brain health. This study was designed to explore the association between PFCs and cognitive ability in older adults.
We assessed the association between four PFCs, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), and self-reported limitation due to difficulty remembering or periods of confusion using data from participants aged 60–85 from the 1999–2000 and 2003–2008 National Health and Nutrition Examination Surveys. We also considered whether diabetic status or diabetic medication use modifies this association in light of in vitro evidence that PFCs may act on the same receptors as some diabetic medications.
In multivariable adjusted models, point estimates suggest a protective association between PFCs and self-reported cognitive limitation (OR (95% CI) for a doubling in PFOS, 0.90 (0.78, 1.03); PFOA, 0.92 (0.78, 1.09); PFNA, 0.91 (0.79, 1.04); PFHxS, 0.93 (0.82, 1.06)). The protective association was concentrated in diabetics, with strong, significant protective associations in non-medicated diabetics.
This cross-sectional study suggests that there may be a protective association between exposure to PFCs and cognition in older adults, particularly diabetics.
PMCID: PMC3658136  PMID: 23095808
NHANES; National Health and Nutrition Examination Survey; CDC; Centers for Disease Control; cognitive function; polyfluoroalkyl chemicals; PFCs; epidemiology; risk factor
25.  Can a screening questionnaire accurately identify Mild Parkinsonian Signs? 
Neuroepidemiology  2012;39(3-4):171-175.
Mild Parkinsonian Signs (MPS) are early features that, when present, increase risk of neurodegenerative disease and mortality. Current methods to identify MPS are limited to neurological examination. Our objective was to assess the ability of a 9-item Parkinson’s Disease Screening Questionnaire (PDSQ), which has high sensitivity in the detection of overt Parkinson’s disease (PD), to detect Mild Parkinsonian Signs.
Measures including the PDSQ, Unified Parkinson’s Disease Rating Scale and University of Pennsylvania Smell Identification Test were administered to 267 participants without neurodegenerative disease. Two published definitions of MPS were used to classify cases.
PDSQ scores were higher for cases compared to controls (p < 0.001 for the first case definition and 0.07 for the second). However, the questionnaire had low sensitivity (47 and 59%) and specificity (62 and 63%) in the detection of MPS. Adding factors such as age, gender, and smell test score to the questionnaire in a predictive model only marginally improved the test characteristics.
The results show the screening questionnaire does not accurately identify Mild Parkinsonian Signs. More accurate tests are needed to improve detection of this early syndrome which can lead to motor disability, neurodegenerative disease and mortality.
PMCID: PMC3513756  PMID: 22948126
Mild Parkinsonian Signs; screening questionnaire; validity; sensitivity; specificity

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