Design and Feasibility Analysis of a Smartphone-Based Digital Cognitive Assessment Study in the Framingham Heart Study.

BACKGROUND: Smartphone-based digital technology is increasingly being recognized as a cost-effective, scalable, and noninvasive method of collecting longitudinal cognitive and behavioral data. Accordingly, a state-of-the-art 3-year longitudinal project focused on collecting multimodal digital data for early detection of cognitive impairment was developed. METHODS AND RESULTS: A smartphone application collected 2 modalities of cognitive data, digital voice and screen-based behaviors, from the FHS (Framingham Heart Study) multigenerational Generation 2 (Gen 2) and Generation 3 (Gen 3) cohorts. To understand the feasibility of conducting a smartphone-based study, participants completed a series of questions about their smartphone and app use, as well as sensory and environmental factors that they encountered while completing the tasks on the app. Baseline data collected to date were from 537 participants (mean age=66.6 years, SD=7.0; 58.47% female). Across the younger participants from the Gen 3 cohort (n=455; mean age=60.8 years, SD=8.2; 59.12% female) and older participants from the Gen 2 cohort (n=82; mean age=74.2 years, SD=5.8; 54.88% female), an average of 76% participants agreed or strongly agreed that they felt confident about using the app, 77% on average agreed or strongly agreed that they were able to use the app on their own, and 81% on average rated the app as easy to use. CONCLUSIONS: Based on participant ratings, the study findings are promising. At baseline, the majority of participants are able to complete the app-related tasks, follow the instructions, and encounter minimal barriers to completing the tasks independently. These data provide evidence that designing and collecting smartphone application data in an unsupervised, remote, and naturalistic setting in a large, community-based population is feasible.

A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores.

BACKGROUND: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. METHODS: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. RESULTS: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10-9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10-8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10-8). GRN (rs5848, P = 4.21 × 10-8) and PURG (rs117523305, P = 1.73 × 10-8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10-8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10-9) and PTPRD (rs145989094, P = 8.34 × 10-9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10-8) and PTPRD (rs145989094, P = 3.85 × 10-8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. CONCLUSION: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Is dietary choline intake related to dementia and Alzheimer's disease risks? Results from the Framingham Heart Study.

BACKGROUND: The positive association of choline for cognition has been reported in both animal and human studies, yet the associations of choline with the risks of incident dementia or Alzheimer's disease (AD) in humans is unclear. OBJECTIVES: Our objective was to test the hypothesis that lower or higher dietary choline intake is associated with increased or decreased, respectively, risks of incident dementia and AD. METHODS: Data from the Framingham Heart Study Offspring Cohort exam 5 to exam 9 were used. Participants were free of dementia and stroke, with a valid self-reported 126-item Harvard FFQ at exam 5. The intakes of total choline, its contributing compounds, and betaine were estimated based on a published nutrient database. The intakes were updated at each exam to represent the cumulative average intake across the 5 exams. The associations between dietary choline intakes and incident dementia and AD were examined in mixed-effect Cox proportional hazard models, adjusting for covariates. RESULTS: A total of 3224 participants (53.8% female; mean ± SD age, 54.5 ± 9.7 y) were followed up for a mean ± SD of 16.1 ± 5.1 y (1991-2011). There were 247 incident dementia cases, of which 177 were AD. Dietary choline intake showed nonlinear relationships with incident dementia and AD. After adjusting for covariates, low choline intake (defined as ≤ 219 and ≤ 215 mg/d for dementia and AD, respectively) was significantly associated with incident dementia and incident AD. CONCLUSIONS: Low choline intake was associated with increased risks of incident dementia and AD.

Neuropsychological Criteria for Mild Cognitive Impairment in the Framingham Heart Study's Old-Old.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. METHODS: A total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. RESULTS: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. CONCLUSIONS: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.

Population Normative Data for the CERAD Word List and Victoria Stroop Test in Younger- and Middle-Aged Adults: Cross-Sectional Analyses from the Framingham Heart Study.

BACKGROUND/STUDY CONTEXT: To provide baseline normative data on tests of verbal memory and executive function for nondemented younger- and middle-aged adults. METHODS: The Consortium to Establish a Registry for Alzheimer's Disease word list memory task (CERAD-WL) and Victoria Stroop Test (VST) were administered to 3362 Framingham Heart Study (FHS) volunteer participants aged 24-78 years. Analyses of the effects of age, gender, and education were conducted. Normative data on traditional measures and error responses are reported for each test. RESULTS: Traditional measures were significantly associated with both age and education in this cohort. Error responses also evidenced significant age and education effects. CONCLUSION: These data provide a normative comparison for assessment of verbal memory and executive functioning capabilities in younger- and middle-aged adults and may be utilized as a tool for preclinical studies of disease in this population.

Qualitative neuropsychological measures: normative data on executive functioning tests from the Framingham offspring study.

UNLABELLED: BACKGROUND/STUDY CONTEXT: Studies have found that executive functioning is affected early in the pathophysiological processes associated with Alzheimer's disease and vascular dementia. There also exists a range of functioning on executive tasks during normal aging. Although qualitative data are commonly utilized in clinical practice for evaluating subtle changes in cognitive functioning and diagnostic discernment, it is not clear whether error responses used in clinical practice are also evident as normative behavior. METHODS: As part of an extensive battery of neuropsychological tests, executive functioning measures (i.e., Trail Making Test Part B, Similarities and Verbal Fluency tests) were administered via standardized administration prescript. Regression analyses were used to determine associations between vascular aging indices and qualitative performance measures. Descriptive statistics are included for 1907 cognitively normal individuals. RESULTS: Results suggest that although qualitative errors do occur, they are relatively infrequent within a presumably cognitively normal sample. Error commission rates on executive functioning tests are significantly associated with both age and education. CONCLUSION: Provided is a baseline profile of errors committed on tests of executive function across a range of age and educational levels. The normative data sets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations.

The Framingham Heart Study clock drawing performance: normative data from the offspring cohort.

UNLABELLED: BACKGROUND/STUDY CONTEXT: Although the Clock Drawing Test (CDT) is a popular tool used to assess cognitive function, limited normative data on CDT performance exist. The objective of the current study was to provide normative data on an expanded version of previous CDT scoring protocols from a large community-based sample of middle to older adults (aged 43 to 91) from the Framingham Heart Study. METHODS: The CDT was administered to 1476 Framingham Heart Study Offspring Cohort participants using a scoring protocol that assigned error scores to drawn features. Total error scores were computed, as well as for subscales pertaining to outline, numeral placement, time-setting, center, and "other." RESULTS: Higher levels of education were significantly associated with fewer errors for time-setting (Command: p < .001; Copy: p = .003), numerals (Command: p < .001), and "other" (Command: p < .001) subscales. Older age was significantly associated with more errors for time-setting (Command: p < .001; Copy: p = .003), numerals (Command: p < .001), and "other" (Command: p < .001) subscales. Significant differences were also found between education groups on the Command condition for all but the oldest age group (75+). CONCLUSION: Results provide normative data on CDT performance within a community-based cohort. Errors appear to be more prevalent in older compared with younger individuals, and may be less prevalent in individuals who completed at least some college compared with those who did not. Future studies are needed to determine whether this expanded scoring system allows detection of preclinical symptoms of future risk for dementia.

MRI and neuropsychological correlates of carbon monoxide exposure: a case report.

A 45-year-old woman experienced long-term, chronic exposure to carbon monoxide in the restaurant kitchen where she was employed as a cook. After returning to the restaurant after 5 days off work, she noticed that her symptoms returned immediately; she then aired out the room and called the gas company. Approximately 6 hr after a leak was detected, the patient went to the hospital, where her carboxyhemoglobin was found to be within normal limits and results of a neurologic examination were described as normal. Based on her symptoms, the patient believed she had been exposed to CO for at least 1 year before the leak was discovered. Initially, she experienced flu-like symptoms, which eventually resolved. At the time of her first neuropsychological evaluation (17 months after the exposure was identified), her persisting complaints included difficulties in reading, writing, speaking and word retrieval. The test results were consistent with secondary frontal lobe dysfunction associated with subcortical disorders such as those seen after CO exposure. Results of a subsequent neuropsychological examination (29 months postexposure) showed slight improvement in performance, but her performance was still consistent with mild frontal/subcortical dysfunction. Although the initial screening of a brain magnetic resonance image (MRI) performed 15 months after the exposure was interpreted as being within normal limits, two subsequent blind reviews of the same scans identified multiple bilateral lesions in the basal ganglia, which were consistent with chronic CO exposure. We present this case as an example of the utility of MRI and neuropsychological examinations in detecting central nervous system dysfunction secondary to CO exposure.