Ganesh M. Babulal

Clinical Features of Alzheimer Disease With and Without Lewy Bodies

IMPORTANCE Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings. OBJECTIVE To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD. DESIGN, SETTING, AND PARTICIPANTS Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging-Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013. EXPOSURES Standardized neuropathologic assessment and then brain autopsy after death. MAIN OUTCOMES AND MEASURES Clinical and neuropsychiatric test scores. RESULTS The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75-9.42] vs 5.49 [1.39] [95% CI, 2.76-8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45-1.17] vs 0.54 [0.18] [95% CI, 0.19-0.88]; P < .001) than did participants who had AD without Lewy bodies. CONCLUSIONS AND RELEVANCE Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.

Mood Changes in Cognitively Normal Older Adults are Linked to Alzheimer Disease Biomarker Levels.

OBJECTIVES To evaluate whether cerebrospinal fluid (CSF) and PET Pittsburgh Compound B (PiB) biomarkers of underlying Alzheimer disease (AD) pathology (β-amyloid42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, ptau181/Aβ42 and mean cortical binding potential [MCBP] for PET-PiB) predict changes in mood in cognitively normal older adults. SETTING Knight Alzheimers Disease Research Center (ADRC) at Washington University (WU). PARTICIPANTS Participants, 65 years of age or older, were enrolled from longitudinal studies at the WU Knight ADRC. MEASUREMENTS CSF, PET-PiB biomarkers, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Profile of Mood States-Short Form (POMS-SF), the Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS Data from 118 participants at baseline and 66 participants at one-year follow-up were analyzed. CSF and PET biomarkers were not associated cross-sectionally with any mood disturbances at baseline (p > 0.05). Changes in mood as indicated by the total mood disturbance score on the POMS-SF, selected POMS-SF subscales, GDS, and NPI-Q scores from baseline to one-year follow-up were associated with (p < 0.05) CSF and PET-PiB biomarkers. There was no statistically significant decline in cognitive functioning. CONCLUSIONS Generally, higher values of CSF and PET-PiB biomarkers are associated with more changes in mood in cognitively normal older adults. Further work is needed to understand the temporal development of mood changes over several years during the phase of preclinical AD. Evaluating mood as a noncognitive outcome may provide further insight into the development of preclinical AD in cognitively normal older adults.

Development and validation of the 34-Item disability screening questionnaire (DSQ-34) for use in low and middle income countries epidemiological and development surveys

Background Although 80% of persons with disabilities live in low and middle-income countries, there is still a lack of comprehensive, cross-culturally validated tools to identify persons facing activity limitations and functioning difficulties in these settings. In absence of such a tool, disability estimates vary considerably according to the methodology used, and policies are based on unreliable estimates. Methods and Findings The Disability Screening Questionnaire composed of 27 items (DSQ-27) was initially designed by a group of international experts in survey development and disability in Afghanistan for a national survey. Items were selected based on major domains of activity limitations and functioning difficulties linked to an impairment as defined by the International Classification of Functioning, Disability and Health. Face, content and construct validity, as well as sensitivity and specificity were examined. Based on the results obtained, the tool was subsequently refined and expanded to 34 items, tested and validated in Darfur, Sudan. Internal consistency for the total DSQ-34 using a raw and standardized Cronbach’s Alpha and within each domain using a standardized Cronbach’s Alpha was examined in the Asian context (India and Nepal). Exploratory factor analysis (EFA) using principal axis factoring (PAF) evaluated the lowest number of factors to account for the common variance among the questions in the screen. Test-retest reliability was determined by calculating intraclass correlation (ICC) and inter-rater reliability by calculating the kappa statistic; results were checked using Bland-Altman plots. The DSQ-34 was further tested for standard error of measurement (SEM) and for the minimum detectable change (MDC). Good internal consistency was indicated by Cronbach’s Alpha of 0.83/0.82 for India and 0.76/0.78 for Nepal. We confirmed our assumption for EFA using the Kaiser-Meyer-Olkin measure of sampling well above the accepted cutoff of 0.40 for India (0.82) and Nepal (0.82). The criteria for Bartlett’s test of sphericity were also met for both India (< .001) and Nepal (< .001). Estimates of reliability from the two countries reached acceptable levels of ICC of 0.75 (p<0.001) for India of 0.77 for Nepal (p<0.001) and good strength of agreement for weighted kappa (respectively 0.77 and 0.79). The SEM/MDC was 0.80/2.22 for India and 0.96/2.66 for Nepal indicating a smaller amount of measurement error in the screen. Conclusions In Nepal and India, the DSQ-34 shows strong psychometric properties that indicate that it effectively discriminates between persons with and without disabilities. This instrument can be used in association with other instruments for the purpose of comparing health outcomes of persons with and without disabilities in LMICs.

Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF A&bgr;42, tau, ptau181, tau/A&bgr;42, ptau181/A&bgr;42). Higher ratios of CSF tau/A&bgr;42, ptau181/A&bgr;42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.

The Accountability–Well-Being–Ethics framework: A new philosophical foundation for occupational therapy: Le cadre Accountability–Well-Being–Ethics : un nouveau fondement philosophique pour l’ergothérapie

Background. The context that supported occupational therapy’s inception has been replaced with new challenges brought on by globalization and dramatic changes in health care. Thus, the profession’s philosophical grounding needs to be reframed to (a) achieve balance between science-driven and holistic elements, (b) operate within larger contexts on problems brought on by sociopolitical and natural determinants of health, and (c) maintain an ethical identity across all arenas of practice. Purpose. This paper presents a brief discussion of the philosophical underpinnings in occupational therapy’s history, outlines new global challenges for the profession, and proposes a new framework to address these challenges through education, practice, and research. Key Issues. Occupational therapy finds itself practising in a growing number of middle- and low-income countries where its roles and values need to be context and culture specific. Implications. The Accountability–Well-Being–Ethics framework guides the three domains of education, research, and practice to be relevant in an increasingly complex world.

Cognitive impairments and mood disruptions negatively impact instrumental activities of daily living performance in the first three months after a first stroke.

Abstract Background: Cognition and mood play crucial roles in post-stroke recovery; however, the stroke literature is unclear as to how impairments in both domains influence performance of instrumental activities of daily living (IADL). Objective: (1) Evaluate the extent to which mood and cognition at two weeks post-stroke predict performance three months post-stroke. (2) Assess performance differences in patients with impairments in both cognition and mood to patients with impairments in either cognition or mood. Methods: Inpatients with a first-ever ischemic or hemorrhagic stroke were assessed at 2 weeks (n = 52) and at 3 months (n = 41) post-stroke. Patients completed a battery of neuropsychological tests, self-report measures and performance-based tests. Cognitive impairments and mood disruptions were assessed at 2 weeks and three months and IADL performance, as assessed by the Executive Function Performance Test, was evaluated at three months. Results: Complete data from the 41 patients assessed at both time points were analyzed. Regression analysis showed that composite cognition and composite mood variables at two weeks post-stroke predicted 48% of the variance in IADL performance at three months (F3,37 = 12.04; adjusted R2 = 0.48, P < 0.001). Statistically significant differences were found in performance scores for patients with a single impairment (M = 7.86, SD = 7.81) and for those with impairments in both mood and cognition (M = 19.2, SD = 13.2) (t(39) = − 3.41, P = 0.008). Conclusion: The results of this study suggest that cognitive and mood impairments at two weeks post-stroke are important predictors of performance in complex activities required for full independence at home and should be routinely assessed in stroke rehabilitation.

Preclinical Alzheimer's disease and longitudinal driving decline

Links between preclinical Alzheimers disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs.

Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research.

Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer’s disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD. Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval. Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation. Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction. However, these devices require strict protocols and controlled testing for adoption into research paradigms. After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD. Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.

A Naturalistic Study of Driving Behavior in Older Adults and Preclinical Alzheimer Disease: A Pilot Study

A clinical consequence of symptomatic Alzheimer’s disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with (n = 10) and without (n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

Association of Functional Impairments and Co-Morbid Conditions with Driving Performance among Cognitively Normal Older Adults

Objectives To examine the relationship between key functional impairments, co-morbid conditions and driving performance in a sample of cognitively normal older adults. Design Prospective observational study Setting The Knight Alzheimer’s Disease Research Center, Washington University at St. Louis Participants Individuals with normal cognition, 64.9 to 88.2 years old (N = 129), with a valid driver’s license, who were currently driving at least once per week, and who had participated in longitudinal studies at the Knight Alzheimer’s Disease Research Center Measurements Static visual acuity, contrast sensitivity, physical frailty measures, motor skills, total medical conditions, and the modified Washington University Road Test. Results When controlling for age, race, gender, APOE, and education the total number of medical conditions was unassociated with both road test scores (pass vs. marginal + fail) and the total driver error count. There were marginal associations of our measure of physical frailty (p = 0.06) and contrast sensitivity score (p = 0.06) with total driving error count. Conclusion Future research that focuses on older adults and driving should consider adopting measures of physical frailty and contrast sensitivity, especially in samples that may have a propensity for disease impacting visual and/or physical function (e.g. osteoarthritis, Parkinson’s, eye disorders, advanced age >80 years, etc.).