Jerri D. Edwards, Ph.D. - US grants

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) affects about 1 million individuals in the United States. In addition to the typical motor dysfunction, PD also affects cognition and vision, even in early stages of the disease, impairing instrumental activities of daily living such as driving. Reduced cognitive speed of processing, or bradyphrenia, strongly contributes to cognitive decline in PD. Recent research has demonstrated that interventions can enhance cognitive speed of processing, protect against further cognitive decline, and improve the everyday functioning of relatively healthy, older adults. However, the potential of such training techniques to enhance cognitive functions among subpopulations with different disease states, such as PD, has not been thoroughly investigated. The proposed study will further examine the feasibility and test the efficacy of a well-established cognitive training tool among individuals in the early stages of PD who have not been diagnosed with dementia. A variety of factors have been found to influence cognitive performance among persons with PD and may moderate their ability to benefit from cognitive training such as age at disease onset, disease duration, manifestiation, severity, and medication use as well as concomitant depression. These factors along with demographic variables will be evaluated as moderators of training benefit. Baseline cognitive assessments will be completed among seventy-five individuals with PD who will be randomized to cognitive training or a treatment-delayed control condition. The efficacy of training to immediately enhance cognitive functioning will be evaulated through a post-training (or equivalent delay) assessment. Disease and demographic factors that may impact the efficiacy of cognitive training for persons with PD will be examined in relation to training gains. Considering that cognitive function among individuals with PD is a strong predictor of everyday functioning and subsequent need for long term care, enhancing cognitive function of individuals with PD through training has great potential to prolong such persons'productivity, independence, and quality of life. The information gained from this study will be useful for identifying individuals with PD who are most likely to benefit from cognitive training as well as the development, refinement, and implementation of appropriate cognitive interventions for this population. PUBLIC HEALTH RELEVANCE: Parkinson's disease affects about 1 million individuals in the United States. The proposed study will pilot test the feasibility of using cognitive speed of processing training among persons with Parkinson's disease to improve cognitive functioning. Enhancing cognitive function of individuals with Parkinson's disease through training has great potential to prolong such persons'productivity, independence, and quality of life.

PROJECT SUMMARY Different cognitive intervention approaches have been developed to attenuate decline (e.g., cognitive engage- ment, training, or stimulation), but it is not clear which approaches are efficacious. It is also not clear when, along the continuum of normal cognitive aging to mild cognitive impairment (MCI-a transitional stage before dementia onset), it is most effective to intervene. Crucially, the underlying mechanisms of effective cognitive in- terventions are not known; a critical barrier to progress in this field. There is an urgent need to identify effective approaches to curb the increasing prevalence of dementia. The overall objective is to apply the best cognitive interventions to attenuate cognitive and functional decline and curb dementia prevalence. The long-term goals are to promote maintained health and independence among older adults. [This randomized clinical trial will de- termine the efficacy of a novel cognitive engagement intervention approach (intense piano training) as com- pared to cognitive stimulation (which will serve as a stringent, active control)]. Grounded in theory, the central hypothesis is that interventions enhancing central auditory processing (CAP), a strong, longitudinal predictor of MCI and dementia, will improve cognition. Music training is increasingly recognized as a feasible means to at- tenuate age-related cognitive decline. Prior research and our preliminary data suggest that intense piano train- ing may enhance CAP and is likely more effective than cognitive stimulation. [Correlational studies indicate su- perior CAP, executive function, and other cognitive abilities for adults with formal music training compared to non-musicians. Our results across three pilot randomized trials show that piano training improves older adults' CAP and executive function, including those with MCI]. The specific aims of the study are to examine the effi- cacy of intense piano training relative to cognitive stimulation (active controls) to improve CAP, cognition, and everyday function among older adults with and without MCI. The efficacy of piano training will be established and moderating effects of MCI status will be examined. The proposed study further aims to elucidate the un- derlying mechanisms of effective cognitive intervention approaches by exploring mediators of training gains. Study outcomes will be identification of effective intervention approaches to attenuate age-related cognitive and functional decline and elucidation of the mechanisms. The proposed study is innovative, in our opinion, as the first phase II randomized trial of piano training to enhance older adults' cognition. Moreover, this study is innovative by including older individuals with and without MCI and assessing effects on everyday functional performance. Most importantly, to advance this field, we will use mediation analyses to elucidate the underlying mechanisms of intervention effects. The contributions will be significant, advancing our understanding of how cognitive interventions produce cognitive and functional change. Results will facilitate improved design and im- plementation of effective interventions to attenuate cognitive decline and curb the prevalence of dementia, thereby improving public health.

PROJECT SUMMARY Dementia is the most expensive medical condition in the US and is a risk factor for nursing home admission. More than a million older adults reside in nursing homes in the US. This number will increase as our older adult population rapidly expands. Thus, innovative approaches to reducing dementia incidence, subsequent nursing home admissions, and associated costs are urgently needed. Increasing evidence indicates that sensory/per- ceptual and motor declines are early markers of dementia, and may be ideal therapeutic targets. Along these lines, recent analyses demonstrate that older adults randomized to perceptual/cognitive training (i.e., useful field of view training- UFOVT) are up to 48% less likely to develop dementia. Across 18 randomized clinical trials UFOVT demonstrates numerous benefits including improved motor, cognitive, and everyday function, prolonged health and well-being, and reduced projected healthcare expenditures. Thus, it is likely that UFOVT has clinically-meaningful public health benefits. However, no study has quantified the effects of UFOVT on the clinical diagnosis of dementia, rates of nursing home admission, or actual healthcare cost. Our overall objectives are to 1) elucidate the longitudinal contributions of sensory/perceptual, cognitive, and motor function to dementia and related outcomes; and 2) quantify the longitudinal effects of UFOVT on dementia diagnosis, nursing home admission rates, and associated cost. Our central hypothesis is that sensory/perceptual and motor difficulties precede the cognitive and functional impairments that are the hallmarks of dementia. Thus, targeting early perceptual processing may be an ideal approach to reduce dementia risk. Data from a large sample of older adults enrolled in two randomized trials of UFOVT (i.e., SKILL and Accelerate studies) will be linked to data from the Center for Medicare and Medicaid Services (CMS). These two NIH-funded studies included 1475 community-dwelling older adults who completed thorough sensory/perceptual, motor, and cognitive assessments. Participants were randomized to UFOVT or an active control condition and followed over three years. The proposed project will add objective health outcomes to the existing cohort data including diagnosis of dementia, nursing home admissions, permanent nursing home placements, and healthcare utilization and cost outcomes spanning 10 years. The resulting data will equip us to examine novel predictors of dementia and evaluate the sustainability of UFOVT effects on clinically meaningful health outcomes. Findings from this study will have important long term implications for designing interventions and implementing policies to extend the independence of older adults for the benefit of public health. Results will inform the design of future epidemiologic and intervention studies. The resulting database will enable contin- ued investigation of innovative hypotheses in clinical aging research, thereby exerting a sustained influence in the field. The proposed project is thus an efficient approach to meet the objectives of PA-17-089 exploratory analyses of existing cohorts to address clinical aging research questions.

SUMMARY OF FUNDED GRANT (R01AG056428, Interventions to Attenuate Cognitive Decline) Different cognitive intervention approaches have been developed to attenuate decline (e.g., cognitive engagement, training, or stimulation), but it is not clear which approaches are efficacious. It is also not clear when, along the continuum of normal cognitive aging to mild cognitive impairment (MCI-a transitional stage before dementia onset), it is most effective to intervene. Crucially, the underlying mechanisms of effective cognitive interventions are not known; a critical barrier to progress in this field. There is an urgent need to identify effective approaches to curb the increasing prevalence of dementia. The overall objective is to apply the best cognitive interventions to attenuate cognitive and functional decline and curb dementia prevalence. The long-term goals are to promote maintained health and independence among older adults. This randomized clinical trial will determine the efficacy of a novel cognitive engagement intervention approach (intense piano training) as compared to cognitive stimulation (which will serve as a stringent, active control). Grounded in theory, the central hypothesis is that interventions enhancing central auditory processing (CAP), a strong, longitudinal predictor of MCI and dementia, will improve cognition. Music training is increasingly recognized as a feasible means to attenuate age-related cognitive decline. Prior research and our preliminary data suggest that intense piano training may enhance CAP and is likely more effective than cognitive stimulation. Correlational studies indicate superior CAP, executive function, and other cognitive abilities for adults with formal music training compared to non-musicians. Our results across three pilot randomized trials show that piano training improves older adults? CAP and executive function, including those with MCI. The specific aims of the study are to examine the efficacy of intense piano training relative to cognitive stimulation (active controls) to improve CAP, cognition, and everyday function among older adults with and without MCI. The efficacy of piano training will be established, and moderating effects of MCI status will be examined. The proposed study further aims to elucidate the underlying mechanisms of effective cognitive intervention approaches by exploring mediators of training gains. Study outcomes will be identification of effective intervention approaches to attenuate age-related cognitive and functional decline and elucidation of the mechanisms. The proposed study is innovative, in our opinion, as the first phase II randomized trial of piano training to enhance older adults? cognition. Moreover, this study is innovative by including older individuals with and without MCI and assessing effects on everyday functional performance. Most importantly, to advance this field, we will use mediation analyses to elucidate the underlying mechanisms of intervention effects. The contributions will be significant, advancing our understanding of how cognitive interventions produce cognitive and functional change. Results will facilitate improved design and implementation of effective interventions to attenuate cognitive decline and curb the prevalence of dementia, thereby improving public health.

PROJECT SUMMARY Our analyses from the ACTIVE study showed that one type of targeted cognitive training (CT) reduced risk of dementia by up to 48% across 10 years. While these results are encouraging, evidence is inconclusive to rec- ommend CT for dementia prevention. Many efficacious CT techniques now exist, but have distinct cognitive effects. Given that cognitive deficits are varied among those at risk for dementia, a combination of CT tech- niques may be most efficacious. Emerging evidence indicates that combining CT techniques can either en- hance or attenuate cognitive gains. However, no studies have been designed to determine the most efficacious CT combinations. Furthermore, no studies have been designed to examine the longitudinal effects of CT on dementia diagnoses. We will engage international experts in CT, mild cognitive impairment (MCI)/dementia, recruitment and retention, neuropsychological assessment, neuroimaging, biomarkers, and adaptive trial de- sign to plan and pilot test an adaptive randomized clinical trial (RCT). The RCT will determine the most effica- cious combinations of CT exercises to attenuate functional decline and delay dementia among older adults at risk due to MCI. We will first develop an effective recruitment plan of community engagement to include those often under-represented in clinical research and enroll a sample representative of the US older adult popula- tion with regard to sex, ethnicity, race, and education. In phase I a pilot trial will be conducted to refine the re- cruitment and retention plan, establish feasibility and finalize procedures, and examine the potential efficacy of 4 CT arms relative to an active control. We will apply improved methodology by comparing the CT arms to a stringent active control condition of cognitive stimulation with equivalent participant expectations and social in- teraction. Measures will include innovative indices of instrumental activities of daily living (IADL), standard cog- nitive assessments, as well as neuroimaging and blood-based biomarkers. Potential moderators of CT will also be assessed. The phase I pilot data will inform statistical simulations to design a seamless phase II/III adaptive RCT. We will simulate participant accrual and several treatment scenarios. For each scenario, we will deter- mine statistical power and sample size required for trial success. The results of these statistical simulations will be applied to optimize design and power for the phase II/III adaptive RCT. The resulting RCT will be innova- tive, in our opinion, in the application of adaptive trial methodology to efficiently identify the most efficacious combinations of CT exercises to delay dementia onset. We will plan the first trial to compare combinations of CT exercises on conversion to dementia among persons with MCI. We will document CT-related changes in the brain with neuroimaging and explore blood-based biomarkers as potential intermediary outcomes of CT. The long term goal is to apply the best CT techniques to delay dementia onset, thereby promoting public health. The contributions will be significant, advancing our understanding of how CT may be implemented to curb dementia prevalence.

PROJECT SUMMARY Dementia is the most expensive medical condition in the US. There is an urgent need to intervene to curb the increasing prevalence of dementia in our population. Research demonstrates that computerized, cognitive speed of processing training (SPT) improves cognition and transfers to improved instrumental activities of daily living. However, an unanswered question is whether SPT can be successfully implemented to decrease incidence of mild cognitive impairment (MCI) or dementia. Analyses of 10-year data from the ACTIVE trial revealed that older adults randomized to SPT were 29% less likely to develop dementia. Moreover, those who completed additional training had a 48% reduced risk of dementia over 10 years. Two major limitations of this exciting study was a lack of clinical diagnosis of dementia and use of a no-contact control condition. The proposed field trial will advance prior research by implementing SPT in a large population of cognitively normal older adults in Florida. Older adults will be randomized to SPT or an active control condition of cognitive stimulation (i.e., computer games) and progression to MCI or dementia will be clinically assessed over time. We further will determine if SPT effects are specific for those with/without amyloid pathology or Apolipoprotein E4, and quantify the effects of SPT on subsequent healthcare costs and utilization. Leveraging our existing Community-Based Memory Screening program, we will identify and enroll a diverse sample of thousands (N=7600) of older adults without evidence of cognitive impairment who can potentially benefit from SPT over 3 years. We have already screened ~5000 individuals in this program, which will be expanded for the proposed study. Our primary goal will be to examine the effectiveness of SPT to reduce incidence of MCI or dementia. After 3 years, we will begin repeating memory screenings of participants to identify those exhibiting cognitive decline. Such participants will be provided a thorough medical evaluation to clinically ascertain MCI or dementia. Participants will complete genetic testing and receive an amyloid PET scan to further determine the cause of cognitive decline. Given the 7-year funding period, our sample size will yield a sufficient number of diagnosed MCI/dementia cases within the last four years of the study. The primary contribution of the proposed research will be the determination of whether SPT successfully reduces incidence of MCI and/or dementia. This contribution will be significant in that if an intervention could delay the onset of Alzheimer's disease by only one year, there would be ~9.2 million fewer cases of the disease in 2050, substantially reducing costs. Results will inform subsequent research and clinical practice by facilitating implementation of effective interventions to attenuate cognitive and functional decline and thereby improve public health.

PROJECT SUMMARY Dementia is the most expensive medical condition in the US. There is an urgent need to intervene to curb the increasing prevalence of dementia in our population. Strong preliminary data from more than 18 ran- domized clinical trials demonstrate that computerized, cognitive speed of processing training (SPT) im- proves cognition and transfers to improved instrumental activities of daily living. Recent evidence further indicates that SPT may reduce dementia risk. Analyses of 10-year data from the ACTIVE trial revealed that older adults randomized to SPT were 29% less likely to develop dementia. Moreover, those who com- pleted additional training had a 48% reduced risk of dementia across 10 years. Two limitations of this study were a lack of clinical diagnosis of dementia and use of a no-contact control condition. Thus, an im- portant question is, ?Can SPT be successfully implemented to reduce incidence of mild cognitive impair- ment (MCI) or dementia??. Our primary goal is to test the effectiveness of SPT to reduce incidence of MCI or dementia. The Preventing Alzheimer's with Cognitive Training-PACT field trial advances prior research by rigorously implementing SPT in a large population of cognitively normal older adults and ex- amining the primary endpoint of MCI or dementia clinical diagnoses. Older adults are randomized to SPT or an active control arm of cognitive stimulation (i.e., computer games) and progression to MCI or demen- tia will be clinically assessed after 3 years. We further will explore if SPT effects are moderated by the de- gree of amyloid pathology or apolipoprotein E4 status. To demonstrate feasibility, our investigative team is implementing the study protocol in an R56 phase and successfully enrolled 744 older adults at the time of proposal submission. Three years after enrollment, we will re-assess study participants to identify those exhibiting cognitive decline. Such participants will be provided a thorough medical evaluation to clinically ascertain MCI or dementia diagnosis. Those classified as MCI or dementia will further complete an amy- loid PET scan and genetic testing. This non-pharmacological prevention trial is innovative with a highly efficient experimental design and optimized SPT training protocols including an active control group. The proposed research will determine if SPT successfully reduces incidence of MCI or dementia. This out- come will be significant in that if an intervention can delay the onset of dementia by only one year, there will be ~9.2 million fewer cases of the disease by 2050, substantially reducing cost. Positive results would support use of a relatively inexpensive and easy to apply intervention that could delay or prevent the on- set of Alzheimer?s disease and/or related dementias. Such an outcome would justify further research to identify mechanisms of action. Results will inform clinical practice of effective interventions to attenuate age-related cognitive and functional decline and thereby improve public health.