Interventions that affect many different aspects of human ability rather than just one aspect of human health are more likely to be successful in preventing and treating Alzheimer's disease (AD). Functional decline in AD is severely impacted by impaired ability to do physical actions while having to make decisions and concentrating, something scientists call motor-cognitive integration. Combined motor and cognitive training has been recommended for people with early AD, thus this study will use partnered, rhythmic rehabilitation (PRR), as an intervention to simultaneously target cardiovascular, social and motor-cognitive domains important to AD. PRR is moderate intensity, cognitively-engaging social dance that targets postural control systems, involves learning multiple, varied stepping and rhythmic patterns, and fosters tactile communication of motor goals between partners, enhancing social interaction's effect on cognition. Previous research demonstrates that PRR classes are safe and result in no injurious falls. This study is a 12-month long Phase II single- blind randomized clinical trial using PRR in 66 patients with early AD. Participants with early AD will be randomly assigned to participate in PRR or a walking program for three months of biweekly sessions, followed by nine months of weekly sessions of PRR or walking. The overarching hypothesis is that PRR is safe, tolerable and associated with improved motor-cognitive function, and brain (neuronal), vascular (blood vessels) and inflammatory biomarkers that might affect function.
For people with early Alzheimer's disease (AD), treatment options to prevent declined function are extremely limited, because AD affects many areas of function. In early AD, people may have trouble physically doing things while also thinking, which is necessary for many activities in daily life. This problem might be helped by doing activities that challenge the mind and the body at the same time. Partnered rhythmic rehabilitation (PRR), which targets fitness, cognition, mobility and social engagement and may prevent future functional problems in AD. This is a phase II single-blind randomized clinical trial to assess the safety, tolerability, and efficacy of PRR in individuals in the early stages of AD, also called prodromal AD (pAD) . Participants will be randomly assigned to 90-minute PRR or WALK classes. Both interventions will receive equal contact and monitoring from study staff. Participants will have two phases of intervention. In the three-month Training phase, participants will be assigned to 20, biweekly (90-minute) lessons over 12 weeks. In the nine-month Maintenance phase, participants will attend weekly lessons at least 3 times per month. Participants will undergo either PRR or Walking Exercise (WALK) interventions for one year, which will use de-escalating doses: two times per week for three months (Training) and weekly for nine months (Maintenance). The first study aim is to determine acceptability, safety, tolerability and satisfaction with PRR in pAD. The second aim is to determine a) efficacy of PRR vs. WALK for improving motor-cognitive integration in pAD; b) to identify sensitive endpoints to power a future phase III trial. The researchers will also explore potential mechanisms by which PRR affects pAD. These mechanisms include functional brain measures, vascular, and inflammation measures (arterial stiffness; cerebral perfusion, task functional magnetic resonance imaging \[fMRI\]; inflammatory markers: cytokines and chemokines, endothelial adhesion markers.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
66
Partnered Rhythmic Rehabilitation (PRR) is moderate intensity, cognitively-engaging social dance that targets postural control systems. PRR involves learning complex stepping patterns and fosters tactile communication of motor goals between partners, enhancing social interaction's effect on cognition. Class sizes will consist of 10 or fewer pairs of participants with pAD and partners to maximize safety. Participants will engage in partnering exercises on how to interpret motor goals through touch, exercises to develop understanding of temporal relationship of movement to music, novel step introduction, connecting previously learned and novel step elements. Classes include practicing previously-learned steps, a 20-minute standing warm-up, and partnering and rhythmic enhancement exercises.
WALK sessions consist of 10 minutes of warm-up, and evaluation/tips for practicing safe walking form mechanics (i.e., head up, shoulders relaxed, abdominals engaged, heel strike, roll and toe off; keep natural stride length, and speed up cadence if increased speed is desired), 55 minutes of walking with breaks, and 20 minutes of balance and stretching. WALK will take place in small groups with research assistants and trained family members and/or caregivers to control for social effects/contact of intervention. Participants of similar walking abilities will be 'buddied' with research assistants and trained physical therapy students who will act as group backmarkers, although participants will lead the pace. WALK participants will keep walking logs documenting their progress. WALK is expected to expend 3 metabolic equivalents (METs), like that of PRR.
Emory University
Atlanta, Georgia, United States
RECRUITINGChange in Four Square Step Test (FSST) Time
The Four Square Step Test (FSST) assesses mechanisms underlying motor-cognitive integration. FSST requires participants to step clockwise then counterclockwise into four squares created by rods arranged on the ground in a cross. Participants are instructed to perform FSST "as quickly and as safely as you can," to not touch the rods and make both feet contact the floor in each square. Timing begins when the participant initiates movement and stops when both feet are back in the starting square after completing the sequence. Trials will be repeated if the participant does not understand the instructions, fails to complete the sequence accurately, loses balance, or touches a rod. Three successful trials will be recorded and fastest time selected for analyses.
Time frame: Baseline, 3 months, 12 months
Change in Acceptability
Acceptability of the intervention will be assessed by conducting two pre-session focus groups with 8-10 pAD participants. Focus groups will assess barriers and facilitators of PRR as therapy for motor-cognitive performance of functional activity issues. Post training, the researchers will conduct two focus groups with 8 participants each to assess satisfaction with PRR, perceived effect of PRR on participation in life's activities, impact of touch on therapy, overall perceived impact of cognitive impairment on benefits/results from PRR, and solicit recommendations for improvement. Responses will be open ended rather than on a pre-determined scale.
Time frame: Baseline, Month 12
Number of Injurious Falls
The primary safety outcome is the number of injurious falls as a result of participation in PRR. PRR will be considered safe if no injurious falls are observed during PRR instruction.
Time frame: Month 12
Attrition
Tolerability will be assessed by the number of participants completing the study. PRR will be considered tolerable if attrition is less than or equal to 15 percent.
Time frame: Month 12
Change in Timed Up and Go (TUG) Test - Cognitive Time
For the TUG-Cognitive test, participants must pay attention to walking and counting. Participants are instructed to stand up from a chair, walk 3 meters as quickly and safely as possible, cross a line marked on the floor, turn around, walk back, and sit down; at the same time they are asked to count backward by threes from a randomly selected number between 20 and 100. Participants are timed (in seconds) beginning when the test administrator says "go" and ending when the participant completed the task and sits down.
Time frame: Baseline, 3 months, 12 months
Change in Body Position Spatial Task (BPST)
Body Position Spatial Task (BPST), is a validated visuospatial memory task. The BPST incorporates spatial memory and navigational skills while maintaining posture. The examiner verbally and visually shows a series of side, forward and turning steps, which the examinee repeats. If the examinee repeats the entire pattern correctly they are scored with a 1; any incorrect parts of the pattern mean the score will be 0. Participants complete up to 8 different sequences, and have up to 2 tries to perform the sequence correctly. Total scores can range from 0 to 8, with higher values indicating more sequences correctly performed.
Time frame: Baseline, 3 months, 12 months
Change in Lawton Instrumental Activities of Daily Living (IADL) Score
Functional independence will be measured with the Instrumental Activities of Daily Living (IADL) scale. The IADL is an 8-item instrument which assesses how well the respondent can perform daily tasks by rating the responses as 0 or 1. The total score ranges from 0 to 8, with higher scores indicating greater independence.
Time frame: Baseline, 3 months, 12 months
Change in Composite Physical Function (CPF) Scale Score
Functional independence will be measured with the Composite Physical Function (CPF) Scale. The CPF has 12 items where respondents rate how well they can perform certain tasks on a scale of 0 (cannot do) to 2 (can do on own without help). Total scores range from 0 to 24, with higher scores indicating better ability to perform activities without assistance.
Time frame: Baseline, 3 months, 12 months
Change in Short Physical Performance Battery (SPPB) Score
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The SPPB asks participants to perform movements to assess balance, gait, and lower extremity strength and endurance. Total scores range from 0 to 12, with higher scores indicating better physical performance.
Time frame: Baseline, 3 months, 12 months
Change in Mini-Balance Evaluation Systems Test (Mini-BESTest) Score
This clinical balance assessment tool is a shortened version of the Balance Evaluation Systems Test (BESTest). It aims to target and identify 6 different balance control systems so that specific rehabilitation approaches can be designed for different balance deficits. The Mini-BESTest has 14 items that are scores on a scale of 0 (lowest level of function) to 2 (highest level of function). Total scores range from 0 to 28 where higher scores indicate better function.
Time frame: Baseline, 3 months, 12 months
Change in 6 Minute Walk Test (6MWT) Distance
The 6 minute walk test (6MWT) assesses distance, in meters, walked over 6 minutes as a sub-maximal test of aerobic capacity and endurance.
Time frame: Baseline, 3 months, 12 months
Change in Preferred Gait Speed
Gait speed testing will be administered using a GAITRite walkway. GAITRite is a pressure sensitive walkway that can assess gait anomalies. Gait speed while participants walk at their preferred speed will be compared between study arms.
Time frame: Baseline, 3 months, 12 months
Change in Backward Gait Speed
Gait speed testing will be administered using a GAITRite walkway. GAITRite is a pressure sensitive walkway that can assess gait anomalies. Gait speed while walking backwards will be compared between study arms.
Time frame: Baseline, 3 months, 12 months
Change in Fast Gait Speed
Gait speed testing will be administered using a GAITRite walkway. GAITRite is a pressure sensitive walkway that can assess gait anomalies. Gait speed while walking as fast as possible will be compared between study arms.
Time frame: Baseline, 3 months, 12 months
Change in Clinical Dementia Rating (CDR) Questionnaire Score
The CDR is designed to reflect level of cognitive impairment based on a semi-structured interview with an informant and a separate mental status exam with the patient. The clinician rates each of the six general domains involving memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. A global rating is then generated, ranging from 0-no impairment to 3-severe impairment.
Time frame: Baseline, 3 months, 12 months
Change in Flanker Task Score
The Flanker Task of the Executive Abilities Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) instrument involves responding to a central stimulus while ignoring flanking stimuli that are either compatible or incompatible with the central stimulus. Composite scores range from 1 to 10, where higher scores indicate faster and more accurate reactions. The EXAMINER is a 30-40 minute test battery funded with support from the NIH that reliably and validly assesses executive function in clinical trials. This computer administered instrument assesses working memory, response inhibition, set shifting, and phonemic and category fluency.
Time frame: Baseline, 3 months, 12 months
Change in Set Shifting Score
The Set Shifting assessment of the EXAMINER instrument is a measure of mental flexibility assessing the subject's ability to attend to the specific attributes of compound stimuli, and to shift that attention when required. Participants match shapes or colors, as instructed, and composite scores range from 1 to 10, where higher scores indicate greater accuracy. The EXAMINER is a 30-40 minute test battery funded with support from the NIH that reliably and validly assesses executive function in clinical trials. This computer administered instrument assesses working memory, response inhibition, set shifting, and phonemic and category fluency.
Time frame: Baseline, 3 months, 12 months
Change in Spatial 1-Back Test Score
The Spatial 1-Back Test of the EXAMINER instrument assesses spatial working memory. The spatial 1-back test has 30 trials where the number of correct "yes" or "no" responses are tabulated. The total number of correct responses ranges from 0 to 30 with higher scores indicating greater accuracy. The EXAMINER is a 30-40 minute test battery funded with support from the NIH that reliably and validly assesses executive function in clinical trials. This computer administered instrument assesses working memory, response inhibition, set shifting, and phonemic and category fluency.
Time frame: Baseline, 3 months, 12 months
Change in Dot Counting Test Score
The Dot Counting Test of the EXAMINER instrument assesses verbal working memory. The dot counting test includes 6 trials, which progress in difficulty, where participants count dots. Scoring is based on the participant's ability to correctly recall the number of dots they counted. The total number of correct responses ranges from 0 to 27 with higher scores indicating greater accuracy in recall. The EXAMINER is a 30-40 minute test battery funded with support from the NIH that reliably and validly assesses executive function in clinical trials. This computer administered instrument assesses working memory, response inhibition, set shifting, and phonemic and category fluency.
Time frame: Baseline, 3 months, 12 months
Change in Verbal Fluency Test Score
The Verbal Fluency Test of the EXAMINER instrument uses list generation which requires participants to generate words beginning with a specific letter, and category fluency in which the participant generates words from a specified category (e.g., animals, fruits). There are four 1-minute trials where participants name as many items as they can (up to 40) that fit the requested criteria. Total scores range from 0 to 160, where higher values mean that more words fitting the criteria provided. The EXAMINER is a 30-40 minute test battery funded with support from the NIH that reliably and validly assesses executive function in clinical trials. This computer administered instrument assesses working memory, response inhibition, set shifting, and phonemic and category fluency.
Time frame: Baseline, 3 months, 12 months
Change in Reverse Corsi Blocks Levels Completed
Spatial cognition will be assessed by administration of the Reverse Corsi Blocks in which the examiner taps a series of blocks and the participant then produces this pattern but in the opposite order. Up to eight different levels, with increasingly difficult patterns, are performed. The total score for the exam ranges from 1 to 9, with higher values indicating more levels successfully performed.
Time frame: Baseline, 3 months, 12 months
Change in Patient Health Questionnaire (PHQ-9) Score
The Patient Health Questionnaire (PHQ-9) is a 9-item, validated measure of depression severity in dementia. Respondents indicate how bothered by problems they are on a scale from 0 (not at all) to 3 (nearly every day). Total scores range from 0 to 27, where higher scores indicate more severe depression.
Time frame: Baseline, 3 months, 12 months
Change in Multidimensional Scale of Perceived Social Support (MSPSS) Score
The MSPSS has 12 items assessing how social support factors are perceived by individuals. This scale has three subscales to evaluate support by family, friends and significant others. Respondents rate statements on a scale of 1 (very strongly disagree) to 7 (very strongly agree). Total scores range from 12 to 84, where higher scores indicate increased perception of social support.
Time frame: Baseline, 3 months, 12 months
Change in Montreal Cognitive Assessment (MoCA) Score
MoCA is an instrument to screen for mild cognitive dysfunction, assessing the cognitive domains of attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Total scores range from 0 to 30 with higher scores indicating better cognitive function. A normal score is considered to be 26 or higher.
Time frame: Baseline, 3 months, 12 months