Interventions to Attenuate Cognitive Decline
Phase: NA
Conditions: Mild Cognitive Impairment, Age-related Cognitive Decline
Sponsor: University of South Florida

 
 
KEYS TO STAYING SHARP 
 
 
 
Interventions to Attenuate Cognitive Decline 
 
 
 
 
 
Supported by: 
 
The National Institute on Aging 
 
R01 AG056428 
 
Principal Investigator:  Jerri Edwards 
 
 
 
 
 
 

 
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Table of Contents 
1 
SYNOPSIS ..................................................................................................................................................... 5 
1.1 Study Title ............................................................................................................................................................................... 5 
1.2 Objectives ................................................................................................................................................................................ 5 
1.3 Design ...................................................................................................................................................................................... 5 
1.4 Outcomes ................................................................................................................................................................................. 5 
1.5 Interventions and Duration ..................................................................................................................................................... 5 
2 
STUDY OBJECTIVES ............................................................................................................................ 7 
2.1 Primary Objective ................................................................................................................................................................... 7 
2.2 Secondary Objectives .............................................................................................................................................................. 7 
3 
BACKGROUND ...................................................................................................................................... 8 
4 
STUDY DESIGN .................................................................................................................................... 11 
5 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................................ 11 
5.1 Inclusion Criteria .................................................................................................................................................................. 11 
5.2 Exclusion Criteria .................................................................................................................................................................. 11 
5.3 Enrollment Procedures .......................................................................................................................................................... 13 
5.4 Describe consent procedures. ................................................................................................................................................ 14 
5.5 Describe the procedure for obtaining intervention group assignment ................................................................................. 15 
5.6 STUDY INTERVENTIONS .................................................................................................................................................. 16 
5.7 Interventions, Administration, and Duration ....................................................................................................................... 16 
5.7.1 
Prohibited Interventions ........................................................................................................................................................ 16 
5.8 Adherence Assessment .......................................................................................................................................................... 17 
6 
CLINICAL AND LABORATORY EVALUATIONS .......................................................................... 18 
6.1 Timing of Evaluations ........................................................................................................................................................... 21 
6.1.1 
Pre-Randomization Evaluations ............................................................................................................................................ 22 

 
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6.1.2 
Intervention Phase................................................................................................................................................................. 22 
6.1.3 
Post-Test ............................................................................................................................................................................... 23 
6.2 Overall Project Timeline ....................................................................................................................................................... 23 
6.3 Intervention Discontinuation Evaluations Retention ............................................................................................................ 24 
6.3.1 
Retention ............................................................................................................................................................................... 24 
6.3.2 
Documentation of MCI or dementia ..................................................................................................................................... 25 
6.3.3 
Concomitant Treatments ....................................................................................................................................................... 25 
6.3.4 
Study Intervention Modifications ......................................................................................................................................... 25 
6.3.5 
Measures ............................................................................................................................................................................... 25 
6.3.6 
Questionnaires ...................................................................................................................................................................... 30 
7 
MANAGEMENT OF ADVERSE EVENTS ......................................................................................... 31 
8 
CRITERIA FOR PARTICIPANT DISCONTINUATION .................................................................. 31 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 31 
9.1 General Design Issues ............................................................................................................................................................ 31 
9.2 Primary Objectives ................................................................................................................................................................ 31 
9.2.1 
Primary outcomes ................................................................................................................................................................. 32 
Secondary Objectives ..................................................................................................................................................................... 32 
9.3 Sample Size ............................................................................................................................................................................ 32 
9.4 Data Monitoring .................................................................................................................................................................... 33 
9.5 Interim Data Analyses ........................................................................................................................................................... 33 
9.6 Final Data Analyses ............................................................................................................................................................... 34 
9.7 Sensitivity Analyses ............................................................................................................................................................... 36 
9.8 Exploratory Subgroup Analyses ........................................................................................................................................... 36 
10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING .... 38 
10.1 Records to Be Kept ................................................................................................................................................................ 38 
10.2 Data Management ................................................................................................................................................................. 38 
10.2.1 
Clinical site responsibilities in data collection and management. .................................................................................... 38 
11 QUALITY ASSURANCE ...................................................................................................................... 39 
11.1 Adverse Experience Reporting .............................................................................................................................................. 40 

 
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11.2 Follow-up for Adverse Events ............................................................................................................................................... 41 
11.3 Safety Monitoring .................................................................................................................................................................. 41 
11.4 Confidentiality ....................................................................................................................................................................... 41 
11.5 Study Modification/Discontinuation ..................................................................................................................................... 41 
12 REFERENCES ...................................................................................................................................... 44 
 
13. DATA AVAILABILITY 
50 
 
14. RESULTS 
50 
 
14.1 Participant characteristics by randomized arm and cognitive status. 
54 
 
14.2 The effects of randomization to piano training as compared to music listening from baseline to post-
training across composite outcomes of central auditory processing, cognition, and everyday function.  
55 
 
14.3 Effect sizes for piano training relative to music listening across composite outcomes and assessments for 
the analytic sample overall, among those adherent, and by cognitive status. 
57 
 
15. CONSORT CHART 
59 

 
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1 SYNOPSIS 
1.1 Study Title 
Interventions to Attentuate Cognitive Decline:  Keys to Staying Sharp. 
1.2 Objectives 
 
The primary objectives are: 
 
• To examine the efficacy of piano training to improve central auditory processing (CAP), cognition, and 
everyday function among older adults with and without mild cognitive impairment (MCI).  
 
The secondary objectives are: 
• To examine the moderating effects of MCI on piano training efficacy.   
• To explore mediators of intervention effects.  
 
1.3 Design 
The design is a two arm randomized clinical trial examining the efficacy of piano training relative to music lis-
tening instruction to improve CAP, cognition, and everyday function in older adults with and without MCI 
across two time points (baseline and immediate post-test). This is a phase II trial to test the efficacy of promis-
ing behavioral intervention (i.e., piano training) in a research setting. The primary outcome of interest is cogni-
tion1. 
 
1.4 Outcomes 
 
We will quantify the effects of piano training on CAP, cognition, and everyday functional performance.  
 
CAP measures will include:  Time Compressed Speech 65%, Words-in-Noise, Dichotic Digits Test, Dichotic 
Sentence Identification, and Adaptive Tests of Temporal Resolution. 
 
Cognition measures will include:  Verbal Fluency Test (phonemic fluency, category fluency, and category 
switching), Trail Making Test, and Digit Coding. 
 
Everyday Function measures will include:  Timed Instrumental Activities of Daily Living and Test of Everyday 
Attention. 
 
1.5 Interventions and Duration 
 
Piano Training.  Piano training will consist of basic piano technique, dexterity exercises, piano literature, and 
music theory.  At each bi-weekly training session, participants will be trained in groups and will be expected to 

 
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perform all technique (scales/finger dexterity exercises), piano repertoire (Alfred Basic All-in-One Method), 
and complete music theory assignments.  Each class session will be structured with a short review followed by 
an intense focus on new skill development (e.g., scales; chord progressions) and concept formation (e.g., inter-
vals).  At least one five-minute break will occur in each session.   
 
Music Listening Instruction Condition.  Participants randomized to the music listening instruction condition 
will engage in music listening and appreciation.  The participants read about, listen to, view diagrams of, and 
answer questions about the music.  Each lesson will cover chapters from Music Listening Today over 90 
minutes.  Each lesson will be structured as follows: Overview of chapter material and group listening activity, 
participants read over chapter on their own, active listening activity, five question quiz, overview of next chap-
ter material and group listening activity, participants read over chapter on their own, active listening activity, 
and five question quiz.  At least one five-minute break will occur in each session.  This structure is equivalent to 
the switching between ensemble/individual approach to teaching in the piano training condition.  
 
The two training conditions will be equivalent in terms of frequency and duration of each session (90 min/day, 
two days/wk, 10 weeks) and social contact (led by trainer and conducted in groups of up to 10 persons).  Both 
conditions will be described as “music training”.   
 
Sample Size and Population 
 
Our goal is to have up to 360 participants complete the study.  Individuals with normal cognition and those with 
a clinical diagnosis of MCI will be recruited for this study.  Inclusion and exclusion criteria are detailed below. 

 
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2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is: 
 
• To examine the efficacy of piano training to improve CAP, cognition, and everyday function among 
older adults across baseline to immediate post-test.  We will assess the effects of piano training (inter-
vention) as compared to music listening instruction (active control) on CAP, cognition, and everyday 
function.  The primary outcome of interest is cognition.  
 
Hypotheses:  The piano training group will outperform the music listening instruction group on 
measures of CAP, cognition, and everyday function immediately post-intervention.  
 
Rationale: The efficacy of a novel intervention will be established relative to an active control group.  
There is compelling evidence that CAP deficits contribute to cognitive difficulties 2-5 and are a risk fac-
tor for dementia 3, 6, 7.  We propose that enhancing CAP may be particularly important to improve cogni-
tive function.  Formal music training is longitudinally associated with enhanced CAP and successful 
cognitive aging.  Piano training is a feasible, potentially efficacious intervention to improve older adults’ 
CAP and cognition.  
 
2.2 Secondary Objectives 
The secondary objectives are: 
 
• To examine the moderating effects of MCI on piano training efficacy.  Moderating effects of MCI status 
will determine if piano training is effective for older adults with and/or without MCI.  
 
 
Rationale: It is possible that piano training is effective prior to cognitive decline, but not in those with 
MCI.  It is also possible that cognitive and/or functional abilities may be differentially enhanced among 
those with and without MCI.  Delineating the effects of piano training among those with and without 
MCI will discern who is most likely to benefit from piano training, and for what specific outcomes. We 
do not have a directional hypothesis for this objective.  
 
• To explore mediators of intervention effects.  
 
Hypothesis: Grounded in theory8 and prior research9-11, we hypothesize that piano training will improve 
CAP and cognitive performance, leading to functional improvements.  We expect that enhanced CAP 
will mediate cognitive gains.  We further hypothesize that cognitive gains will mediate functional im-
provements.   
 
Rationale: Crucially, we must discern the underlying mechanisms of effective interventions in order to 
maximize training gains. 
 

 
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3 BACKGROUND 
 
Cognitive impairment and dementia are the most feared signs of aging12-14.  In addition to the obvious 
health and quality-of-life ramifications for older adults, there are high economic costs (e.g., subsidizing nursing 
home care; lost productivity of family caregivers), when older adults can no longer live independently15.  Thus, 
prevention of cognitive and subsequent functional decline among older adults is of critical importance to public 
health.  Dementia is the most expensive medical condition and increases in prevalence with age16, 17.  Given that 
older adults are the fastest growing segment of the population18, the prevalence of dementia (and its precursor, 
mild cognitive impairment-MCI) has been increasing rapidly19.  Therefore, finding effective strategies for inter-
vention to prevent or delay dementia is imperative to improve public health.  The contribution of the proposed 
research is expected to be the identification of a novel and effective cognitive intervention to counter age-
related cognitive and functional decline, which could potentially delay dementia onset.  We will elucidate the 
underlying mechanisms of effective interventions to facilitate maximizing cognitive gains and improving eve-
ryday function.  The contribution of this research will be significant in that if an intervention could delay the 
onset of Alzheimer’s disease by only one year, there would be about 9.2 million fewer cases of the disease in 
205020, substantially lessening the burden.  Results will inform subsequent research and clinical practice by fa-
cilitating the design and implementation of effective interventions to attenuate cognitive decline and thereby 
improve public health. 
Mild Cognitive Impairment (MCI).  Cognitive status has been conceptualized on a continuum from 
normal cognition to clinically ascertained dementia such as Alzheimer’s disease.  MCI represents a transitional 
phase between normal aging and dementia21, 22.  MCI patients have higher risk of developing dementia12, 23 with 
conversion to dementia of ~12% per year23 (although not all individuals progress across this continuum).  
Among individuals with and without MCI, cognitive interventions may enhance cognition and maintain every-
day functioning, thereby delaying dementia onset24.  A paucity of research and methodological inadequacies 
have limited the implementation of effective cognitive interventions in MCI25, 26.  One avenue to enhance cogni-
tion is the facilitation of central auditory processing (CAP) at initial perceptual stages5, which may potentially 
be achieved by piano training.  Our scientific premise is that piano training will enhance CAP, resulting in im-
proved cognition and subsequently everyday function, thereby delaying the onset of dementia.  The primary 
outcome of interest is cognition.  
Central Auditory Processing (CAP).  One early indicator of cognitive impairment is impaired auditory 
processing. Auditory processing and decoding of sound occurs at multiple levels of the central auditory nervous 
system.  Central auditory processing dysfunction is characterized by deficits in using supra-threshold sound, 
such as poor monaural speech-in-noise perception, binaural speech processing, sound localization and laterali-
zation, and auditory processing speed 27.  When CAP is impaired, information received by the cognitive systems 
is distorted and incomplete, causing information processing difficulties. Auditory processing thus requires 
greater cognitive resources, negatively affecting memory and executive function 8.  Decades of research have 
established that CAP is fundamentally linked with memory and executive functioning4, 5, 28, 29, which are the 
primary deficits in MCI and dementia30, 31.  In support of this premise, CAP longitudinally predicts MCI and 
dementia such as Alzheimer’s disease32-34.  Prior research (e.g., 35, 36) and our pilot data confirm that measures 
of CAP are strong, independent predictors of cognitive function (e.g., memory, executive function), and that 
adults with MCI show significant CAP deficits37, 38.  Deficits in CAP are multifaceted and represented by diffi-
culties with, for example, auditory speed of processing, monaural speech-in-noise recognition, binaural speech 
processing, sound localization and lateralization, and auditory pattern recognition5, 39.  Note that auditory speed 
of processing, a leading indicator of cognitive aging, is one of the key elements of CAP40, as adequate sensory 
functioning is fundamental for normal speed of processing41.  When CAP is impaired, information received by 
the cognitive systems is distorted and incomplete, causing information processing difficulties.  Auditory pro-

 
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cessing thus requires greater cognitive resources, negatively affecting memory and executive function8.  There-
fore, impaired CAP impedes cognitive performance41-45.  In addition to behavioral data, neuroanatomical evi-
dence documents that deficits in CAP46 are related to anterior temporal lobe atrophy and reduced glucose me-
tabolism46-50, brain changes evident in MCI and Alzheimer’s disease51.  Neuroimaging further indicates a link 
between sensory function and cortical integrity, and that decreased volume in the auditory cortex cascades to 
affect higher-order cognitive processing52-54.  In older adults, difficulties with CAP are associated with modified 
patterns of neural activation as well as with reduced gray matter volume in the auditory cortex.  Wong et al. and 
others55, 56 demonstrated that older adults show less activation in the auditory cortex and increased activation in 
the prefrontal cortex to perform cognitive tasks due to declines in CAP.  
Although CAP is a strong longitudinal predictor of cognitive decline, MCI, and dementia3, 34, 35, 57, prior 
research has not examined the effects of interventions targeting CAP on functional abilities of older adults with 
and without MCI.  Re-establishing and/or maintaining adequate CAP may be the first crucial step in efforts to 
improve cognitive abilities of older adults.  Given that multiple studies have shown music experience is strongly 
associated with better CAP58-61, it is likely that piano training enhances CAP, leading to better cognition (See 
Piano Training Rationale below).  
Theoretical Background.  We hypothesize that improving brain function at early perceptual levels (i.e., 
CAP) may be optimal to attenuate cognitive and functional decline and potentially curb dementia prevalence.  
This premise is grounded in the information degradation8 theory.  The information degradation theory8, 62 posits 
that age-related changes in the brain cause initial sensory/perceptual processing errors that lead to difficulties 
with downstream information processing (i.e., CAP) and cognition (i.e., memory/executive function).  Accord-
ing to this and similar theories, neurophysiological decline leads to reduced brain efficiency such that the speed 
and/or quality of processing (e.g., fidelity of representations, speed of neural transmission) is impaired due to 
poor perceptual encoding.  Thus, cognitive interventions should target improving initial perceptual processing 
(i.e., CAP) such that cognition can improve63.  Accordingly, cognitive interventions that target basic perceptual 
processing may be most effective.  Furthermore, cognitive gains will be mediated by improvements in percep-
tual processing (i.e., CAP).  Our recent analyses support this assertion, indicating that intervention targeting 
perceptual processing is more effective to curb dementia prevalence than other approaches64.  The proposed 
study will advance the field by examining CAP as a mechanism of piano training.  
Piano Training Rationale.  Engagement in learning challenging new skills, such as learning to play the 
piano with training, is a promising cognitive intervention approach that is likely more effective than cognitive 
stimulation65.  Piano training can be defined as systematic sequential instruction to acquire piano skills that in-
cludes technique (scales/arpeggios/chords), music theory, and piano repertoire.  Verghese et al. observed that 
older adults who reported playing musical instruments were 69% less likely to develop dementia66.  Increasing 
neuroscience evidence indicates positive, longitudinal associations of music training with enhanced structures 
and function in the brain67, 68.  Thus, music training (piano training, in particular) has been proposed as a viable 
means to attenuate age-related cognitive decline69, 70.  Piano training may be an efficacious cognitive interven-
tion because it requires the simultaneous coupling of sensory processing, motor skills, and complex cognitive 
operations to be executed with temporal precision71.  We propose that piano training is a promising cognitive 
intervention because: 
a- Piano training enhances CAP.  Our central premise is that improving CAP may be the first crucial 
step to augment older adults’ cognition.  Numerous studies insdicate that music experience is strongly associat-
ed with better CAP (e.g., 58, 59-61).  CAP is likely enhanced by piano training due to the multicomponent de-
mands on complex temporal, sequential, and sensorimotor processing.  Correlational studies indicate superior 
CAP for adults with formal music training compared to non-musicians72-74.  Further, Co-I Lister’s studies show 
that adult musicians have enhanced CAP, indicated by faster neurophysiological processing of sound, than their 
nonmusician counterparts9, 75.  Similarly, older musicians do not show age-related neural timing delays, indicat-

 
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ing better CAP76.  Zendel and colleagues also demonstrated that CAP (i.e., auditory processing speed and 
speech-in-noise perception) is less suspectible to age-related decline in musicians59.  We propose to experimen-
tally examine the effects of piano training on older adults’ CAP in a RCT.   
b- Piano training enhances brain structures and function.  Epidemiological data show that music 
training is associated with enhanced structures and function of the brain.  Scientists have hypothesized that pi-
ano training engages frontostriatal cerebellar circuits, including the motor cortex and basal ganglia, and will 
thus result in cognitive improvements among older adults71, 77, 78.  Research demonstrates that long-term piano 
training is associated with greater activation in the cerebellum, an area associated with higher cognition (e.g., 
executive function)79.  Pianists show higher white matter integrity and greater gray matter density in motor are-
as of the brain than non-musicians79.  Neuroimaging research indicates specificity in structural brain differences 
subsequent to piano training80.  Given that piano training is longitudinally associated with improved brain struc-
tures and function, it may attenuate age-related cognitive decline. 
c- Piano training enhances cognition.  Piano training is associated with improved cognitive perfor-
mance81, 82, 83-85.  Hanna-Pladdy and Gajewski demonstrated that as compared to non-musicians matched on age 
and education, older adult musicians performed better on memory (letter number sequencing, verbal learning 
test ds=0.47-0.53) and executive function measures (phonemic fluency d=0.59)86.  Musical training was a 
stronger predictor of older adults’ cognitive performance than lifestyle activities87.  Seinfeld and colleagues 
found that older adults randomized to piano training showed improved speed of processing (d=0.71) and execu-
tive function (ds=1.70-1.85)67.  Co-I Bugos published two pilot randomized trials indicating small to medium 
effects of piano training relative to controls for improved speed of processing and executive function.  Im-
provements in speed of processing were sustained three months after training (for details, see Preliminary 
Studies-Piano Training below).  Combined with our pilot study, these data demonstrate enhanced speed of 
processing and executive function among older adults subsequent to piano training relative to controls81, 82.  
d- Piano training enhances older adults’ mood and quality of life.  In our experience, older adults are 
eager to participate in piano training studies and find the experience to be enjoyable.  Seinfeld and colleagues 
found that older adults completing piano training reported less depression, improved mood, and better quality of 
life67.  Piano training may be a more enjoyable activity than other types of cognitive intervention.  Further, pi-
ano training could be immediately implemented in the community if it is efficacious. 
In summary, we chose piano training because it is a novel cognitive engagement approach that shows 
promise to enhance CAP and cognition.  Although prior epidemiological research and our pilot studies indicate 
the potential efficacy of piano training81, 82, 83-85, statistically powered experimental studies are lacking.  Thus, 
we propose to examine the efficacy of piano training in a phase II randomized trial. Per Onken’s model of be-
havioral interventions, we are examining efficacy in a research setting1.   

 
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4 STUDY DESIGN 
 
A randomized clinial trial (RCT) with two arms (piano training and music listening instruction) across two lev-
els of cognitive functioning (cognitively intact older adults with and without MCI) will be rigorously conducted 
over three project years.  Potentially eligible participants will complete telephone screening, in-person baseline, 
and if needed, a clinical assessment to diagnose MCI, will be randomized to complete piano- or music listening 
instruction, and will complete immediate post-training assessments.  This is a phase II trial to test the efficacy of 
a promising behavioral intervention (i.e., piano training) in a research setting1. 
 
5 SELECTION AND ENROLLMENT OF PARTICIPANTS 
5.1 Inclusion Criteria 
 
Inclusion criteria will be:  
 
• aged 60 years or older  
 
• willingness to provide informed consent  
 
• willingness to complete up to 23 study visits at USF including attending in-lab intervention two times a 
week for a three-month period with the goal of completing 20 sessions.  
 
• ability to speak and understand English 
 
• Montreal Cognitive Assessment score of 20 or higher (score 20 to 30 inclusive)  
 
• intact vision (binocular near visual acuity of 20/50 or better tested with a standard near visual acuity 
chart) 
 
• adequate hearing acuity (no greater than a moderate hearing loss [thresholds <70 dB HL] in the mid-
frequency range  [1000, 2000 Hz] in at least one ear as determined by a standard pure tone hearing eval-
uation) 
 
• Music Reading Assessment score of 18 or lower (score 0-18 inclusive) 
 
• ability to understand study procedures and comply with them for the length of the study in the tester’s 
opinion (and other study personnel opinion who interact with participant, such as the study physician) 
 
5.2 Exclusion Criteria 
 
Exclusion criteria will be:   

 
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• moderate or worse depressive symptoms (GDS short form score >=5)    
 
• previous participation in USF Cognitive Aging Lab or Music Research and Testing lab1 intervention 
studies  
 
• previous participation in 10 or more hours of a computerized cognitive intervention computer programs 
(e.g., Lumosity, Posit Science Brain Fitness, InSight, or Brain HQ; Lace, CogMed, CogniFit, Happy 
Neuron, Dakim, DriveSharp or Staying Sharp by AARP programs)  
 
• currently enrolled in another research study 
 
• planning on being away for two or more weeks during the next five months (recruit later)  
 
• undergoing chemotherapy or radiation treatment or planning surgeries or other procedures requiring an-
esthesia within the next five months (recruit later)  
 
• four or more years of formal music training such as private lessons or group lessons on a specific in-
strument 
 
• ability to read music on two or more of the following clefs: Treble clef, Bass clef, Alto clef 
 
• four or more years of playing any one musical instrument 
 
• currently practicing or participating in any music activities- such as music performance or music reading 
or music lessons or music related courses 
 
• difficulty and pain in moving hands or fingers, or neuropathy (e.g., numbness or tingling) affecting 
hands, which interferes with the ability to use a keyboard2, or tremor in either hand, or missing any fin-
ger or portion of a finger 
 
• self-reported diagnosis of dementia, stroke, serious brain injury or neurological disorder 
 
• diagnosed by a physician or nurse with a TIA that occurred within the last 18 months  
 
• inability or unwillingness to give written informed consent at baseline 
 
• Clinical Dementia Rating Scale score of 1 or greater 
 
• Clinical diagnosis of dementia or other disorder that in the study physician’s opinion would limit the 
persons ability to participate in the study or benefit from the interventions  
 
 
1 Although the “Music Research and Testing Lab” was omitted from version 1, this criteria was included in telephone screening from 
the study onset. Potential participants were excluded if they reported prior participation in Music Research and Testing Lab studies. 
2 We added this clarification, “that interferes with ability to use a keyboard” to the screening process. 

 
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5.3 Enrollment Procedures 
Participants will primarily be recruited through the community, the Cognitive and Neurophysiology of Aging 
Lab registry, and mailing list of older adults residing in the area.  We may also use the Byrd Alzheimer’s Insti-
tute Community-Based Memory Screening program and the Department of Psychiatry and Behavioral Neuro-
sciences Memory Disorders Clinic (MDC) to enroll participants in the study.   
 
Recruitment and enrollment will occur across a pilot and five or six replicates.  Pilot replicate data will only be 
included in interim or final analyses if no significant changes to the study procedures or this protocol are made 
after the pilot replicate is completed.  Any changes to the protocol will be noted with the effective date and jus-
tification.   
 
Throughout the study period at least one Research Assistant in the Cognitive and Neurophysiology of Aging 
Lab will make recruitment phone calls and answer potential participant emails/calls.  Individuals who have ex-
pressed interest in our research will be telephone screened (i.e., inclusion/exclusion questionnaire) by lab staff.  
The study script should be followed for describing the study and answering any participant questions.  Screen-
ers will emphasize to the participants that they are committing to complete up to 23 in-person study visits (i.e., 3 
testing sessions and 20 intervention sessions) over the next five months.  Once eligibility and interest has been 
assessed, the final outcome is coded.  The final recruitment outcome will be coded as 1) Scheduled; 2) Not 
Scheduled and Will Not Try Again; or 3) Not Scheduled, Will Try Again. 
 
If the participant is not eligible because they are planning on being away or unavailable for more than 2 weeks 
in the next 5 months, or are planning on having major surgery or undergoing any type of anesthesia, chemother-
apy, or radiation treatment in the next 5 months, we will attempt to recruit them for the next replicate.   
 
The study coordinator will oversee recruitment and serve as a primary contact for study participants.   
 
Those deemed initially eligible from telephone screening will complete an in-person screening at the Cognitive 
and Neurophysiology of Aging Lab.  This in-person screening will include the Montreal Cognitive Assessment 
(MoCA), Geriatric Depression Scale, vision and hearing screenings as well as the Music Reading Assessment 
(MRA) to further confirm eligibility (See Inclusion/Exclusion above for details).  
 
Those potentially eligible based on completion of these measures will further complete baseline cognitive, CAP, 
and everyday functional measures.  
 
Those eligible who score 263 or better on the MoCA will be enrolled in the study and referred to the study co-
ordinator for randomization.   
 
Those potentially eligible who score between 20 to 25 on the MoCA who were not referred by the MDC or 
study physician will also complete a clinical evaluation visit.  A cut-point of 20-25 on the MoCA is indicative 
of probable MCI, while less than 20 is suggestive of dementia88.  
 
 
 
3 The MoCA cutpoint was changed from 27 to 26 to use the more traditional and accepted value for impairment. Those who score be-
tween 20 to 25 will complete the clinical evaluation, rather than those who score 20 to 26.  

 
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The purpose of the clinical evaluation is to determine if participants have MCI or dementia. The clinical evalua-
tion visit will include subtests of the National Alzheimer’s Coordinating Center Uniform Data Set (NACC) neu-
ropsychological battery and an exam by a study physician.  Subtests of the NACC battery will be used to deter-
mine MCI status and exclude dementia.  The NACC battery subtests to be administered include the Clinical 
Dementia Rating Scale, the Multilingual Naming Test, the Benson Complex Figure Copy immediate and de-
layed subtests, the Craft Story 21 immediate and delayed recall subtests, Functional Assessment Scales, and 
Clinical Diagnosis Form, completed by a study physician who is a geriatric psychiatrist. 
 
An exception to the above procedure will be for patients with MCI who were referred from the USF Health 
Memory Disorders Clinic (MDC) or a study physician who have already undergone clinical evaluation in the 
past 6 months.  Eligible and enrolled participants referred from the clinic with prior MCI diagnosis and evalua-
tion in the clinic completed within the past 6 months will be referred to study coordinator for randomization. 
 
In replicate 1 and later replicates, we plan to request lab results from the past year from those who score 20-25 
on the MoCA.  The purpose is to rule out medical causes of cognitive decline that are treatable.  If copies of lab 
results are not obtained at the baseline visit, we will request that the participant complete a release of medical 
records.  If we do not receive medical records by the clinical evaluation, and the study physician recommends it, 
we may draw blood and order lab tests that may include: 
• 
CBC  
• 
Metabolic panel 
• 
Thyroid Stimulating Hormone (TSH) 
• 
B12 
• 
D 
• 
Folic Acid 
 
Any results not within normal limits will be reviewed by a study physician and communicated to the participant.   
 
Those without any clinically significant abnormalities that would likely interfere with their ability to benefit 
from intervention4 will continue in the study.  
 
5.4  Describe consent procedures.  
 
Written informed consent from participants will be obtained prior to in-person screening at the first study visit.  
Research Assistants who have completed human subjects training and are approved by the Institutional Review 
Board will explain the study procedures, offer to read the consent form to the participant (and will do so, if de-
sired), answer any questions, and obtain informed consent.  A flow chart that details the study visits and time-
line will be provided to the participant to help explain the study procedures.  Participants will be encouraged to 
take time to consider whether they wish to participate in the study.  The person obtaining consent will leave the 
room to provide the participant time to read and consider the informed consent statement.  The participant will 
be provided an opportunity to ask questions prior to signing the consent (as well as throughout the study).  A 
copy of the consent form will be provided to the participant.  
 
 
4 We added “and communicated to the participant”, and we added the clarification, “that would likely interfere with their ability to 
benefit from intervention”.   

 
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All signed consent forms will be kept in a locked filing cabinet separate from the data to ensure confidentiality.  
In the data quality control process, each consent form will be reviewed to ensure accurate completion and pro-
tocol adherence.   
 
• Informed consent will be an agreement between the investigators and each participant having the capaci-
ty to understand and make an informed decision.  Consent will be obtained prior to each potential partic-
ipant’s participation in this study.  
 
• Each individual participating in this study will be made aware of the fact that his or her participation in-
volves research and the intent of the research, the expected duration of their participation and a descrip-
tion of the procedures that will be followed.   
 
• Each participant will be made aware of the reasonably expected benefits he or she might receive, as well 
as any risks or potential discomfort that are involved.   
 
• Each participant will be made aware of alternative procedures that are available to him or her.   
 
• Each participant will be made aware that his or her records will remain confidential, but that the NIH, 
IRB, and OHRP have the right to inspect his or her records.   
 
• Each participant will be told that his or her participation in the clinical study is voluntary, without force 
or influence from the investigators or research staff. 
 
• Each participant will be given the name and method of contacting the appropriate person(s) to answer 
his or her questions about the research and in the unlikely event of research-related injury. 
 
5.5 Describe the procedure for obtaining intervention group assignment 
 
The study coordinator with the statistician will randomize participants stratified by MCI status.  Participants 
with and without MCI will be randomized in a 1:1 ratio to either piano training or the active control condition of 
music listening instruction.  To ensure balance throughout enrollment, randomization will be stratified by MCI 
status (present vs. absent) and conducted in varying blocks of participants as designed by Co-I Ji.  Dr. Ji will 
generate the stratified permuted random blocks using R.   Dr. Ji will maintain the random seed and the computer 
codes and will send the randomization list to the clinical trial coordinator.  The treatment allocation will be de-
noted as A or B and recorded on the randomization form by the clinical trial coordinator.  The study coordinator 
will control access to the randomization list and know whether A (B) stands for intervention (control).  Study 
investigators Edwards, Lister, and Andel will remain blind to participant condition.  The testers will remain 
blind to participant condition. The trainers (including Co-I Bugos) and clinical trial coordinator will be aware of 
participants’ randomized condition.  
 

 
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5.6 STUDY INTERVENTIONS 
5.7 Interventions, Administration, and Duration 
 
There are two arms in this study including group piano training (intervention) and music listening instruction 
(active control).  Both of these arms are described to participants as “music training”.  The detailed procedural 
protocol for both training arms can be found here:  P:\CBCS\CSD CAL\Study 15 Music Training NIA\Trainer 
Docs\Study 15 Music Training Procedure Protocol…. or upon request to the PI.   
 
The content protocol for the piano training arm can be found here P:\CBCS\CSD CAL\Study 15 Music Train-
ing NIA\Trainer Docs\Piano training Manual_JB_Copyright_2018.docx or upon request to Co-I Bugos. 
 
The content protocol for the music listening instruction arm can be found here P:\CBCS\CSD CAL\Study 15 
Music Training NIA\Trainer Docs\Music Listening PowerPoints.zip or upon request to the PI.   
 
Participants will be scheduled by the trainers or study coordinator for in-lab intervention phase sessions in 
groups of up to 10 individuals by randomized condition.  We are limited to 10 persons per class due to the phys-
ical space available for the music listening condition.  The piano and music listening labs are located on the 
USF campus and both can accommodate 10 participants in a group intervention session.  Scheduled participants 
will be sent an appointment letter with directions and a map (by mail if visit is 8 or more days, by email if visit 
is within the next 7 days).  Participants will be reminded one to three days prior to the first intervention visit by 
telephone by a Research Assistant.   
 
Both conditions will attend training two times a week for 10 weeks with the goal of completing a total of 20 
sessions before post-testing.  Participants will be encouraged to complete training two times a week without 
missing two or more consecutive sessions.  Make up sessions will be held for each condition weekly, as need-
ed5.  The training phase can be extended up to a maximum of 15 weeks, if needed to complete 20 sessions.  Par-
ticipants will be encouraged to complete post-test regardless of intervention adherence.  We will code partici-
pants as completing training if 16 or more sessions are completed (16 to 20 sessions inclusive).  All training 
sessions must be completed within 15 weeks of training start date.  The Trainers will confirm or reschedule the 
participant to complete an immediate post-intervention assessment within 2-60 days of their final in-lab inter-
vention session (i.e., training completion date), or within 18 weeks of baseline if none of the the intervention 
phase was completed.  See further details below in Intervention Phase and Retention. 
5.7.1 Prohibited Interventions 
 
Participation in cognitive interventions aimed toward enhancing or maintaining cognitive abilities will not be 
allowed.  This includes computerized cognitive training or stimulation exercises aimed at countering cognitive 
decline.  Participants will be instructed not to participate in such activities during the entire study period.  For-
mal music training, such as private music lessons or group music classes or courses related to music (as exam-
ple voice instruction or musical instrument instruction or a music appreciation class), outside of the assigned 
activities will not be allowed.  Individuals who participate in such interventions will be dropped from the study.  
 
 
5 The following sentences were omitted:  Each of the conditions will have a textbook and will be assigned weekly homework. Partici-
pants will be asked to report the amount of time they spend outside of class completing such activities.  

 
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Only data points prior to such participation will be included in analyses.  Participant will be deemed ineligible 
at the time such an incident occurs.  
 
If the participant opts to undergo a surgical procedure that requires general anesthesia or chemotherapy or radia-
tion, we will attempt to complete post-test prior to the surgery or procedure.  If the participant undergoes gen-
eral anesthesia, chemotherapy, radiation, experiences a head injury, stroke, or heart attack, the participant will 
be withdrawn from the study.  All available data points prior to the incident will be used in analyses.  The par-
ticipant will be deemed ineligible at the time of the incident.  
 
Participants will be provided a post-test appointment letter that will include instructions regarding these items 
when scheduled for post-test.  Also, the trainers will remind participants of these instructions on the first day of 
training.   
 
5.8 Adherence Assessment 
To address the study aims, we will use intent-to-treat analyses as detailed in section 9.5 below.  We will report 
the percent of participants who were adherent to the assigned piano training or music instruction exercises.  Par-
ticipants will be considered adherent if they complete at least 80% of the assigned sessions (at least 16 of 20 
sessions).  The Research Assistant Trainers will record dates that participants attended in-lab training.  Partici-
pants will be allowed up to 15 weeks to complete the assigned exercises between baseline and post-test.   
 
Primary data analyses will be intent-to-treat.  Sensitivity analyses will further examine effects of piano training 
relative to music instruction among those who were adherent (i.e., who completed 16 or more hours) in both 
conditions.   

 
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6 CLINICAL AND LABORATORY EVALUATIONS 
Schedule of Evaluations 
Evaluation 
Measure 
type 
Telephone 
Screening 
(≤ 60 days) 
Baseline 
Clinical Evalua-
tion 
(≤ 45 days) 
Randomization 
<3  
wks 
Intervention 
Up to 15 
wks 
Post-Test  
>2 days 
and <=60 
days  
Informed Consent 
R 
 
X 
 
 
 
 
Inclusion/Exclusion Questionnaire 
I/E 
X 
X 
X 
 
 
X 
Geriatric Depression Scale (GDS) 
I/E, C 
 
X 
 
 
 
 
Demographic Data 
C 
 
X 
 
 
 
 
Montreal Cognitive Assessment (MoCA) 
I/E, C 
 
X 
 
 
 
 
Memory Screening History 
IV 
 
X 
 
 
 
 
Hearing and vision screening 
Pure-tone Hearing Thresholds 
Speech Recognition Threshold 
Near Visual Acuity 
 
I/E, C 
 
X 
 
 
 
X 
Music Reading Assessment 
I/E 
 
X 
 
 
 
 
Central Auditory Processing 
Time Compressed Speech 65% 
Words-in-Noise Test 
Dichotic Digits Test 
Dichotic Sentence Identification test 
ATTR 
O 
 
X 
 
 
 
X 

 
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Evaluation 
Measure 
type 
Telephone 
Screening 
(≤ 60 days) 
Baseline 
Clinical Evalua-
tion 
(≤ 45 days) 
Randomization 
<3  
wks 
Intervention 
Up to 15 
wks 
Post-Test  
>2 days 
and <=60 
days  
Cognitive Assessment Battery 
Trail Making Test 
Digit Coding 
Verbal Fluency 
- BHR, Clothes/ Girls’ Names, Vegetables/ 
Musical Instruments (baseline) 
- FAS, Animals/ Boys’ Names, 
Fruits/Furniture (post-test) 
 
O 
 
 
X 
 
 
 
 
 
X 
Everyday Functional Assessment 
Timed IADL Test  
Test of Everyday Attention 
 
O 
 
X 
 
 
 
X 
Questionnaires 
Health Questionnaire 
Medication Audit 
Health Changes  
SC 
 
 
X 
X 
 
 
 
 
 
 
X 
Adverse Events 
R 
 
X 
X 
 
X 
X 
Clinical Evaluation 
NACC assessments: 
-Clinical Dementia Rating Scale 
-Craft Story 21 Recall - Immediate and De-
layed  
-Benson Complex Figure Copy and recall 
-Multilingual Naming Test 
-Functional Assessment Scale 
-Clinician Diagnosis form 
SC 
 
 
X 
 
 
 

 
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Evaluation 
Measure 
type 
Telephone 
Screening 
(≤ 60 days) 
Baseline 
Clinical Evalua-
tion 
(≤ 45 days) 
Randomization 
<3  
wks 
Intervention 
Up to 15 
wks 
Post-Test  
>2 days 
and <=60 
days  
Lab Assessments (upon IRB approval) 
CBC  
Metabolic panel 
Thyroid Stimulating Hormone (TSH) 
B12 
D 
Folic Acid 
MRI (if funding acquired) 
IV 
 
 
X 
 
 
 
Randomization 
IV 
 
 
 
X 
 
 
Advanced Measures of Music Audiation 
(AMMA)- Day 1 of Training 
E 
 
 
 
 
X 
 
Basic Piano Measure (BPM) OR 
Music Listening Measure (MLM)- At days 1 
and 20 of training 
E 
 
 
 
 
X 
 
General Self-Efficacy and Music Perfor-
mance Self-Efficacy (At days 1 and 20 of 
training) 
E 
 
 
 
 
X 
 
Intervention sessions   
C 
 
 
 
 
X 
 
NICT Expectations Questionnaire (Between 
days 17 and 20 of training) 
IV, C 
 
 
 
 
X 
 
Tester blinding assessment 
IV 
 
 
 
 
 
X 
C=covariate, E=exploratory, I/E=inclusion/exclusion, IV=internal validity, O=outcome, R=regulatory, SC=sample characterization   

 
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6.1 Timing of Evaluations 
 
Prior to Randomization: The baseline visit should be scheduled within 60 days of the telephone screening inter-
view.  Informed consent must be obtained first at the baseline study visit prior to any data collection.  The GDS, 
MoCA, Music Reading Assessment, as well as hearing and vision screenings must be completed at baseline, 
prior to the clinical evaluation.  The central auditory processing measures, cognitive assessment battery, every-
day functional assessments and health questionnaire should be completed at baseline, but missing items can be 
administered at the beginning of the clinical evaluation, if needed.  The clinical evaluation should be completed 
within 45 days of the baseline visit completion.  The NACC assessments will be completed at the clinical eval-
uation.  All the aforementioned measures for the baseline and clinical evaluations should be completed prior to 
randomization and must be completed prior to the training content being administered.  It will be allowable to 
administer any of the aforementioned measures that are missing from the baseline or clinical visits after ran-
domization, but administration will not be allowed once the participant has received any piano or music listen-
ing training.   
 
Prior to Training Content:  Any biomarker assessments must be completed prior to training content (blooddraw, 
mri, etc.).  The general and music self efficacy measures can be administered at either baseline or after random-
ization on day 1 of training, but must be administered prior to participants receiving any piano- or music listen-
ing- content training.  If the basic piano or music listening measures are administered prior to randomization, 
the participant will be withdrawn from the trial and a protocol deviation will be noted.  The pre-training basic 
piano and music listening measures must be administered after randomization and must be administered before 
training content is delivered.  If any of the aforementioned baseline, clinical, or pre-training measures are ad-
ministered after the training content began, a protocol deviation will be noted.  Such measures will be coded as 
missing and will not be used in analyses.   
 
Intervention Content:  The AMMA should be administered on day 1 of training, but it will be allowable to ad-
minister the AMMA within the first three training sessions.  The NICT questionnaire should be administered 
between days 17 and 20 of training, but can be administered at the beginning of the post-test visit if it not com-
pleted during the intervention phase.  The NICT questionnaire must be administered prior to the post-test as-
sessments of CAP, cognition, or everyday function.  If the NICT questionnaire is administered after the post-
test assessments of CAP, cognition, or everyday function a protocol deviation will be noted.  In this instance the 
NICT questionnaire will be coded as missing and will not be used in analyses.  The post-training basic piano 
measure and music listening measure must be completed after all training content is delivered and prior to the 
post-test assessment visit.  The trainer should confirm with the study coordinator that all scheduled intervention 
sessions have been completed and the basic piano or music listening assessments are completed prior to the 
post-test visit.  The post-test visit can be rescheduled, if needed, but must occur within 18 weeks of baseline if 
no intervention was completed, or within 60 days of training completion date (>= 16 sessions completed).  Par-
ticipant post-tests will be conducted after the intervention phase for those who complete between 1-15 sessions. 
6 
 
 
 
6 The sentence “Participant post-tests will be conducted after the intervention phase for those who complete between 1-15 sessions” 
and “(>= 16 sessions completed)” was added for clarification. 

 
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Post-Test Content:  The post-training general and music self-efficacy measures must be completed after all 
training content is delivered, but may be completed at the beginning of the post-test visit, if needed.  The post-
test assessments of CAP, cognition, and everyday functional measures cannot be completed until after a delay 
of at least 24 hours after the final intervention session (i.e., training completion date).  The post-test assessments 
of CAP, cognition, and everyday function should ideally take place within 2-30 days of the training completion 
date (>= 16 sessions completed).  The maximum window for post-test is that it must be completed within 60 
days of training completion, or within 18 weeks of baseline if no intervention phase was completed.  Participant 
post-tests will be conducted after the intervention phase for those who complete between 1-15 sessions.6 
6.1.1 Pre-Randomization Evaluations 
 
Telephone screening is an initial interview conducted by Cognitive and Neurophysiology of Aging Lab staff to 
ascertain potential eligibility of the participants per the inclusion and exclusion criteria.  Eligibility will be eval-
uated by the telephone screening.  If ineligible the reason will be documented.  Procedures for eligibility and 
enrollment are detailed above.  Those potentially eligible will be scheduled to complete a baseline visit within 
30 days.  If the telephone screening questionnaire has not been completed within 60 days of scheduling base-
line, it should be repeated.   
 
A subject ID number will be assigned on the participants visit control sheet (VCS) by the tester at their first 
study visit.  Informed consent will be obtained at the beginning of the first-in person visit, the baseline visit.  
Participants will be provided a flow chart that explains all of the study visits, duration of the visits, and the tim-
ing of the visits during the consent process.  At the baseline visit, participants will complete the MoCA, GDS, 
hearing, and vision screenings, and MRA to determine eligibility.  Those not eligible due to MoCA, GDS, hear-
ing or vision scores will be referred to the appropriate professionals for treatment.  Additionally, participants for 
whom outer or middle ear pathology is indicated through otoscopic examination will be referred to an otolaryn-
gologist or other professional and will not continue in the study.  Those participants who are eligible will be en-
rolled in the study and will further complete thorough assessments of CAP, cognition, and everyday function.  
A questionnaire assessing health will be completed.  Research Assistant Testers who will remain blind to partic-
ipant condition will complete these assessments.  Participants will be referred to the study coordinator for ran-
domization.   
 
If the participant meets eligibility criteria, was not referred from the MDC or a study physician, but scores be-
tween 20-25 on the MoCA, a clinical evaluation will be performed by a study physician to ascertain diagnosis 
of mild cognitive impairment and ensure that clinical inclusion criteria are met and no exclusion criteria are ev-
ident.  Reasons for ineligibility will be documented.  This clinical evaluation should be completed as soon as 
possible following the baseline visit and should take place within 45 days after the baseline visit. 
 
6.1.2 Intervention Phase 
 
Within three weeks of baseline or clinical evaluation phase completion for each replicate, the Clinical Research 
Coordinator and/or Research Assistant Trainers will randomize enrolled participants in collaboration with Dr. Ji 
and schedule their first intervention visit.  Participants will complete randomized exercises in groups of up to 10 
individuals at in-lab sessions that are 90 minutes in duration, occurring two times a week over the subsequent 
~3 months.  The goal will be for 95% of the training sessions to be conducted in groups of 3-10 persons. Clas-

 
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ses will be arranged such that those with MCI primarily train together within randomized condition.  The inter-
vention phase will continue until 20 total sessions are completed or 15 weeks have passed.  The trainers will 
confirm or reschedule the participant to complete an immediate post-intervention assessment.  The trainers will 
make certain that all scheduled intervention sessions are completed prior to the post-test visit and that no train-
ing sessions are scheduled after the post-test visit. Fidelity will be assured as described below (See Quality As-
surance below). 
 
At the first training sessions the trainers will administer the Advanced Measure of Music Audiation (AMMA), 
General Self-Efficacy Form, and the Music Performance Self-Efficacy form.  Those in the music listening con-
trol group will complete the music listening measure while those in piano training will complete the basic piano 
measure.  The training protocols detail all of the procedures and content protocols detail the training arms.  
Please see: P:\CBCS\CSD CAL\Study 15 Music Training NIA\Trainer Docs\Study 15 Music Training proce-
dure protocol.   
 
Between sessions 17 and 20, the trainers will administer the The Cognitive Training Expectations NICT ques-
tionnaire to examine participants’ attitudes and expectations about the potential effects of the intervention com-
pleted.  If a participant does not complete this questionnaire during the intervention phase, it may be completed 
at the beginning of the post-test visit.   
 
At the participants’ last training visit, the self efficacy measures will again be completed, and the trainer will 
verify that participants learned basic musical concepts and skills introduced in the program with at least 70% 
accuracy.  If participants score less than 70% correct on the Basic Piano Measure (for piano training condition) 
or Music Listening Measure (for music listening condition), as applicable to randomized condition, at their last 
scheduled training session and if they have completed less than 20 sessions, then the trainer will an attempt to 
schedule additional make-up training sessions to complete up to 20 sessions.  The trainers will make certain that 
the post-test visit is rescheduled, if needed.  All training sessions must be completed within 15 weeks of training 
start date.  
 
6.1.3 Post-Test 
 
At the post-test visits, cognition-,CAP- and everyday function outcome measures will be re-administered by 
blinded Research Assistant Testers.  Participants will complete the CAP, cognition, and everyday function 
measures administered at baseline.  Alternative forms will be used, as available.  The Tester will complete a 
form indicating whether or not they know the randomized condition of the participant to assess success of blind-
ing and will confirm continued eligibility.  A questionnaire will be administered to check for adverse events 
during the course of the study.  Participants will be encouraged to complete post-test regardless of adherence.  
We will attempt to complete post test for up to 60 days after the training completion date (>=16 sessions com-
pleted) or 18 weeks post baseline if intervention was not attempted or completed.  Participant post-tests will be 
conducted after the intervention phase for those who complete between 1-15 sessions.6 
 
6.2 Overall Project Timeline 
A detailed and up-to-date field schedule will be maintained to indicate the dates of each phase of the study for 
each of the pilot and five to six replicates.  This schedule can be located at P:\CBCS\CSD CAL\Study 15 Music 

 
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Training NIA.  Study data will be collected across a pilot and five to six replicates.  The field schedule indicates 
the timeline for each phase of data collection during each replicate.  Each replicate will last between 180 to 210 
days.  There should be at least two weeks between completion of the baseline/clinical phase and beginning of 
training phase to allow for randomization, scheduling, and coordination of intervention phase.  The training 
phase will be 10-15 weeks in duration.  We will attempt to complete post test for up to 60 days after training 
completion date (or 18 weeks post baseline if intervention was not completed).   
 
6.3 Intervention Discontinuation Evaluations Retention 
 
A CONSORT chart will be completed at the end of the trial.  Participant status (e.g., screened, enrolled, refused, 
ineligible) will be recorded at each assessment.  Reasons for ineligibility will be documented.   
 
We will employ an intent-to-treat design as detailed in section 9.5 below.  Participants who discontinue inter-
vention will be encouraged to complete study visits and we will make every effort to follow and evaluate all 
enrolled participants.  
 
6.3.1 Retention 
 
We will employ several methods to encourage participation.  In the consent process, we will stress that enrol-
ling in the study involves a commitment to complete up to 23 in person visits: 3 testing visits and up to 20, 90-
minute, in-lab training visits.   
 
We find that asking participants to schedule their next appointment visit at the end of each study visit encour-
ages continued participation.  At each testing visit, we will provide a copy of the study flow chart with ap-
pointment times completed to remind them of the study visits and their progress.   
 
Participants will be reminded the day before all scheduled testing visits by phone of their appointment time.  
They will be reminded 1-3 days prior to their first intervention (i.e., training) session.   
 
We will indicate for each participant the best manner (e.g., email, phone, cell) and times to contact them to fa-
cilitate communication.  We will also ascertain information for a secondary contact person for each study par-
ticipant to facilitate follow-up.  Such secondary contact individuals will be approached if we lose contact with 
the enrolled study participant with no response to phone calls or a letter after repeated attempts over a 90-day 
period.   
 
At the first in-lab intervention visit, participants will complete a statement indicating their commitment to com-
plete training sessions two times a week in order to complete 20 sessions.  The statement will be signed by the 
participant and a witness.  For any planned absences, an alternative make-up session will be scheduled.  Typi-
cally in-lab intervention sessions are offered at regular times on Tuesday, Thursday or Monday, Wednesday, 
with make-up sessions scheduled on Friday.  However, every effort will be made to accomodate participants’ 
schedules (e.g., offering Saturday training sessions).  The trainers will provide a schedule of in-lab training at 
the first intervention study visit.  In week 8 of training, the trainers will confirm post-test visits for each partici-
pant.  At this time, participants will again each be provided with a flow chart of the study visits with their spe-

 
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cific study visit dates indicated.  For any participant who could not be confirmed or rescheduled, the trainer will 
refer this person to the study coordinator who will assist.   
 
Participants who miss an in-lab training session unexpectedly (i.e., without having a make-up session sched-
uled) will be contacted by the Research Assistant Trainer or lab staff within 3 days of the missed session.  Par-
ticipants will be requested to schedule a make-up in-lab training session as soon as possible.  Participants will 
be reminded that their goal is to complete 20 sessions before post-test I visit.  We will further encourage the 
participant to return for their post-test assessment visit regardless of training adherence.  If we do not success-
fully make contact with the participant within the first three days, we will continue to attempt to contact them 2-
3 times per week for three weeks.  If we are still unable to reach the participants, we will send a letter requesting 
a reply.  Secondary contact individuals will be approached if we lose contact with the enrolled study participant 
with no response to phone calls or a letter after repeated attempts over a 90-day period.   
 
If participants are finding it difficult to attend the in-lab sessions, we will allow up to three sessions of training 
to be completed each week (1 session per 24 hours) until the intervention phase has ended or 15 weeks have 
passed since training began.  
 
6.3.2 Documentation of MCI or dementia 
For participants that score between 20-25 on the MoCA and who have not been referred by a study physician, 
the clinical evaluation visit will be completed.  The clinical evaluation visit will be completed after baseline and 
before randomization.  It should take place within 45 days of baseline, if possible.  Participants will be request-
ed to bring an informant (a relative or spouse or close friend who has regular contact with them who could re-
port on their everyday activities).  The informant will provide assent to participate in the study.  We will allow 
informants to be interviewed by telephone, if unable to attend in-person.  An evaluation will be performed by a 
qualified clinician to determine/confirm a diagnosis of MCI or dementia.  After the participants complete 
NACC assessments, study physicians will evaluate the participant at the end of the clinical evaluation visit.  The 
study physician will complete the Clinical Diagnosis Form and determine eligibility.  
6.3.3 Concomitant Treatments 
 
Participants will be allowed to undergo their usual treatment for health conditions.   
6.3.4 Study Intervention Modifications 
 
If at interim analyses, an effect size of d= 0.25 or greater reflecting improvements from piano training relative 
to controls is not observed on at least one of the cognitive outcomes measures (verbal fluency, Trails, Digit 
Coding) relative to controls, we will randomize the remaining participants to 25 sessions (i.e., 37.5 hours) in-
stead of 20 sessions (i.e., 30 hours) of training.  
6.3.5 Measures  
• Eligibility will be assessed in-person by measuring near visual acuity, hearing, cognitive status (MoCA), 
Music Reading Assessment (MRA), and depressive symptoms (GDS).  These variables and 
demographic information may also be considered as covariates in analyses.  

 
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o Near Visual Acuity will be measured at 40 cm using standard procedures with a Sloan letter 
chart, and the log minimum visual angle resolvable will be quantified 89.   
o Hearing thresholds will be assessed using standard procedures (American Speech-Language-
Hearing Association. (2005). Guidelines for manual pure-tone threshold audiometry [Guidelines].  
Available from www.asha.org/policy.) and calibrated equipment from the USF Hearing Clinic.  
Otoscopic exam will be performed prior to inserting ear phones for pure tone testing. Pure tone 
air conduction thresholds in dB will be measured at 250, 500, 1000, 2000, 4000, 6000, and 8000 
Hz in each ear.  At post-test, these thresholds will be re-measured only if the participant reports a 
noticeable change in hearing since baseline testing (per Health Changes Checklist).  Prescription 
for, use of (e.g., hours per day), and type of hearing aids will be recorded for each ear. 
o Speech Recognition Threshold (SRT) will be assessed using standard procedures (American 
Speech-Language-Hearing Association. (1988). Determining threshold level for speech [Guidelines]. 
Available from www.asha.org/policy.) and calibrated equipment from the USF Hearing Clinic.  
An SRT will be measured for each ear.  At post-test, these thresholds will be verified and presen-
tation levels of all auditory tests will be adjusted if the SRT in either ear varies by more than +/- 
5 dB.  
o The Montreal Cognitive Assessment (MoCA) will be used to examine participants’ cognitive sta-
tus 88.  This assessment has good internal consistency, Cronbach’s α=.83, and test-retest reliabil-
ity, r=.92 88.   
o The Geriatric Depression Scale (GDS) will be used to screen depressive symptoms.  The GDS 
has 92% sensitivity and 89% specificity to detect depression and has good test-retest reliability 
of r=.75-.81 90, 91.   
o Music Reading Assessment (MRA) 92 consists of a 40-item measure of basic music reading abil-
ity with 20 treble clef items and 20 bass clef items.  
 
• Outcomes include binaural central auditory processing (CAP) measures of: Time Compressed Speech 
65%, Words-in-Noise, Dichotic Digits Test, Dichotic Sentence Identification, and Adaptive Tests of 
Temporal Resolution.  If any participant expresses discomfort with the presentation level, it will be ad-
justed to a comfortable level.  The presentation level is recorded for each measure. 
 
o Time Compressed Speech Test (TCS).  The TCS test assesses both auditory temporal pro-
cessing and degraded speech understanding.  It is a word recognition task in which the timing 
feature of the speech is digitally manipulated to resemble rapid speech 93, 94.  TCS performance 
worsens with age 95.  Auditec Recordings Northwestern University Auditory Test Number 6 rec-
orded sentences (e.g., “Say the word jug”) are available at both 45% and 65% compression (65% 
is faster).  The listener must repeat the last word (test item), after the introductory sentence “Say 
the word”, which preceeds every test item.  The talker is female and approximately 4 sec of si-
lence separate the stimuli.  Participants are asked to repeat 50 words delivered through insert 
earphones at a level of 50 dB SL (re: SRT), and percent correct is calculated.  Normative data on 
time compressed speech performance in adults have been described elsewhere 96.  For the present 
study, only the 65% condition will be used. 
o Words-in-Noise Test (WIN).  The WIN is a test of degraded speech understanding or speech 
understanding in noise.  It was developed as an instrument that quantifies the ability of listeners 
to understand speech in background multi-talker babble 97.  The stimuli are the Northwestern 
University Auditory Test Number 6 monosyllabic words with a static preceding sentence (e.g., 
“Say the word road”) and a background of multi-talker babble.  The talker is female and approx-

 
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imately 3 seconds separate each sentence.  Two 35-word lists are used; 5 words are presented at 
each of 7 signal-to-noise ratios (SNRs).  The SNRs are presented in a decending manner, from 
24 to 0 in 4-dB increments.  The babble is maintained at a fixed level.  Listeners must repeat the 
last word of the sentence, ignoring the babble.  The WIN uses a modified method of constants to 
establish the SNR at which 50% correct performance is achieved on the materials.  The 50% 
point is computed with the Spearman-Kärber equation 98, 99 [50% = 26 – (#correct)(0.8); “0.8” is 
the attenuation step size (4 dB) divided by the number of words per step (5)].  The WIN has been 
established as a reliable measure (intra-class correlation coefficient = 0.88) 100, 101. 
o Dichotic Digits Test (DDT).  The DDT is a test of binaural processing that uses a closed set of 
stimuli (numbers), thus having a relatively low linguistic load.  The DDT consists of numbers 
between one and nine, excluding the two-syllable number seven (r=.79-.97)102.  Two numbers 
are presented to the right ear while two numbers are presented simultaneously to the left ear, for 
a total of four numbers.  The talker is male.  Approximately four seconds of silence separate each 
set of four numbers, and approximately one second separates the individual pairs within a set of 
four.  The participants are instructed to repeat all four numbers that were presented to them, in 
any order.  Twenty-five sets of four numbers each are presented, for a total of 100 stimuli.  The 
test is scored as a percent correct out of the 100 numbers presented.   
o Dichotic Sentence Identification (DSI).  The DSI test is used to assess binaural speech under-
standing in competition and also falls into the broad category of degraded speech understanding.  
The DSI stimuli are identical to those of the Synthetic Speech Identification Test (SSI) 103, rec-
orded grammatically correct yet meaningless sentences (e.g., “Small boat with picture has be-
come”).  Unlike the SSI, for the DSI a competing sentence is delivered to the contralateral ear.  
The DSI is presented at a level of 50 dB SL (re: SRT) via insert earphones; the talker is male and 
approximately 8 sec of silence separate the sentences.  Participants are required to select both 
sentences heard from a closed set list of 6 sentences, and results are scored as percent correct.  
Test-retest reliability of the DSI is high in older adults, r = .79 - .97.  Deficits in DSI perfor-
mance may be predictive of cognitive decline 104. 
o Adaptive Tests of Temporal Resolution (ATTR).  The ATTR105 is a copyrighted and freely 
downloadable test of auditory temporal processing.  Details regarding the ATTR have been pub-
lished previously105-107.  Briefly, the ATTR is used to measure gap detection thresholds using a 
three-interval, two-alternative forced-choice adaptive procedure targeting 70.7% correct gap de-
tection.  The stimuli used to define the silent gaps are ¼ octave narrow bands of noise (NBN) 
centered on either 1 kHz or 2 kHz.  Before the silent gap, the NBN is 300 ms in duration.  After 
the silent gap, the NBN varies randomly in duration between 250 and 350 ms.  The participant is 
presented with three intervals of sound, a reference interval, a standard interval identical to the 
reference interval, and a target interval.  In the reference and standard intervals, two NBNs sepa-
rated by a 1-ms gap are presented.  In the target interval, two NBNs separated by a gap of adap-
tively varying duration are presented.  The reference interval is presented first and the standard 
and target intervals are presented in random order, following the reference interval.  The partici-
pant’s  goal is to select the target interval from among the standard and target intervals.  The par-
ticipant is not allowed to select the reference interval.  Two subtests of the ATTR were used in 
the present study, the within-channel subtest for which NBNs before and after the gap are both 
centered on 2 kHz and the across-channel subtest for which the NBN before the gap is centered 
on 2 kHz and the NBN after the gap is centered on 1 kHz.  The ATTR was presented at a high, 
comfortable level, self-selected by each participant as described by Cox108.  Reliability for the 
ATTR has been established with intraclass r =.58-.87105. 

 
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• Outcomes also include cognitive measures:  Verbal Fluency Test (phonemic fluency, category fluency, 
and category switching), Trail Making Test, and Digit Coding 
o Verbal Fluency109.  Executive function will be assessed with phonemic, category, and category 
switching verbal fluency tasks.  Phonemic fluency consists of three, one-minute trials during 
which the examinee names as many words as can be thought of that begin with a given letter, ex-
cluding proper nouns, numbers, and the same word with a different suffix will also be assessed 
(test-retest reliability=.88)110.  Category fluency is designed to measure the speed and flexibility 
of verbal thought processes (r=0.82; sensitivity=.88; specificity=.96)109, 111.  A switching condi-
tion is included that requires participants to alternate between sets (e.g. naming fruits and furni-
ture) (r=0.51).  Different versions of this measure will be administered at baseline and post-test.  
The BHR, Clothes/Girls’ Names, and Vegetables/Musical Instruments will be administered at 
baseline while the FAS, Animals/Boys’ Names, and Fruits/Furniture version will be adminis-
tered at post-test. The recorded score is the number of correct items for each task.  
o Trail Making Test Part A.  Speed of processing is evaluated using the Trail Making Test Part 
A.  This test (r=.53-.64), requires participants to draw a line connecting a series of numbers in 
sequential order (1-2-3, etc)112.  The recorded score is the time required to complete the task113. 
o Trail Making Test Part B.  Executive function is evaluated using the Trail Making Test Part B, 
which is a reliable measure (r=.54-.62) that requires participants to draw a line connecting a se-
ries of number and letters in alternating, sequential order (1-A-2-B, etc) (Strauss et al., 2006).  
The recorded score is the time required to complete the task113, 114. 
o Digit Symbol Coding.  Cognitive speed of processing is evaluated using Digit Symbol Coding 
109.  This test consists of 135 blank squares that are paired with a number from one to nine.  A 
reference key links each number to a different geometric figure.  Using the reference key, partic-
ipants have 120 seconds to copy the geometric figure assigned to the number into the blank box-
es.  Scaled scores are obtained by subtracting the number of errors from the number of correct 
responses.  Lower scores indicate better performance.  Psychometric properties are reported in 
the manual. 
 
• Outcomes of everyday function include the Timed IADL and TEA tests 
o Timed IADL involves timed performance of five tasks encountered in daily life.  The previously 
validated tasks115 utilize real-world stimuli and represent five IADL domains, including commu-
nication (finding a telephone number in a phone book), finance (making change), cooking (read-
ing the first three ingredients on a can of food), shopping (finding two items on a shelf of pack-
aged foods) and medication management (reading the directions on a medicine bottle label).  
Scores are generated by combining the completion time and error code for each task per standard 
procedure.  Task scores are combined into a single composite by taking the average of z scores 
computed for each of the five tasks after error correction.  Test-retest reliability of the Timed 
IADL is r = .85 115. 
o The Test of Everyday Attention (TEA)116, 117 consists of eight sub-tests designed to measure 
different types of attention.  The subtests are designed to mimic everyday tasks that encompass 
both visual and auditory domains.  The test-retest reliability of versions A to B range from .59-
.86116.  Four of the eight subtests will be administered in this study and include: 
 Visual Elevator.  Participants count up and down floors as they follow a series of visual-
ly presented doors and arrows.  An accuracy (how many final floor numbers the partici-
pant gets correct out of 10) and timing scores (total time taken for the correct items) are 

 
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obtained.  The reported score is the total time taken divided by the number of switches 
for the correct items and the scaled score.  This subtest measures attentional switching117.  
 Elevator Counting wth Reversal.  As with the Visual Elevator subtest, participants 
count up and down as they follow a series of visually presented doors.  In this subtest 
however, the tones are at a fixed speed.  The recorded score is the number of correct an-
swers out of 10 and the scaled score.  This subtest measures auditory-verbal working 
memory117.  
 Telephone Search.  Participants search for symbols while searching for entries on a rep-
licated page of a telephone directory.  The recorded score is the time per target score 
(number of correctly detected symbols divided by the time taken to identify the correctly 
detected symbols) and the scaled score.  This subtest measures selective attention117.  
 Telephone Search While Counting.  Participants search the telephone directory while 
counting strings of tones simultaneously.  The recorded score is obtained by the com-
bined performance on the Telephone Search and Telephone Search While Counting gives 
a measure of divided attention, as well as the scaled score.  This subtest measures sus-
tained attention117.  
 
Exploratory measures  
 
Exploratory mesures include a measure of music aptitude and two self-efficacy measures.   
 
Advanced Measures of Music Audiation (AMMA) consists of 30 paired piano melodies that is used to evaluate 
music aptitude118.  Test -retesteliability for music majors is r=.89 and non-music majors, r=.83118.   
 
The General Self-Efficacy119 is comprised of 23 positive and negative items on a 14-point Likert scale ranging 
from strongly disagree (1) to strongly agree (14).  Internal reliability is established (α=.86-.71).  Items are de-
signed to reflect elements of effort, initiation, and persistence as described in Bandura’s social cognitive theory.  
 
An adapted version of the Music Performance Self-Efficacy Measure120 will be used.  This questionnaire 
(α=.97) consists of 24 items to which participants respond by selecting a number (0–100) to reflect strength of 
agreement to a specific statement regarding musical beliefs (0 = strongly disagree … 100 = strongly agree).  
The items included are based on Bandura’s sociocognitive theory and assess domains: mastery experiences 
(eight items), vicarious experiences (five items), verbal/social persuasion (six items), and physiological state 
(five items).  An example of an item from this measure is, “I have had positive experiences performing music in 
the past.” This measure has been used in studies with older adults121.  The adaptation from the original version 
includes a change in the order of the questions and changes in the wording of 7 questions.  More specifically, 
the question, “I have improved my music performance skills by watching professional musicians, who are simi-
lar to me in some way, perform well”, was changed to “I have improved my music performance skills by watch-
ing professional musicians perform well”.  The question, “My friends think I am a good performer on my pri-
mary instrument”, was changed to “My friends think I am a good performer on my piano”.  The question, “I 
have had positive experiences performing in large ensembles” was changed to “I have had positive experiences 
performing in large ensembles (more than 11 performers)”.  The question, “I have improved my music perfor-
mance skills by watching other students, who are similar to me in some way, perform well” was changed to “I 
have improved my music performance skills by watching someone I know perform well (parent, brother, sister, 
church member, etc,)”.  The question “I have had positive experiences performing solo, or, in a small ensemble” 
was changed to “I have had positive experiences performing music solo”.  The question, “I have had positive 

 
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experiences performing music in large ensembles” was changed to “ I have had positive experiences pefor-
maing music in a small ensemble (2-10 performers)”.  Lastly, the question “Performing with my instrument 
makes me feel good” was changed to “Performing on piano makes me feel good”.  
6.3.6 Questionnaires 
 
A health questionnaire will be administered at baseline to characterize the sample.  Participants are asked 
whether a doctor or nurse every told them that they any of the following conditions: arthritis, asthma and/or 
other breathing problems, cancer (other than skin cancer), chronic skin problems, diabetes, heart disease, heart 
problems (other than heart disease), high cholesterol, hypertention or high blood pressure, mood problems or 
anxiety, multiple sclerosis, osteoporosis, parkinson’s disease, stroke, TIA/mini-stroke within last 18 months, 
mild cognitive impairment or memory impairment, neuropathy, or any other significant illness.  
 
Participants’ expectations about the effects of intervention/control exercises on post-test outcomes will be ex-
amined as a potential covariate.  During the last week of the intervention stage, the Trainers will administer a 
modified version of the The Cognitive Training Expectations questionnaire to examine participants’ attitudes 
and expectations about the effects of the intervention received on cognition and everyday function122.  The 
NICT questionnaire was modified to refer to “music training” or “piano training”, and the “memory” and “rea-
soning” questions were omitted since we are not assessing these abilities.  The quesionnaire explains that cogni-
tive function refers to abilities such as attention, memory, visual perception, information processing, and rea-
soning; and that cognitive training refers to activities that aim to improve cognitive functions by training within 
a specific timeframe (i.e., several weeks or months).  The questionnaire then asks participants to rate what ef-
fects they expect the intervention exercises to have including whether the exercises will result in improved gen-
eral cognitive function, memory, concentration, distractability, reasoning, multi-tasking, and everday perfor-
mance.  Ratings are on a 7-point Likert scale ranging from completely unsuccessful (1), to no expectations (4), 
to completely successful (7).  Participants also rate the degree to which the intervention was engaging, enjoya-
ble, and challenging on a 7-point scale ranging from very strongly agree (7), to neither agree or disagree (4), to 
very strongly disagree (1).  Finally, participants rate whether or not they were satisfied with the program rang-
ing from extremely satisfied (7), to neither satisfied or dissatisfied (4), to extremely dissatisfied (7) and indicate 
whether they felt that they had “trained their brain” (yes/no).  This questionnaire has been successfully imple-
mented in others’ and our prior cognitive intervention studies. 
 
At the baseline visit, a list of prescription medications that the participants’ are taking will be recorded.  For 
those who score 20-25 on the MoCA who will be completing a clinical evaluation, the medication list will be 
provided for the study physician to review.  At the clinical evalution visit, the tester will review the list of medi-
cations with the participant and document any changes prior to the participant seeing the study physician.  The 
study physician uses this information in the clinical diagnosis or exclusion of MCI.  
 
A questionnaire will be administered at post-test to assess if any health-changes were experienced by the partic-
ipants during the trial that could affect cognitive or functional performance.  Participants are asked if they expe-
rienced any significant changes in health conditions such as head injury, chemotherapy or radiation treatment, 
heart attack or myocardial infarction, changes in vision or hearing, or underwent general anesthesia.  They are 
also asked if they had any new diagnoses of stroke, mini-stroke, TIA, heart disease or congestive heart failure, 
Parkinson’s disease, mild cognitive imairment or memory impairment, Alzheimer’s disease, and Multiple Scle-
rosis.  
 

 
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7 MANAGEMENT OF ADVERSE EVENTS 
We will track safety throughout the trial.  Participants will be queried as to whether or not they experienced any 
discomfort at the end of each study visit.  See Reporting of Adverse Events below for further details. Data and 
safety monitoring will focus on participant recruitment, data quality, and safety (confidentiality, minimization 
of risks, and surveillance for adverse events).  The study team will meet weekly to discuss the progress of the 
trial.  Details on adverse event monitoring and reporting are provided below.   
 
An adverse event (AE) is defined as any unfavorable and unintended diagnosis, symptom, sign, syndrome or 
disease which either occurs during the study, having been absent at baseline, or if present at baseline, appears to 
worsen.  Adverse events are to be recorded regardless of their relationship to the study intervention.   
 
Participants may experience fatigue or frustration from completing the intervention exercises.  Prolonged sitting 
activity can result in muscle/joint soreness (e.g., wrist, elbow, fingers, hip flexors, neck, back, buttock), eye 
strain, muscle cramping or stiffness, or headaches.  Any of these symptoms that increase in frequency and last 
more than 24 hours after participating in intervention exercises will be considered an adverse event.  The partic-
ipant will be advised to seek treatment and not be continued until a physician clears such activity.  Serious ad-
verse effects from prior research of the interventions have not been reported. 
 
A serious adverse event (SAE) is generally defined as any untoward medical occurrence that results in death, is 
life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent 
or significant disability/incapacity.  
 
8 CRITERIA FOR PARTICIPANT DISCONTINUATION 
 
Participants who undergo any surgical procedures requiring anesthesia, chemotherapy, or radiation during the 
study period will be excluded.  Participants who experience a stroke, TIA, or head injury during the study peri-
od will be excluded.  Participants who complete any other cognitive intervention not assigned to them during 
the course of the study will be excluded.  In these situations, only data points collected prior to the event will be 
used in analyses.  If plans to undergo such events are known, and 80% of assigned intervention sessions have 
been offered, an attempt to complete post-test prior to the event will be made.   
9 STATISTICAL CONSIDERATIONS 
9.1 General Design Issues 
 
We will employ a randomized clinical trial design to accomplish the study objectives.  Randomization will be 
stratified based on MCI status.  Regardless of randomization or adherence, each eligible and enrolled participant 
will be encouraged to complete post-test.  Participants may be followed longer with positive results and addi-
tional funding.   
9.2 Primary Objectives 
The primary and secondary outcome measures are detailed above.   

 
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9.2.1 Primary outcomes  
• To examine the efficacy of piano training to improve CAP, cognition, and everyday function among 
older adults.  We will assess the effects of piano training as compared to music listening instruction on 
CAP, cognition, and everyday function.  
 
CAP includes Time Compressed Speech, Words-in-Noise, Dichotic Digits Test, Dichotic Sentence Identifica-
tion and Adaptive Tests of Temporal Resolution.  All are parametric tests of perception.   
 
Cognition includes Verbal Fluency (phonemic, category, and switching), Digit Coding, and Trail Making test.  
All are parametric tests of cognitive function.   
 
Everyday function includes the Timed IADL test and Test of Everyday Attention both parametric measures.  
Both measures will be examined individually.   
 
Principal Component Analyses (PCA) will be performed with CAP, cognitive and functional measures to form 
composites of outcomes for use in analyses to reduce the number of comparisons. 
 
Hypotheses: The piano training group will outperform the music listening instruction group on measures of 
CAP, cognition, and everyday function immediately post-intervention.  
Secondary Objectives 
 
The secondary objectives are: 
 
• 
To examine the moderating effects of MCI on piano training efficacy.  Moderating effects of MCI status 
will determine if piano training is effective for older adults with and/or without MCI.  We do not have a 
directional hypothesis for this objective.  
 
• To explore mediators of intervention effects.  
 
Hypothesis: Grounded in theory8 and prior research9-11, we hypothesize that piano training will improve 
CAP and cognitive performance, leading to functional improvements.  We expect that enhanced CAP 
will mediate cognitive gains.  We further hypothesize that cognitive gains will mediate functional im-
provements.   
 
9.3 Sample Size  
 
We expect up to 20% attrition after the initial in-person visit across the time period in which cognitive interven-
tion study protocols will be administered.  Our goal is to complete in-person screening visits for up to 450 par-
ticipants in order to have up to 360 participants complete the study.  We can tolerate higher rates of attrition.  
We require a minimum of 198 eligible participants with at least 99 individuals randomized to each condition 
(piano training, controls) to have adequate statistical power.  With stratified randomization, this will result in at 
least 48 persons per MCI/no MCI subgroup.   
 

 
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Statistical power analysis using G*Power123 in consideration of our pilot data effect sizes as well as attrition 
was conducted to estimate power.  We will control type I error at .05 to achieve at least 80% statistical power.   
 
To power Specific Aim 1: To examine the efficacy of piano training to improve CAP, cognition, and eve-
ryday function among older adults, a final n of 198 participants (n=99 per randomized condition) will achieve 
95% power to detect a significant group x time interaction across baseline to immediate post-test, with an alpha 
of .05.  This assumes a small effect size ( f ) of 0.10124 (Cohen’s f effect sizes are 0.10- small, 0.25- medium: f is 
roughly equivalent to ½ of d when comparing two groups)124.  
 
To power Specific Aim 2: To examine the moderating effects of MCI on intervention efficacy, a final n of 
168 will have .95 power at alpha .05 to detect medium effects (f=.10) for significant group x time x moderator 
three way interactions. 
 
9.4 Data Monitoring 
To achieve robust and unbiased results, data will undergo a rigorous quality control process to ensure 
consistency in scoring, coding and accuracy of data entry.  Additionally, 20% of all data folders will undergo a 
random audit every replicate.  Also see Data Management procedures and Quality Assurance detailed below.   
 
9.5 Interim Data Analyses 
Interim analyses will be conducted in June of 2019, after the pilot, first, and second replicates are completed.  
We expect that 140 participants will have completed post-test at this time.  The purpose will be to confirm fea-
sibility of the training conditions, to assess effect size on cognitive measures from pre- to post- training and 
adapt number of sessions, if warranted, and to monitor safety.   
 
Interim analyses will be conducted to ensure the safety of the trial.  Per NIA, this project does not meet the cri-
teria for requiring a formal Data and Safety Monitoring Plan or Data Safety Monitoring Board because it is not 
a Phase III clinical trial as defined by NIH. As a behavioral intervention study, this is a phase II efficacy trial1.  
At interim analysis, Dr. Ji will compare the number of adverse events between the two randomized conditions 
to assess safety.  The two groups will also be compared on attrition rates.  Any significant differences between 
the two conditions in adverse events or attrition rates will be further investigated by Dr. Ji.  If there is a signifi-
cant imbalance, confirmed, then Dr.Ji will report the findings to the Clinical Trial Coordinator, Dr. Hudak, who 
is unblinded.  The Clinical Trial Coordinator will work with the IRB to decide if the study should be terminated 
early.   
 
Interim analyses will be conducted to ensure the feasibility of study intervention adherence.  If at interim anal-
yses, less than 75% of participants randomized to an arm complete at least 16 sessions (80% of prescribed 20), 
the intervention arm will be deemed not feasible.  If this occurred for both arms, the study will end.   
 
Finally, interim analyses will examine the potential efficacy of the piano training arm.  Effect sizes and confi-
dence intervals for all cognitive outcomes will be calculated for pre- to post- training relative to controls.  We 
expect that the piano training arm will produce an improvement of at least d=0.25 from baseline to post-test on 
at least one of the cognitive measures of verbal fluency (phonemic, category or switching), Trails A or B, or 
Digit Coding, relative to active controls.  If an effect size from pre- to post- training relative to controls of this 

 
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magnitude is not observed on at least one of these outcomes, we will adapt study procedures by changing the 
number of training sessions from 20 to 25.  In this instance number of training sessions completed will be exam-
ined as a covariate in final analyses.  
 
9.6 Final Data Analyses 
 
Dealing with Score Distribution.  We will inspect the distribution of scores to confirm that parametric 
statistical testing is appropriate.  In the event that distributional properties do not support parametric tests, we 
will compare the results from conventional parametric analyses with (a) results from similar nonparametric 
testing (e.g., Wilcoxon signed ranks test), (b) results from parametric analyses conducted after the non-normally 
distributed variables are transformed to improve normality to compare the results with the conventional para-
metric analyses, and (c) Any illegal values or outliers of >= +/-3z will be checked for accuracy with the raw da-
ta. 
 
Composite Outcomes.  Data reduction in the form of principal component factor analysis (PCA) will be used 
to derive composite outcomes of CAP,cognition, and everyday function for analyses to reduce the number of 
comparisons.  Baseline data across CAP, cognitive, and everyday function outcomes will be factor analyzed us-
ing pairwise deletions.  Based on the number of factors derived and factor loadings of the individual measures 
(.4 or greater), outcome composite scores will be calculated after transforming the baseline data to z scores 
while taking into account the directional scaling of the items.  Post-test scores will be standardized based upon 
the baseline mean and SD.  The baseline factors and loadings will be applied to calculate post-test composite 
scores.  
 
Preliminary/Descriptive Analyses.  Prior to the analyses described below, we will conduct one-way ANOVA 
or Chi-square analyses as appropriate comparing the randomized groups at baseline on age, race, education, sex, 
MoCA, GDS, hearing and vision, to ensure that the study randomization procedures were successful.  We will 
also confirm the equivalence of the two randomized conditions by comparing the NICT questionnaire respons-
es.  The total across the six items relevant to cognition will be calculated and examined in analyses.  If even a 
marginally significant (p<.1) difference is observed for any of these study variables, the pertinent variables will 
be included as covariates in subsequent analyses. 
 
Specific Aim 1: To examine the efficacy of piano training to improve CAP, cognition, and everyday func-
tion among older adults.  We will compare changes in performance for piano training relative to control across 
the two measurement points (baseline, immediate post-test).  We will use the PCA-derived composites of CAP 
and cognition, and everyday functioning as outcomes.  We will use repeated measures analyses of variance 
within the mixed effects models, examining group as the between-subjects factor and time as the within-
subjects factor.  The group x time interaction will indicate whether the participants randomized to piano training 
change at differential rates over time relative to those randomized to the control group.  This output will be ob-
tained for each of the composite outcomes (CAP, cognition, and functional abilities).  For aim 1 analyses and 
the composite outcomes of CAP, cognition, and everyay function, we will apply Holm-Bonferroni 
adjustments125 to reduce Type I error.  Specifically, the Holm-Bonferroni procedure uses a step-down process 
whereby p-values are sorted from lowest to highest, then the lowest p-value is used in it raw version, the second 
lowest p-value is multiplied by two, the third lowest p-value is multiplied by three and so on until the adjusted 

 
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p-value reaches or exceeds the pre-specified threshold for statistical significance, in our case a two-tailed p val-
ue of .05.  
 
Intent-To-Treat Approach.  We expect that some participants will not complete their intended followup ac-
cording to the protocol for a variety of reasons, generating missing values.  Intent-to-treat (ITT) analysis has 
become a widely accepted method for dealing with this issue.  To maximize available information, we will 
employ statistical techniques that allow for the inclusion of missing data.  Specifically, we will use linear mixed 
effects models to analyze data.  This advanced analytical method allows for the inclusion of participants with 
missing data, so long as data are missing at random and offers flexibility with regard to the specification of the 
variance/covariance structure, which often leads to improved fit of the analytical model to the actual data.  If 
there is non-ignorable missing data, we will apply pattern-mixture mixed effects models to assess the sensitivity 
of our findings with regard to missing data 126.   
 
Specific Aim 2: To examine the moderating effects of MCI on intervention efficacy.  We will also test for 
moderation effects to determine at what stage along the cognitive status continuum—without MCI vs. MCI—
intervention is most effective.  To do so, we will examine three-way interactions (MCI x training group x time) 
for the CAP, cognitive, and everyday function composites.  When an interaction is significant, we will stratify 
analyses by MCI status and examine effect sizes.  Effect sizes from pre- to post- training relative to controls will 
be compared for participants with/without MCI.  An alpha of .05 will be used for these analyses.  
 
Participants who score 26 or higher on the MoCA will be defined as no MCI (i.e., cognitively normal).  Those 
participants who score a 20-25 on the MoCA will be defined as MCI if they score a 0.5 on the CDR and have 
performance at or 1 SD below their age, sex, and education norms on any of the following measures:  Trails, 
Verbal Fluency, Digit Coding, Craft Story Recall, Multilingual Naming Test, or Benson Complex Figure.  
Those with MoCA scores 20-25 who score 0 on the CDR, but have performance at or 1SD below expected for 
age, sex, and education will be adjudicated prior to analyses.  If an individual scores 20-25 on the MoCA, and 
0.5 on the CDR, but has performance above expected on all of the aforementioned measures, their case will be 
adjudicated prior to analyses.  The study physicians will adjudicate such cases prior to coding of MCI status for 
final analyses.   
 
To quantify the effects of piano training further, in addition to examining composite outcomes as detailed 
above, we will calculate and report effect sizes for pre-to-post change of piano training relative to controls for 
each individual measure of CAP, cognition, and everyday function for the sample overall as well as stratified by 
MCI status and among those who were adherent only (80% or more of sessions completed).   
 
Additional Analyses.  To address exploratory aim 3, with identification of significant effects from the analyses 
for aim 1, we will examine behavioral mediators of interventions to determine mechanisms.  We hypothesize 
that improved CAP will mediate cognitive gains.  We hypothesize that cognitive gains will mediate functional 
gains.  Formal mediation tests using a bootstrapping technique as outlined by Hayes127 and Selig and 
Preacher128 will be used to examine these hypotheses.  The pre-to-post differences will be captured by a latent 
score128, whereby the post-test score will serve as the outcome with pre-test score covaried.  Results yield esti-
mates and confidence intervals for the indirect and total effects.  The procedure allows simultaneous estimation 
of all three pathways (M on Y; X on M; X on Y, where M=mediator (CAP score), Y=outcome (cognition), and 
X=predictor (group assignment)) as well as adjustment for covariates (e.g., depression).  The use of bootstrap-
ping will ensure that power is not reduced from the main effect analyses129.  An alpha of .05 will be used for 
these analyses.    

 
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9.7 Sensitivity Analyses 
 
Sensitivity analyses will be conducted to examine if missing data or outliers significantly affected results.  We 
will conduct sensitivity analysis for missing data by using pattern mixture models.  The pattern of results will be 
compared to ITT analyses.  Results will also be conducted after any outliers, defined as observations with val-
ues of greater than +3 or smaller than -3 z score units, are removed and compared to primary results.   
 
9.8 Exploratory Subgroup Analyses   
 
Pursuant to NIH guidelines on examining sex as a biological variable, we will examine if sex moderates any 
significant intervention effects identified in aim 1 or aim 2 analyses by examining sex x group x time interac-
tions.  Effect sizes will be reported by sex if there are any significant differences (alpha .05).   
 
Relevant to aim 1 and 2 analyses, exploratory analyses will further examine effect size for the pre-to post-
change of piano training relative to music listening instruction among those who were adherent (i.e., who com-
pleted 80% or more of assigned number of sessions) in both conditions.  Analyses detailed above for specific 
aims 1 and 2 will be repeated among this subsample.  Results and effects sizes among the adherent sample will 
be compared to the ITT derived results and effect sizes.   
 
Relevant to aim 1 and 2 analyses, we will further examine if effects were moderated by a better ear pure-tone 
average (PTA).  In these analyses we will examine if there are significant training group x time x hearing inter-
actions on CAP, cognition, or everyday function, using an alpha of .05.  
 
As it is possible that training will be differentially effective for those with CAP disorders (CAPD), we will iden-
tify a subgroup of participants (regardless of MCI status) who could be diagnosed with CAPD.  Diagnosis of 
(C)APD requires performance deficits on the order of at least two standard deviations below the mean on two or 
more of the following tests39, 130:  temporal processing (TCS, ATTR), degraded speech understanding (WIN), or 
binaural processing (DDT, DST).  Analyses for the cognition and everyday function outcomes will be repeated 
with groups defined as with/without CAPD as an independent variable.  We will examine if there are significant 
training group x time x ADP status interactions using an alpha of .05.  
 
We may also explore moderation effects of covariates such as MCI subtype (amnestic, non-amnestic, multiple 
domain) to determine who is most likely to benefit from the intervention among participants with MCI.  To do 
so, we will examine three-way interactions (covariate x training group x time) stratified by MCI status, if MCI 
was a significant moderator in results of analyses for aim 2 described above.  Effect sizes will be examined.    
 
The self-efficacy measures (general self-efficacy and music performance self-efficacy) will be examined as ex-
ploratory outcomes by comparing the two randomized conditions across the two measurement points (be-
fore/after training).  Analyses will include ordinal logistic regression analyses across levels of self-eficacy con-
ducted within the generalized estimating equations (GEE) statistical framework to account for repeated meas-
urements.  Significant improvements on either measures demonstrated in this analyses will be followed by ex-
ploratory mediation analyses to examine if improvements in self-efficacy can account for any observed training 

 
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effects on CAP, cognition, or everyday function.  Thus, we will examine an alternative hypothesis that training 
gains can be attributed to improved self-efficay.  An alpha of .05 will be used.  
 
To explore if initial music aptitude affects performance within each of the training conditions, AMMA at base-
line will be examined as a covariate (i.e., modifier) of Basic Piano Measure performance (BPM) from the first 
to the final day of training among those in the piano training condition.  Similarly, baseline AMMA will be ex-
amined as a covariate on the Music Listening Measure (MLM) across the same two time points within the con-
trol group.  Again, ordinal logistic regression with GEE will be used given the ordinal scaling of the outcomes.  
An alpha of .05 will be used.  

 
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10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERI-
ENCE REPORTING 
10.1 Records to Be Kept 
 
A visit control sheet (VCS) will be the only document indicating the participants name and subject id.  This data 
form will be kept in a locked filing cabinet separate from the study data.  This data form will be accessible to 
the Testers and Trainers as well as PIs, only.   
 
Signed consent forms will be kept in locked filing cabinets separate from the data forms and will not contain the 
subject id number.   
 
We will keep all completed telephone screening interviews to track the number of screenings completed, num-
ber scheduled, and reasons ineligible.  We will keep the data forms completed and intervention records, which 
will contain subject id only, in a locked filing cabinet.    
 
All documents will be kept for at least 5 years post-study close out (or longer if required by site IRB or NIH or 
other governing body).   
  
The study database will not include participant names or other identifying information.  When the study data are 
released for sharing, the data will be completely de-identified with any potentially identifying information (e.g., 
date of birth) removed. 
 
10.2 Data Management 
10.2.1 Clinical site responsibilities in data collection and management. 
 
Each study participant will have a folder with participant id for all assessments completed for each study visit 
and for the intervention phase.  Every data form (page) will include the participant id and date the form was 
administered.   
 
Original versions of the data forms arranged by study visit will be kept in a locked filing cabinet in the lab noted 
with an electronic file location in the footer.  Data forms will only be copied from these originals only.  Each 
testing visit will include a detailed checklist of all measures to be administered and procedures to be followed, 
which will be initialed by the tester upon completion.   
 
Immediately after completing a participant visit, the tester will score the assessments and check all forms for 
completion, and within 21 days a different tester should use a detailed checklist to review all of the data forms 
for accuracy and completion.  Any unclear or missing items are queried to the Tester or study participant as ap-
propriate.  This quality control process helps to avoid missing data.  This process will be repeated as necessary 
prior to data entry until the checklist is completed.  This rescoring process is the first step of our data quality 
control process.   
 

 
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At the end of each testing visit and intervention phase, every data form will be reviewed in a five-step quality 
control audit (scoring, rescoring, entry, checking, reconciling) with each subsequent step performed by a differ-
ent Research Assistant.   
 
The data will be entered into a custom-designed MS Access database that uses MS SQL Server as the back end 
relational database and completely integrates study management (e.g., create forms, collect data, generate re-
ports, prepare for analysis).  The database is designed to ensure access control, audit control, data integrity, user 
authentication, and transmission security.  The data quality control and custom database function to minimize 
missing data and ensure data integrity.   
 
Only individuals trained by the PI or Study Coordinator to use the MS Access database will enter data.  Reports 
reflecting entered data will be printed for each testing visit of each participant upon data entry.  The data report 
will be checked for accuracy with the raw data by a trained staff member other than who entered the data.  Er-
rors or omissions will be returned for reconciliation and the process will be repeated until the entered data are 
deemed error free.  Additionally, a random audit of 20% of folders entered will be completed each replicate.   
11 Quality Assurance 
 
The study protocol including a priori hypotheses and data analytic plan will be published online within 90 days 
of commencement of data collection.  Any changes to the protocol or analytic plans will be documented with 
date of change and justification.   
 
All study staff who recruit, interview, or assess study participants will be required to attend a weekly staff meet-
ing with the Principal Investigator throughout the data collection phase of the study.  Recruitment goals and 
procedures will be reviewed.  Problems or issues will be discussed and resolved.  Detailed minutes of the meet-
ings proceedings will be kept for review by any personnel who are on vacation or ill and miss a meeting.  If 
staff change, new personnel will review all previous study meeting minutes prior to working on the project.  
The study coordinator will keep these records from each staff meeting.   
 
The study investigators will meet about monthly during the first quarter of the study, will meet at interim anal-
yses, and at least annually to review/monitor any adverse events, if they occur.  The study investigators may 
also meet monthly in the final quarter of the study to complete data analysis, interpretation, and publication.   
 
All study staff will read, be instructed in, and may be asked to pass a certification exam on the study protocol 
before working on assigned study activities.  All study staff will be required to complete IRB Human Subjects 
training prior to working on the project with re-certification completed as required by the NIH or IRB.  This 
will be monitored and implemeneted by the study coordinator.   
 
Telephone screeners will be required to complete two practice inteviews with the first actual study interview 
supervised and evaluated by the Principal Investigator, Study Coordinator, or trained and certified telephone 
screener.  The Study coordinator or other site personnel appointed to do will audit the first telephone screening 
interview completed and will continue to do so until the questionnaire and final outcome are completed without 
error. 
 

 
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The Testers, who will administer the baseline, clinical and post-test visits, will be required to practice admin-
istration of all study measures per the study protocol with three persons.  The testing must be completed with at 
least two individuals who meet the study age requirements.  The third practice visit will be supervised by the 
Principal Investigator, Clinical Coordinator, or a trained and certified tester (more practice may be deemed nec-
essary by the observer).  The first actual study assessment visit will also be supervised and evaluated by one of 
these study personnel.  To further achieve internal validity and inter-rater reliability, the testers will observe and 
evaluate each other at least once per replicate and audit each other’s testing records.  Participant data forms 
should be audited by a different tester within 21 days of completion per a detailed rescoring checklist.  Any 
missing, incomplete, or unclear items will be queried to the tester or participant as appropriate.  The Study Co-
ordinator will implement and monitor this process.  Additional training and certification is required to adminis-
ter the Clinical Dementia Rating Scale.   
 
A detailed intervention protocol will be developed for Trainers.  The Trainers may be required to pass a certifi-
cation test of the intervention protocol prior to interacting with study participants during the intervention phase.  
The Trainers will be required to complete at least 5 hours of training activities that they will administer as a part 
of their training, prior to administering the intervention exercises to actual study participants.  They will com-
plete an initial mock training session under the observation of the PI, Study Coordinator, or another trained Re-
search Assistant Trainer prior to conducting an actual study intervention visit.  To further achieve internal valid-
ity and intervention fidelity, the trainers will observe and evaluate each other at least once per replicate and au-
dit each other’s intervention records.  The first actual intervention visit conducted by the trainer will also be su-
pervised and evaluated by the study coordinator or a certified trainer.  Participant training data forms will be 
audited by a different trainer within 21 days of completion per a detailed rescoring checklist.  Any missing, in-
complete, or unclear items will be queried to the trainer or participant as appropriate.  The Study Coordinator 
will implement and monitor this process.   
 
The Study coordinator or other site personnel appointed to do will audit the first testing/intervention folder 
completed and rescored by each tester/trainer, and will continue to do so until the procedure is completed with-
out error.  Random quality control audits will be performed on 20% of the participant folders each replicate.   
 
Study documents and pertinent records will be available for inspection by monitoring authorities (e.g., NIH or 
IRB) as requested.   
 
11.1 Adverse Experience Reporting 
 
Study staff will monitor participants and be alert to any adverse events at each study..  Testers and Trainers will 
ask participants about any adverse events at the end of each testing and intervention visit.  Furthermore, the par-
ticipants will be interviewed about any such events throughout their study participation at the post-test visit.  
Study staff will be alert to any volunteered adverse events.  All such events will be documented on a 
standardized form.  At all in-person contacts and at any other applicable time throughout the study, any poten-
tial adverse events reported by a subject or observed by the research staff will be recorded and subsequently 
evaluated by the Principal Investigator for its relation to the study research procedures and whether or not any 
corrective action need be taken.  It is unlikely and not expected that any adverse incident will result from im-
plementation of this study protocol.  However, any and all adverse events that may occur will be recorded on 
the appropriate forms, and reported to the governing IRB, as applicable. 

 
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Any adverse events will be reported to the site IRB within 72 hours of occurrence or detection by PI Edwards.  
In the unlikely event of a serious adverse event this report will be made within 24 hours and reported also to the 
NIH Project Officer.  In the unlikely case of study-related serious adverse events, an interim analysis will be 
performed in order to determine whether a change in the risk/benefit ratio has occurred and reviewed by the 
statistician Dr. Ji.  If so, this change will be brought to the attention of the USF IRB for review, current and fu-
ture participants will be notified of this change, and stopping rules will be considered.  
 
11.2 Follow-up for Adverse Events 
Research Assistants will monitor participants for any adverse events at study visits.  At the post-test study visit, 
participants will be directly interviewed about any possible adverse events that occurred since their initial visit.  
A study physician and/or Dr. Edwards will follow-up with the participant for any adverse events.  The partici-
pant will be referred to proper treatment. 
 
11.3 Safety Monitoring  
The PI and the Study Physicians will be responsible for ensuring participants’ safety.  
 
Dr. Ji will perform analyses to monitor participant safety, evaluate the progress of the study, to review proce-
dures for maintaining the confidentiality of data, the quality of data collection, management, and analyses.  
 
All OHRP and local IRB requirements for reporting adverse events will be followed.   
 
11.4 Confidentiality 
 
All evaluation forms, reports, recordings, and other records that leave the site will be identified only by the par-
ticipant id number to maintain subject confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry of data forms will be done using participant ids only and without participant names.  Clinical 
information will not be released without written permission of the participant, except as necessary for monitor-
ing by IRB, NIH, or the OHRP  
11.5 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the NIH, the OHRP, or other government 
agencies as part of their duties to ensure that research subjects are protected. 
 
Study Modifications 
Date Imple-
mented 
Modification 
Rationale 
04/23/2018 
For the pilot replicate, the FAS, 
Animals/ Boys’ Names, and 
Fruits/ Furniture version will be 
administered at baseline and 
The music listening condition 
involves a lesson on musical 
intstruments. Thus, we decided 
that using this version of verbal 

 
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also at post test.  
fluency category switching at 
post would unfairly bias the ac-
tive control condition. We did 
not realize this until during the 
training phase of the pilot repli-
cate. We changed the order for 
furture replicates such that Veg-
etables/Musical Instruments 
version is administered at base-
line and the Fruits/Furniture ver-
sion will be administered at 
post-test. 
07/16/2018 
Page 12, 5.2 Exclusion Criteria.  
We clarified that individuals who 
have previously participated in 
the USF Music Research and 
Testing Lab studies are exclud-
ed.  
This was inadvertently omitted 
from the protocol version 1. All 
individuals screened for the 
study were excluded if they re-
ported prior participation in the 
Music Research and Testing 
Lab. The rationale is such indi-
viduals would have completed 
similar or the same measures 
as administered in this study 
and may have received music 
training. 
07/16/2018 
Page 15,  5.7 Interventions Ad-
ministration and Duration.  We 
omitted the sentence that indi-
cated a textbook will be provid-
ed and weekly homework will be 
assigned. 
The study investigators met to 
discuss the study progress and 
any modifications needed since 
completion of the pilot replicate. 
The trainers and a Co-I noted 
that it was difficult to make the 
homework assignments and en-
gagment equivalent across the 
two conditions. It was decided 
that we will omit the homework 
for replicate 1 and the remain-
der of the study.  Participants 
will only access the textbooks 
during the in-lab training ses-
sions. There is no evidence that 
homework is required for piano 
training to be efficacious.  En-
suring equivalency of the two 
conditions is the rationale.  
07/16/2018 
Page 12, 5.2 Exclusion criteria. 
We added, “which interferes 
The PI and study coordinator 
felt the exclusion criteria of any 

 
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with ability to use a keyboard” to 
exclusion criteria regarding 
numbness or tingling. 
numbness or tingling in any fin-
ger was too conservative and 
that individuals were being ex-
cluded that would be able to 
successfully participate in the 
study.  We decided to add this 
phrase in an attempt to only ex-
clude those who would not be 
able to successfully complete 
the intervention.  
07/16/2018 
Pages 13-14, 5.3 Enrollment 
Procedures.  Those who score a 
26 or better on the MoCA will be 
enrolled in the study (not 27). 
Those potentially eligible who 
score between 20 to 25 (not 26) 
on the MoCA who were not re-
ferred by the MDC or study phy-
sician will also complete a clini-
cal evaluation visit.   
The PI and Study Coordinator 
felt the criteria for clinical evalu-
ation were too stringent. The 
study investigators decided to 
use the traditional cut-point of 
26 for MoCA to determine who 
is eligible and who requires fur-
ther evaluation.   
07/30/2018 
Page 14, 5.3 Enrollment Proce-
dures. We clarify that clinically 
significant abnormalities are 
shared with the participants who 
are encouraged to seek treat-
ment.  We added the phrase, 
“that would likely interfere with 
their ability to benefit from inter-
vention” regarding any signifi-
cant clinical abnormalities.  
This has been our procedure 
beginning in replicate 1. The 
goal is to be inclusive and to al-
low those who could potentially 
benefit from intervention to con-
tinue participation in the study. 
 

 
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13. Data availability: The data from this study are publicly available. Please contact PI Edwards at jed-
wards1@usf.edu to request the data.    
 
14. Results 
 
Recruitment and enrollment began in January 2018 and continued through December 2020, with data 
collection completed in April 2021. Seventy-six percent of randomized participants completed post-test. Nine-

 
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teen participants were excluded from analyses due to a head injury (n=1), undergoing anesthesia (n=10), or 
hospitalization (n=8) before post-test. Please see Figure 1 for details.  
The randomized groups did not differ in sex, χ2(1)=.787, p=.375, ethnicity χ2(1)=.167, p=.683, or race, 
χ2(1)=.045, p=.832. The Music Reading Assessment scores did not differ between the two groups, t(266)=-.958, 
p=.338. The randomized groups did not significantly differ in age, F(1,266)=.293, p=.589, education, 
F(1,266)=.369, p=.544, MoCA, F(1,266)=.427, p=.514, or GDS, F(1,266)=.943, p=.332. However, there were 
marginally significant group differences for PTA in the left ear, F(1,266)=3.31, p=.070 and statistically signifi-
cant group differences for both PTA in the right ear, F(1,266)=6.69, p=.010, and visual acuity, F(1,266)=8.99, 
p=.003. The music listening group tended to have worse hearing, while the piano training group tended to have 
worse visual acuity. See Table 1. The groups also differed significantly in their expectations regarding potential 
benefits of their randomized group, F(1,214)=15.07, p<.001. The piano training group had an average rating of 
5.55 while the music listening group had an average rating of 4.99, indicating the piano training condition had 
higher expectations about the potential effects of their randomized condition. The piano training group also rat-
ed their condition as more challenging with 92% agreeing that the intervention was challenging as compared to 
86.3% of the music listening group indicating their condition was challenging (p<.001). 
Principal component analysis with varimax rotation was conducted to reduce the number of variables for 
analyses. Please see Supplemental Table A for details. The first factor reflected cognitive performance speed 
and included the Trail Making Test, Digit Coding, and the TEA visual elevator and phone search subtests. The 
second factor included all three verbal fluency subtests. The third factor reflected CAP and included DDT, DSI, 
TCS, and WIN. The fourth factor included two indices from the TEA phone search while counting and visual 
elevator accuracy. The fifth composite included ATTR across- and within- channel performance. Baseline com-
posites of cognitive performance, verbal fluency, ATTR, CAP, and everyday function were created by averag-
ing z scores after the reverse-scaling of items with negative factor loadings. Post-test scores were standardized 

 
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by baseline means and SDs. Timed IADL performance did not significantly load on any factor and was thus ex-
amined separately.  
In the primary analyses, we examined whether performance changed differentially by random assign-
ment across composite outcomes from baseline to post-test as indicated by a significant group-by-time interac-
tion. Covariates included hearing PTA, visual acuity, and expectations. The group-by-time interactions were not 
statistically significant for any of the outcomes (ps>.194). See Table 2. The results did not change when we in-
cluded only those who were adherent (ps>.180). See Supplementary Table B. Piano training did not significant-
ly enhance CAP, cognition, or everyday function as compared to music listening. We further examined if inter-
vention effects varied by MCI status (Supplementary Table B). There were no significant group-by-time-by-
MCI status interactions indicating those with and without MCI did not show differential benefit (ps>.245). 
Thus, MCI did not significantly moderate the effects of piano training.  
Effect sizes for piano training as compared to music listening are shown in Table 3. Improvements were 
not evident in the primary analyses, adherent analyses, or the subsample without MCI on measures of CAP, 
cognition, or everyday function. Participants with MCI randomized to piano training showed potential small 
effect sizes for improvement relative to music listening on Trails A, Digit Symbol Coding, and one subtest of 
the TEA (ds>=0.25). Raincloud plots of individual assessment and composite variables are included in the sup-
plemental materials.  
Results indicated significant effects of time for ATTR in all models and significant effects of time for 
CAP in the primary and adherent analyses indicating improved performance from pre- to post- training. Signifi-
cant effects of time were found for cognition and TEA in the primary and adherent analyses, indicating a ten-
dency for decline across time. With respect to covariate effects, CAP, ATTR, and cognitive performance were 
significantly impacted by hearing. Similarly, Timed IADL and cognitive performance varied significantly by 
visual acuity. Those with poorer hearing or vision tended to perform worse on these outcomes. Interestingly, 

 
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expectations about the assigned condition were significantly related to composite outcomes of CAP and cogni-
tion. However, having greater expectations that the randomized condition would positively affect abilities was 
associated with poorer performance. See Table 2. Additional sensitivity analyses examined if there were differ-
ential effects by sex. No significant group-time-sex interactions were evident (ps>.119), and the pattern of re-
sults was the same when analyses were stratified by sex.   

 
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Table 14.1. Participant characteristics by randomized arm and cognitive status. 
 
Piano Training 
Music Listening 
Cognitive status 
Non-MCI 
M (SD) 
MCI 
M (SD) 
Non-MCI 
M (SD) 
MCI 
M (SD) 
 
n (%) 
n (%) 
n (%) 
n (%) 
Age in years 
69.1 (5.5) 
71.4 (7.1) 
69.6 (5.2) 
72.1 (5.7) 
Education in years 
16.0 (2.3) 
16.5 (2.2) 
16.0 (2.1) 
15.4 (2.3) 
Sex (% female) 
63 (65%) 
18 (48%) 
58 (59%) 
17 (44%) 
Music Reading Assessment 
score (/40) 
2.52 (4.31) 
2.43 (3.83) 
3.42 (5.41) 
2.08 (4.29) 
Montreal Cognitive Assessment 
score (/30) 
26.6 (2.1) 
23.3 (1.4) 
26.6 (1.9) 
22.8 (1.6) 
Geriatric Depression Scale 
short-form score (/15) 
0.9 (1.2) 
1.1 (1.1) 
0.9 (1.1) 
0.6 (0.9) 
Pure tone average left ear (dB)+ 
19.8 (9.4) 
20.4 (9.4) 
20.9 (10.8) 
27.7 (15.9) 
Pure tone average right ear 
(dB)+* 
18.6 (10.3) 
20.4 (9.9) 
22.4 (14.0) 
25.8 (11.6) 
Visual acuity (logMAR)+* 
.04 (.12)  
.09 (.15) 
.01 (.13) 
.01 (.10) 
Expectations (rating/7)* 
5.4 (1.2) 
5.8 (0.8) 
4.9 (0.8 
5.3 (0.8) 
Note.  MCI=mild cognitive impairment. +Lower scores reflect better performance. *Significant differences 
by randomized group were evident in pure tone average right ear, visual acuity, and expectations (ps<.01). 

 
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Table 14.2. The effects of randomization to piano training as compared to music listening from 
baseline to post-training across composite outcomes of central auditory processing, cognition, 
and everyday function. 
Estimate 
SE 
p 
Estimate 
SE 
p 
 
ATTR+ 
  
Central auditory processing 
Intercept 
53.90 
1.17 
<.001   
46.25 
0.73 
<.001 
Group 
-2.24 
2.37 
.346   
-1.72 
1.49 
.249 
Time 
-2.77 
0.68 
<.001   
2.29 
0.36 
<.001 
Group x time 
1.51 
1.35 
.265   
.465 
0.71 
.515 
Hearing 
0.12 
0.06 
.030   
-0.63 
0.04 
<.001 
Visual acuity 
6.24 
4.71 
.187   
-7.270 
3.97 
0.07 
Expectations 
0.79 
0.59 
.185   
-1.20 
0.49 
.016 
  
Verbal fluency 
  
Cognition 
Intercept 
49.32 
0.98 
<.001 
  
51.81 
0.90 
<.001 
Group 
-1.81 
2.00 
.367 
  
-2.62 
1.84 
.157 
Time 
0.41 
0.48 
.393 
  
-1.40 
0.42 
.001 
Group x time 
-0.29 
0.96 
.763 
  
0.39 
0.84 
.638 
Hearing 
-0.09 
0.06 
.134   
-0.14 
0.06 
.016 
Visual acuity 
-6.55 
5.33 
.220 
  
-15.45 
5.12 
.003 
Expectations 
-0.79 
0.67 
.234 
  
-1.96 
0.64 
.003 
Timed IADL+ 
  
Test of Everyday Attention 
Intercept 
48.89 
1.32 
<.001 
62.34 
1.15 
<.001 

 
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Group 
3.15 
2.67 
.240 
1.37 
2.33 
.557 
Time 
0.14 
0.79 
.863 
-8.61 
0.67 
<.001 
Group x time 
-1.53 
1.58 
.327 
-0.40 
1.340 
.765 
Hearing 
0.07 
0.57 
.194 
-0.02 
0.05 
.603 
Visual acuity 
12.75 
4.770 
.008 
0.24 
4.470 
.957 
Expectations 
1.02 
0.59 
.089 
-0.79 
0.56 
.157 
Note.  ATTR=Adaptive Tests of Temporal Resolution, IADL=instrumental activities of daily 
living.  MCI=mild cognitive impairment. +For ATTR and Timed IADL lower scores reflect 
better performance. 
 

 
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Table 14.3.  Effect sizes for piano training relative to music listening across composite outcomes and assess-
ments for the analytic sample overall, among those adherent, and by cognitive status. 
Outcome Measure 
d Effect Size 
 
 
Overall 
(n=198) 
 
Adherent 
(n=189) 
Non-
MCI 
(n=146) 
 
MCI 
(n=52) 
Central auditory processing composite 
-0.01 
-0.01 
0.00 
-0.07 
   Dichotic Digits 
-0.06 
-0.07 
-0.03 
-0.14 
   Dichotic Sentence Identification 
0.01 
0.01 
0.02 
-0.07 
   Time Compressed Speech 
-0.01 
0.01 
0.03 
-0.06 
   Words in noise 
0.03 
0.03 
0.12 
0.01 
Adaptive Tests of Temporal Resolution compo-
site 
0.17 
0.20 
-0.09 
0.24 
Cognitive composite 
-0.03 
-0.03 
-0.10 
0.08 
   Trails A 
0.03 
0.06 
0.00 
0.43 
   Trails B 
-0.17 
-0.20 
0.01 
-0.54 
   Digit Symbol Coding 
0.08 
0.09 
0.06 
0.26 
   Test of Everyday Attention - Visual elevator 
timing subtest 
0.02 
0.02 
0.03 
0.44 
   Test of Everyday Attention - Telephone search 
time 
-0.29 
-0.32 
0.08 
-0.27 
Verbal fluency composite 
0.05 
0.06 
0.09 
-0.12 

 
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   Letter fluency  
0.00 
0.02 
0.09 
-0.36 
   Category fluency  
0.18 
0.20 
0.18 
0.13 
   Switching fluency  
-0.06 
-0.05 
-0.07 
-0.05 
Test of Everyday Attention composite 
0.04 
0.08 
-0.30 
-0.02 
    Visual Elevator accuracy 
0.01 
0.03 
-0.12 
-0.19 
    Dual task decrement 
0.10 
0.13 
-0.18 
0.22 
Timed Instrumental Activities of Daily Living 
composite 
-0.15 
-0.21 
0.09 
-0.13 
Note.  MCI=mild cognitive impairment.  d effect sizes were calculated as pre- to post- change in the piano train-
ing condition relative to the music listening condition divided by the baseline standard deviation such that posi-
tive values would indicate improvement.  Adherent analyses include those who completed 15 or more sessions 
of the assigned condition.