A Randomized, Double-Blinded, Placebo Controlled Pilot Trial of the Feasibility of High Definition Transcranial Direct Current Stimulation and Cognitive Training in Patients With Mild Cognitive Impairment.
Phase: NA
Conditions: Mild Cognitive Impairment, Memory Disorders, Memory Loss
Sponsor: Medical College of Wisconsin

 
 
 
 
 
 
 
A Randomized, Double-Blinded, Placebo Controlled Pilot Trial 
of the Feasibility of High Definition Transcranial Direct Current 
Stimulation and Cognitive Training in Patients with Mild 
Cognitive Impairment. 
 
 
 
 
Protocol Number: 35757 
Principal Investigator: Elias Granadillo, M.D. 
 
 
 
 
Clinical & Translational Science Institute of Southeast Wisconsin 
 
 
This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior 
authorization from the Sponsor or Principal Investigator. 
 
 
 
Protocol Version History 
 
Protocol 
Version 
Version 
Date 
Summary of Revisions Made 
Rationale 
1.0 
12/13/2019 
Initial version 
 
2.0 
10/30/2020 
Revised Cognitive Battery, UW ADRC 
Recruitment letter added, Study Partner 
Questionnaires added to study visits, 
Study Partner Questionnaires description 
added, Study Partner compensation 
added, Quality of Life Questionnaires 
removed from study visits and secondary 
endpoints, exclusion criteria updated to 
reflect need for study partner, Study Visit 
Calendar updated to reflect changes 
 
3.0 
01/13/2021 
Moved follow-up MRI to Month 3, 
expanded visit windows, 3.1 Objectives 
changed, Table 3.2 updated, 6.0 and 
12.1 secondary endpoints updated 
Follow-up MRI moved to Month 3 
as we expect long-term effects of 
this multifield extended approach to 
tDCS, expanded visit windows to 
account for potential COVID-19 
disruptions and increased subject 
retention 

~ ii ~ 
4.0 
04/15/2021 
1. Increased subject recruitment to 
20 subjects and study partners, 
2. removed handedness from 
inclusion/exclusion criteria, 
3. increased Day 1 visit window to 6 
months, 
4. removed Day 1 AE evaluation, 
5. added potential for subject 
interchangeability between sites 
6. formatting modifications 
1. Increased recruitment 
number to account for 
screen fails and withdrawals 
2. Revised inclusion/exclusion 
criteria to improve 
recruitment 
3. Day 1 visit window extended 
to improve subject retention 
4. Day 1 AE evaluation 
removed as visit occurs 
prior to tDCS/sham 
administration 
5. Interchangeability between 
sites added to improve 
subject retention and 
dataset completion 
6. Formatting modifications to 
improve readability   
5.0 
10/15/2021 
1. Section 8.5 – modified to include 
reimbursement for hotel or other 
form of lodging. MCW subjects 
may be eligible to stay at Kathy’s 
House 
1. We are offering lodging 
assistance to improve 
enrollment and retention 
 
 

- i - 
 
 
Table of Contents 
 
1.0 
STATEMENT OF COMPLIANCE ............................................................................................................. 1 
2.0 
LIST OF ABBREVIATIONS ...................................................................................................................... 1 
3.0 
STUDY SUMMARY .................................................................................................................................. 1 
 
Synopsis ........................................................................................................................................................... 1 
 
Schematic of Study Design .............................................................................................................................. 3 
4.0 
KEY ROLES ............................................................................................................................................. 4 
5.0 
INTRODUCTION ...................................................................................................................................... 5 
 
Mild Cognitive Impairment ................................................................................................................................ 5 
 
Current Standard of Care ................................................................................................................................. 5 
 
Transcranial Direct Current Stimulation and cognitive training ........................................................................ 6 
 
Rationale .......................................................................................................................................................... 8 
6.0 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................................. 12 
7.0 
STUDY DESIGN ..................................................................................................................................... 13 
 
General Design .............................................................................................................................................. 13 
 
End of Study Definition ................................................................................................................................... 14 
8.0 
SUBJECT SELECTION .......................................................................................................................... 14 
 
Inclusion & Exclusion Criteria ......................................................................................................................... 14 
 
Vulnerable Populations .................................................................................................................................. 15 
 
Subject Identification ...................................................................................................................................... 15 
 
Subject Recruitment ....................................................................................................................................... 16 
 
Remuneration and Retention Strategies ........................................................................................................ 16 
 
Early Termination and Withdrawal ................................................................................................................. 18 
9.0 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, ETC.) AND/OR PROCEDURAL 
INTERVENTION ..................................................................................................................................... 19 
 
Study Procedural Intervention(s) Description ................................................................................................ 19 
 
Method for Assigning to Treatment Groups ................................................................................................... 24 
 
Unblinding Procedures ................................................................................................................................... 24 
 
Study Intervention Compliance ...................................................................................................................... 24 
 
Concomitant Therapy ..................................................................................................................................... 24 
10.0 STUDY VISITS AND PROCEDURES ..................................................................................................... 25 
 
Study Calendar ............................................................................................................................................... 25 
10.1 Screening and Enrollment ................................................................................................................................... 26 
 
Treatment and Follow-up Visits ...................................................................................................................... 29 
 
Unscheduled Visits ........................................................................................... Error! Bookmark not defined. 
 
Early Termination/Withdrawal Visit ................................................................................................................ 30 
11.0 DATA COLLECTION, HANDLING, SHARING, AND RECORD KEEPING ............................................ 30 
 
Data Collection ............................................................................................................................................... 30 
 
Confidentiality and Privacy ............................................................................................................................. 31 
 
Records Retention.......................................................................................................................................... 31 
 
Protocol Deviations ........................................................................................................................................ 31 
12.0 STUDY ANALYSIS ................................................................................................................................ 31 
 
Statistical Hypotheses .................................................................................................................................... 31 

- ii - 
 
Sample Size Justification ............................................................................................................................... 32 
 
Subject Population(s) for Analysis ................................................................................................................. 32 
 
Statistical Methods ......................................................................................................................................... 32 
 
Planned Interim Analysis ................................................................................................................................ 34 
13.0 RISK/BENEFIT ASSESSMENT ............................................................................................................. 34 
 
Potential Benefits to the Subjects .................................................................................................................. 34 
 
Known Potential Risks ................................................................................................................................... 34 
 
Risk/Benefit Analysis ...................................................................................................................................... 35 
14.0 DATA AND SAFETY MONITORING ...................................................................................................... 35 
 
Adverse Event (AE) Definition ........................................................................................................................ 35 
 
Serious Adverse Event (SAE) Definition ........................................................................................................ 35 
 
Classification of an Adverse Event................................................................................................................. 35 
 
Time Period and Frequency for Event Assessment and Follow-Up .............................................................. 36 
 
Reporting AEs and SAEs ............................................................................................................................... 37 
 
Unanticipated Problems ................................................................................................................................. 37 
 
Unanticipated Adverse Device Effect ............................................................................................................. 37 
 
Incidental Findings ......................................................................................................................................... 38 
 
Study Monitoring ............................................................................................................................................ 38 
 
Study Stopping Rules ..................................................................................................................................... 38 
15.0 STUDY FEASIBILITY ............................................................................................................................. 38 
 
Economic Burden to Subjects ........................................................................................................................ 38 
 
Feasibility of Recruiting the Required Number of Subjects ........................................................................... 38 
16.0 MULTISITE RESEARCH CONSIDERATIONS ....................................................................................... 39 
 
Single IRB (sIRB) Communication Plan ......................................................................................................... 39 
STUDY TEAM COMMUNICATION PLAN ....................................................................................................... 39 
17.0 REFERENCES ....................................................................................................................................... 39 

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1.0 
STATEMENT OF COMPLIANCE 
I confirm that I have read this protocol. I will comply with the IRB-approved protocol, and applicable 
regulations, guidelines, laws, and institutional policies.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitment.  
 
 
 
 
 
Elias Granadillo, MD. 
___________________                   __________________________________ 
___________________ 
Principal investigator                        Signature                                                                  Date 
 
 
 
 
 
 
 
 

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2.0 
LIST OF ABBREVIATIONS 
 
ADCS-PACC 
Alzheimer’s disease cooperative study Preclinical Alzheimer Cognitive Composite 
AE 
Adverse Event 
CCC 
Clinical Coordinating Center 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Cognitive Training 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management Software 
DCC 
Data Coordinating Center 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HD-tDCS 
High Definition Transcranial Direct Current Stimulation 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
IDE 
Investigational Device Exemption 
ICTR 
Institute for Clinical and Translational Research 
IRB 
Institutional Review Board 
 
 
MCI 
Mild cognitive impairment  
MOP 
Manual of Procedures 
NIH 
National Institutes of Health 
MRI 
Magnetic resonance imaging 
OHRP 
Office for Human Research Protections 
OnCore 
Online Collaborative Research Environment 
PHI 
Protected Health Information 
PI 
Principal Investigator 
POC 
Point of Contact 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sIRB 
single IRB 
SMART IRB 
Streamlined, Multisite, Accelerated Resources for Trials IRB 
 
 
SMP 
Study Monitoring Plan 
SMS 
Study Monitoring Service 
UP 
Unanticipated Problem 
 

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3.0 
STUDY SUMMARY 
 Synopsis 
Full Title 
A Randomized, Double-Blinded, Placebo Controlled Pilot Trial of the Feasibility of High 
Definition Transcranial Direct Current Stimulation and Cognitive Training in Patients with Mild 
Cognitive Impairment. 
Short Title 
A pilot study of HD-tDCS and cognitive training to improve cognitive function in MCI 
Protocol Number 
 00035757 
Number of 
Site(s) 
Two clinical sites in the United States 
Phase 
Pilot trial 
Main Inclusion 
Criteria 
1. Age ≥50-90 years  
2. Willing and able to undergo all procedures  
3. Retains decisional capacity at initial visit 
4. Meets criteria for MCI, amnestic type (Petersen, 2004).  
Main Exclusion 
Criteria 
1. Significant kidney injury requiring hemodialysis 
2. Automatic Internal Cardiac Defibrillator (AICD) or Pacemaker 
3. Significant congestive heart failure 
4. History of clinically significant ischemic or hemorrhagic stroke, or lacune or infarct 
considered by radiologist likely to cause or contribute significantly to cognitive 
symptoms   
5. History of thalamic lacunar stroke 
6. Modified Hachinski Ischemia Score >4 points 
7. History of seizure disorder requiring medication 
8. History of brain surgery (for seizure disorder, aneurysms, or benign/malignant tumor) 
9. History of HIV/AIDS 
10. Severe untreated obstructive sleep apnea 
11. Greater than three servings alcohol daily or illicit drug use 
12. Major neurologic disorders other than dementia (e.g., MS, ALS) 
13. Schizophrenia, bipolar disorder, other serious mental illnesses 
14. Other significant medical conditions at investigators’ discretion 
15. Pregnancy 
16. Lack of study partner (Participants are allowed to find a new study partner if the 
original study partner withdraws) 
Endpoints 
Primary Endpoint 
• 
Treatment completion rate.  
 
Secondary Endpoints 

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• 
Consent rate 
• 
ADCS PACC score at 3 and 6 months 
• 
Neurite density (intracellular volume fraction) at 3 months 
• 
Diffusivity indices: Fractional anisotropy (FA), Mean (MD), Axial (AD), Radial (RD) 
Diffusivity at 3 months 
• 
Morphometric indices: Cortical thickness, Surface Area, Volume, gyrification index at 3 
months. 
• 
ASL perfusion indices: blood flow, blood volume, mean transit time, time to peak, at 3 
months 
Study Design 
The study design is a double-blinded, randomized pilot clinical trial of HD-tDCS/sham HD-
tDCS combined with CT, administered to subjects with amnestic MCI (aMCI) in blocks of 5 
daily treatments for a total of 15 sessions. There will be one treatment block/month for a total 
of 3 months. 20 participants with aMCI will be enrolled. There will be 2 treatment groups/arms 
with 10 subjects per group/arm. We anticipate a dropout rate of appr. 10% and aim to 
complete procedures in 20 subjects. 
Study 
Intervention 
High definition transcranial direct current stimulation (HD-tDCS) 
Sham HD-tDCS 
Computerized Cognitive training (CCT) 
Sham CT 
Total Number of 
Subjects 
20 
Study Population Male and females aged 50 to 90 years with established diagnosis of MCI amnestic type.  
Total of 20 subjects 
Statistical 
Methodology 
Given the pilot nature of this study, two feasibility outcomes will be included: Consent rate and 
treatment completion rate. 20 patients are enough to calculate a 90% exact binomial 
confidence interval of (.75, 1) if all 20 are observed to complete treatment. Thus, this sample 
size is large enough to potentially exclude completion rates of 3/4 or lower. The pilot data from 
this study will provide initial estimates of the variability and the effect sizes. This information 
will then be used for the formal calculations of power and sample size necessary to conduct a 
future phase II trial. 
Estimated 
Subject Duration 
The duration of the study for each subject is approximately 6 months. 
Estimated 
Enrollment 
Period & Study 
Duration 
Study enrollment and follow-up will occur over 9 months with the total expected duration of 
the trial to be 12 months.  
 
 
 

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Schematic of Study Design 
 
 
 
 
 
 
 

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4.0 
KEY ROLES 
The following is a list of all key personnel and roles: 
 
Principal Investigator  
Elias Granadillo Deluque, M.D. 
Department of Neurology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
Phone: 414-955-0638 
Email: egranadillo@mcw.edu 
 
MCW Sub-Investigator 
Priyanka Shah-Basak, Ph.D. 
Assistant Professor 
Medical College of Wisconsin 
8701 W Watertown Plank Rd 
Wauwatosa 
Wisconsin 532260 
Phone: 414-955-5752 
Email: prishah@mcw.edu 
 
 
 
Participating Site(s) 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
 
University of Wisconsin Madison 
600 Highland Avenue 
Madison, WI 53792 
 
 
 UW-Madison Co-Investigator (Site PI) 
Hrissanthi (Chris) Ikonomidou, M.D. Ph.D.  
Professor 
Department of Neurology, University of Wisconsin Madison  
1685 Highland Avenue  
Madison WI 53705  
Phone: 608 2656470  
Email: ikonomidou@neurology.wisc.edu 
 UW-Madison Sub-Investigator 
Laura Hancock, Ph.D. 
Assistant Professor 
Department of Neurology 
Division of Neuropsychology 
600 Highland Avenue 
Madison WI 53705 
Phone: 608-263-5448 
Email: hancock@neurology.wisc.edu 

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5.0 
INTRODUCTION 
 Mild Cognitive Impairment 
Mild cognitive impairment (MCI) is currently an area of considerable clinical and research interest 
because of the high rate of conversion from MCI to Alzheimer disease (AD) (Almkvist et al., 1998; 
Collie et al., 2000; Kluger et al. 1999; Morris et al., 2001; Petersen et al., 1999; 2001; Rubin et al., 
1989; Shah et al., 2000; Wolf et al., 1998). Several studies have demonstrated that patients with MCI 
progress to AD at a higher rate (10 to 15% per year) than normal elderly patients (1 to 3% per year). 
Therefore, MCI patients are considered to be at a higher risk for AD. MCI may be classified as either 
amnestic or non-amnestic, with the primary clinical distinction being the presence of prominent 
memory impairment in the former, and the predominant involvement of cognitive domains different 
from memory in the latter. Accordingly, amnestic MCI likely represents a prodromal stage of 
Alzheimer’s dementia (Petersen et al., 2001); it is distinguished by impairment of episodic memory, 
and when contrasted with normal aging amnestic MCI is associated with a high degree of memory 
impairment with little or no impairment in activities of daily living (ADLs) (de Leon et al., 1993; 
Petersen et al., 2001). Individuals with amnestic MCI do not meet the currently accepted clinical 
criteria for probable AD, but the high rate of conversion from amnestic MCI to AD makes early 
diagnosis and treatment an important clinical issue. In its earliest stages, AD manifests primarily as 
cognitive impairment; As AD progresses, there is further loss of cognitive abilities, a loss of functional 
independence, and the development of behavioral problems (Gauthier, 1998). Early diagnosis and 
treatment may delay the onset of these symptoms. 
 Current Standard of Care 
Currently, no drug has proven effective in treatment of MCI. Cholinesterase inhibitors have not been 
shown to decrease risk of progression from MCI to dementia at 1 and 3 years (Lin et al., 2013; 
Petersen et al., 2005; Salloway et al., 2004). In addition, cholinesterase inhibitors have limited or no 
significant effects on cognitive function over the short term (<12 months) and may substantially 
increase adverse effects, based on a meta-analysis of 4 trials (1,960 participants) (Lin et al., 2013) 
and another meta-analysis of 9 trials (5,149 participants) (Russ et al., 2012). Consequently, 
cholinesterase inhibitors and memantine are not recommended for MCI treatment and there are 
currently no FDA-approved medications for MCI (Lin et al., 2013; Russ et al., 2012). Ginkgo biloba, 
a widely used herbal supplement to improve cognition and memory, has not been shown in 
randomized trials to prevent cognitive decline in those with MCI or normal cognition (Snitz et al., 
2009). Similarly, testosterone supplementation in older men showed no benefit for cognitive function 
in a randomized controlled trial (Emmelot-Vonk et al., 2008). 
 
From 1998 to 2019 there have been about 150 failed attempts at developing Alzheimer’s drugs, 
including medications for the management of MCI. The ‘Amyloid Hypothesis’ has been the leading 
scientific framework for the development of AD cures, and despite recent setbacks, a countless 
number of biologically specific AD treatments are currently being tested in clinical trials and in the 
drug development pipeline (Cummings et al., 2018). The recent high-profile failures highlight the 
importance of developing therapies that go beyond the targeting of amyloid and tau in order to help 
restore alternative physio-pathologic mechanisms; this would include changes in metabolism, innate 
immunity, modifiable lifestyle factors, and abnormal patterns of brain network connectivity and 
plasticity.  
 

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The restoration of brain network connectivity and of the brain’s 
intrinsic 
plastic 
properties 
seems 
particularly 
relevant 
considering recent findings suggesting that adult hippocampal 
neurogenesis is active in adult healthy subjects and drops 
markedly in patients with AD (Moreno-Jimenez et al., 2019; 
Boldrini et al., 2018).  
 Transcranial Direct Current Stimulation and cognitive 
training 
5.3.1. 
Transcranial direct current stimulation (tDCS) is 
a method which enables noninvasive electrical stimulation of the 
cortex via electrodes placed on the subject’s head (Paulus, 
2011; Schlaug and Renja, 2008), Anodal stimulation facilitates, 
and cathodal stimulation inhibits spontaneous neuronal activity 
in the underlying cortical areas (Nitsche et al., 2007; 2008; Priori 
et al., 2009). tDCS does not induce neuronal firing, but 
modulates spontaneous neuronal network activity (Bindman et 
al., 1964a; Nitsche and Paulus, 2000; Purpura and McMurty, 
1965). Changes in excitability are reflected in spontaneous firing 
rates and responsiveness to afferent synaptic inputs (Bindman 
et al., 1964b; Creutzfeldt et al., 1962).   
tDCS also elicits a variety of after-effects; it modifies the 
synaptic microenvironment, modifies synaptic strength in an 
NMDA-receptor dependent fashion (similar to long-term 
potentiation), modulates intracortical and corticospinal neurons, 
promotes neurogenesis (Pikhovych et al., 2016; Braun et al., 
2016) and may cause transient changes in the density of protein 
channels in neuronal membranes (Liebetanz et al., 2002; 
Nitsche et al., 2003; Stagg et al., 2009). An interesting after-
effect of tDCS is modulation of spontaneous neuronal 
oscillations (Ardolino et al., 2005). Remarkable is also the fact 
that constant electrical fields influence vessels and connective 
tissue, inflammation, cell migration, vascular motility and cellular 
structures (Merzagova et al., 2010). 
  
In the 1960s, Bindman (et al., 1964b) showed that potential 
gradients produced by currents of the order of 0.1-0.5 mA 
produced neuronal excitability shifts in rat cortex and could last 
for many hours after the current was switched off. Recently, 
modern TMS techniques allowed to prove that tDCS in humans 
can modulate cortical excitability caused by TMS. Cathodal 
polarization reduced the size of the TMS-induced motor evoked 
potentials (MEPs), indicating reduced cortical excitability, while 
anodal stimulation increased the size of the MEPs, suggesting increased excitability (Paulus, 2011). 
The effects outlasted the duration of the stimulation. Improved performance after tDCS has been 
shown in motor learning, visuomotor coordination and probabilistic classification in humans (Paulus, 
2011, Schlaug and Renja, 2008). Sinusoidally applied tACS allows manipulation of intrinsic cortical 
oscillations with externally applied electrical frequencies. Combination of tACS and tDCS has been 
shown to boost memory (Paulus, 2011).  
Figure 1. TDCS setup and montage 
A) TDCS setup using a mobile, 
battery-operated 
direct 
current 
stimulator 
connected 
with 
two 
electrodes. One electrode (active) is 
positioned over C3 (corresponding to 
the 
precentral 
gyrus) 
and 
the 
reference electrode is positioned 
over the contralateral supraorbital 
region. If current flows from C3 to the 
supraorbital region, then the tissue 
underlying C3 is subjected to anodal 
(increase in excitability) stimulation. If 
current is reversed, then the tissue 
underlying 
C3 
is 
subjected 
to 
cathodal (decrease in excitability) 
stimulation; B) Regional cerebral 
blood flow increases in the motor 
region underlying the electrode 7 
positioned over C3 after anodal 
stimulation. Regional cerebral blood 
flow was determined using a non-
invasive 
arterial 
spin-labeling 
technique (adopted from Paulus, 
2011). 

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Our understanding of the mechanisms of tDCS and tACS is emerging. tDCS is said to provide a 
subthreshold stimulus which modulates the likelihood that neurons will fire by hyperpolarizing or 
depolarizing brain tissue. The fact that the effects outlast current stimulation suggests that LTP and 
LTD are modulated (Stagg et al., 2018).  
 
tDCS has been used to modify and study cognitive functions in healthy humans and in patients with 
neuropsychiatric conditions. Anodal and cathodal tDCS modulate visual working memory but can also 
disrupt practice-dependent improvement during a verbal working memory task when the cerebellum 
is stimulated (Ferrucci et al., 2008).  Anodal tDCS to the anterior temporal lobes influences memories, 
improves decision making, attention, learning, language and memory consolidation, improves motor 
function in stroke patients, and improves depressive symptoms (Barham et al., 2016; Boggio et al., 
2007; Brunoni et al., 2012; Cappon et al., 2000; Ferrucci et al., 2008; Fregni et al., 2006; 2007; 2015; 
Mattai et al., 2011; Paulus, 2011; Varga et al., 2011; Young et al., 2013). However, all these 
phenomena are transient. The effects of repeated applications of tDCS and the potential of this 
technique to lead to lasting neurocognitive improvements remain unexplored. 
5.3.2. 
Cognitive Training 
Cognitive decline is associated with risk for functional decline, nursing home placement, and mortality 
(Sands et al., 2002; Yaffe et al., 2002; 2006). In older individuals, concerns about forgetfulness are 
widespread and are associated with depression and anxiety (Reese et al., 1999; Zelinski et al., 2004; 
Mol et al., 2007). Interventions that reliably improve cognitive function thus have the opportunity to 
substantially improve the health and quality of life of older individuals. There is also literature 
suggesting that cognitive training (CT) can improve cognitive performance in older adults, who are at 
risk for dementia and MCI. Reports state that CT may significantly reduce the risk of dementia 
(Edwards et al., 2017). There are encouraging studies which show that CT can slow cognitive decline 
in individuals with MCI (Lin et al., 2016) and improve memory in older adults (Mahncke et al., 2006; 
Smith et al., 2009).  
 
In response to this, two general approaches for maintaining or improving cognitive function in older 
adults emerged. The first focuses on direct instruction of putatively useful strategies (Naveh-Benjamin 
et al., 2007; Derwinger et al., 2005; McDougall, 1999; Rebok and Balcerak 1989; Willis and 
Nesselroade 1999; O’Hara et al., 2007). Although improvement on cognitive tests is generally seen 
after direct strategy instruction, performance gains typically do not generalize beyond tasks 
corresponding directly to the strategies taught (Verhaeghen et al., 1992; Fillit et al., 2002; Rebok et 
al., 2007), and it is not clear that older adults continue to use learned strategies over time (Rebok et 
al., 2007). As a result, strategy training programs have not been widely adopted. A second approach 
is derived from studies in animals (van Praag et al., 2000) and humans (Scarmeas et al., 2001; Wilson 
et al., 2007; Verghese et al., 2003) which suggest that nonspecific cognitive stimulation reduces the 
risk of cognitive decline. This has led to the practice of encouraging older adults to engage in everyday 
cognitively stimulating activities (Fillit et al., 2002; Small 2002; Hultsch et al., 1999), but the 
retrospective and observational designs of the human studies have led to difficulty interpreting the 
direction of causation between cognitive function and cognitively stimulating activities (Hultsch et al., 
1999). 
 
Recognition of the importance of sensory system function to cognitive function has prompted the 
development of a novel approach for treating age-related cognitive decline. It has been proposed that 
age-related reductions in the quality of neural information flowing through peripheral and central 
sensory systems to cognitive systems contribute to age-related cognitive decline (Schneider et al., 
2000; Wingfield and Stine-Morrow 2000). Animal and human studies have demonstrated that the 
performance of sensory systems in the cerebral cortex can be substantially improved through 
intensive learning and practice and that plastic brain changes across networks of relevant cortical 

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areas in the central nervous system mediate these improvements (Gilbert et al., 2001; Buonomano 
and Merzenich 2001). Consequently, a cognitive training program designed to improve central 
sensory system function could potentially improve cognitive function in older adults (Mahncke et al., 
2006).  
 
Researchers utilized a computer-based cognitive training program (Brain Fitness Program, Posit 
Science, San Francisco, CA) in a large randomized controlled two-arm clinical trial called the 
Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study (Smith et 
al., 2009). This program was designed to provide computer-based intervention to improve the function 
of brain systems through intensive brain plasticity–based learning and had shown promise in smaller-
scale studies (Mahncke et al., 2006a; 2006b). 
 
Their primary objective was to evaluate the efficacy of their experimental treatment (ET) training 
program by comparing the magnitude of improvements on untrained measures of memory and 
attention between the ET training program and an active control (AC) training program that engaged 
learning processes but was not designed to improve sensory function. Participants were community-
dwelling adults aged 65 and older without a diagnosis of cognitive impairment. They were randomized 
to receive the ET or a novelty- and intensity- matched general cognitive stimulation program modeling 
treatment (AC). Duration of training was 1 hour per day, 5 days per week, for 8 weeks, for a total of 
40 hours. Results revealed that the ET group demonstrated improvement on neuropsychological 
measures of memory and attention when compared to AC. Multiple secondary measures of memory 
and attention showed significantly greater improvements in the ET group (word list total score, word 
list delayed recall, digits backwards, letter–number sequencing), as did a participant-reported 
outcome measure. However, no advantage for the ET group was seen on a measure of narrative 
memory. This computer-based cognitive training program has since been successfully applied in 
various populations, including MCI, healthy aging, multiple sclerosis, ADHD, schizophrenia, and 
cardiac disease. It is now called Posit Science Brain HQ.   
 Rationale 
Here we propose to study the feasibility and the combined effect of HD-tDCS and CT, on cognitive 
and imaging biomarkers of AD in subjects with aMCI. With CT we aim to activate neuronal networks 
within selected brain regions by engaging participants in suitably chosen tasks, while simultaneously 
boosting synaptic activity and plasticity of activated networks by targeting them with HD-tDCS. We 
will use a self-developed and safety tested HD-tDCS protocol (Turski et al., 2017), sequentially 
stimulate four brain regions while participants simultaneously perform appropriately chosen CT tasks 
that aim to engage networks within those regions. Multifocal stimulation is key to our approach, as, 
in contrast to previous work, we aim to improve multiple components of cognition. We will use 
sequential stimulation of multiple cortical areas over 3 months and will test sustainability of 
achieved effects on cognition at 6 months. We hypothesize that the proposed combined treatment 
will improve cognition in MCI, the effect will be sustainable, and the combination will achieve superior 
effects compared to CT alone. In addition, we will evaluate impact of treatment on quality of life, 
structural markers of neuronal connectivity, and evolution of neurodegeneration. We are 
hopeful that this pilot trial will generate valuable knowledge to help design a large-scale phase II 
clinical trial to further explore whether the combination of HD-tDCS and CT in MCI can prevent 
progression to dementia. 
 

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The overall rationale for HD-tDCS (as opposed to tDCS) is straightforward: tDCS produces low-
intensity electric fields across significant sections of the brain, and, while these intensities and tDCS 
in general are considered well tolerated and safe, the stimulation is not targeted to any particular 
brain region. HD-tDCS aims to produce the same low-intensity electric field but in a limited region of 
the brain (Figure 2). By producing the same intensity electric field in the brain but over a reduced 
area, HD-tDCS may add an additional safety factor to tDCS. HD-tDCS also uses electrodes designed 
and validated specifically for DC stimulation – again while conventional tDCS with sponge-pad based 
approaches is considered well tolerated, this provides an additional safety factor. Generally, the 
present clinical paradigm for tDCS uses two relatively large electrodes to inject current through the 
head resulting in electric fields that are broadly distributed over large regions of the brain. Datta et al 
(2009) proposed a simple method to restrict the spread of current flow using a 4x1 configuration 
(Figure 2). Minhas et al. (2010) showed that optimized HD-electrodes provide control over sensation 
and voltage. Dmochowski et al (2011) presented a method that uses multiple small electrodes (i.e. 
1.2 cm diameter) and systematically optimizes the applied currents to achieve effective and targeted 
stimulation while ensuring safety of stimulation. They described a fundamental trade-off between 
achievable intensity (at the target) and focality, and algorithms to optimize both measures. When 
compared with large pad-electrodes (approximated here by a set of small electrodes covering 25 
cm2), 
the 
proposed 
approach 
achieves 
electric 
fields, 
which 
exhibit 
simultaneously 
greater 
focality 
(80% 
improvement) and higher 
target 
intensity 
(98% 
improvement) at cortical 
targets using the same 
total 
current 
applied. 
These 
improvements 
illustrate the previously 
unrecognized and non-
trivial dependence of the 
optimal 
electrode 
configuration 
on 
the 
desired 
electric 
field 
orientation 
and 
the 
maximum total current 
(due to safety). Similarly, 
by 
exploiting 
idiosyncratic details of 
brain 
anatomy, 
the 
optimization 
approach 
Figure 2: Electric field generated using HD-tDCS. Computational models predict brain targeting by high-definition tDCS 
using the 4 X 1 montage compared with conventional tDCS using a bipolar sponge montage. (Top left) Sample segmentation 
masks of the high resolution individualized head model. (Boxed Right Panel) The high-definition 4 X 1 montage consisted of 
1 anode, positioned over the motor region, surrounded by 4 cathodes at 7 cm radius—all the electrodes were high-definition 
mini electrodes. The conventional sponge montage used 1 anode centered over the motor region and 1 cathode over the 
contralateral supraorbital region—both electrodes were conventional sponge based. (A) High-definition tDCS resulted in 
brain current flow restricted to within the ring with peak brain activation under the center electrodes. (B) Conventional tDCS 
resulted in comparatively diffuse current flow with clustering of peaks between the electrodes (not under the electrodes), 
(From Borckardt et al., 2011). 

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significantly improves upon prior un-optimized approaches using small electrodes. The analysis also 
reveals the optimal use of conventional bipolar montages: maximally intense tangential fields are 
attained with the two electrodes placed at a considerable distance from the target along the direction 
of the desired field; when radial fields are desired, the maximum-intensity configuration consists of 
an electrode placed directly over the target with a distant return electrode. If a target location and 
stimulation orientation can be defined by the clinician, then the proposed technique is superior in 
terms of both focality and intensity as compared to previous solutions and is thus expected to translate 
into improved patient safety and increased clinical efficacy (DaSilva et al., 2015; Dmochowski et al., 
2011; Donnell et al., 2015; Edwards et al., 2013; Garnett et al., 2015; Kuo et al., 2013; Villamar et al., 
2013a). HD-tDCS employs more than two small electrodes. Today, the most frequently used HD-
tDCS montage is the 4X1 ring set-up, which employs a central electrode surrounded by four return 
electrodes arranged in a circle around the central electrode (Dmochowski et al., 2011; Edwards et 
al., 2013; Villamar et al., 2013b).  
 
HD-tDCS enhances motor cortex excitability (Caparelli-Daquer et al., 2012) similar to conventional 
tDCS, significantly improves verbal learning and working memory in healthy individuals (Nikolin et al., 
2015), improves language in patients with stroke (Richardson et al., 2015), and is well tolerated 
(Borckhardt et al., 2012; Brunye et al., 2014; Kuo et al., 2013; Garnett et al., 2015; Richardson et al., 
2015).  As with tDCS, HD-tDCS studies have also been designed to stimulate one brain area for a 
small number of sessions (1-10 sessions). 
tDCS in MCI and Dementia 
Khedr and colleagues conducted a double-blind randomized clinical trial on the efficacy of cortical 
direct current stimulation for the treatment of Alzheimer’s disease. Their cohort included 34 AD 
patients, who received 10 daily stimulations with 2 mA over the left dorsolateral prefrontal cortex. The 
study showed that cathodal and anodal tDCS improved MMSE in contrast to sham tDCS. tDCS also 
reduced the P300 latency of event-related potentials (Khedr et al., 2014). 
 
In a double-blind, cross-over, sham-controlled study, anodal tDCS was administered to the left inferior 
frontal cortex during task-related and resting-state functional MRI to assess its impact on cognition 
and brain functions in MCI. Anodal-tDCS significantly improved performance to the level of controls, 
reduced task-related prefrontal hyperactivity and resulted in normalization of abnormal network 
configuration during resting state fMRI.  

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Summers and colleagues conducted a meta-analysis to evaluate the effects of tDCS on cognitive and 
motor performance in healthy older adults. Of the 81 studies identified, 25 qualified for inclusion. A 
random effects model meta-analysis revealed a significant overall standardized mean difference. Five 
analyses on moderator variables indicated significant tDCS beneficial effects: (a) on both cognitive 
and motor task performances, (b) across a wide-range of cognitive tasks, (c) on specific brain areas, 
(d) stimulation offline (before) or online (during) the cognitive and motor tasks (Summers et al., 2016). 
 
A recent meta-analysis examining the effects on memory of tDCS in persons with MCI and dementia 
revealed a statistically significant medium effect size for immediate effects (Cruz Gonzalez et al., 
2018). Given the neuromodulatory and disease modifying potential of HD-tDCS and traditional 
tDCS, the question is posed whether stimulation of multiple cortical areas over months or 
years might elicit favorable and lasting effects on cognitive function. This might have 
therapeutic value for subjects with evolving dementia syndromes. Whether chronic tDCS or 
HD-tDCS have the potential to modify the clinical course of MCI and early dementias is 
unknown. 
Extended Multiple-field HD-tDCS is well tolerated and safe in healthy adults 
In preparation for this trial, we studied safety, feasibility and tolerability of daily HD-tDCS over 4 brain 
regions for 20 sessions in healthy adults (Turski et al., 2017). Five healthy adults underwent physical 
and neurological examination, electrocardiogram (EKG), electroencephalogram (EEG) and cognitive 
screening (ImpACT) before, during and after HD-tDCS. Four networks (left/right temporoparietal and 
frontal) were stimulated in sequence (20 min each) using HD-tDCS in 20 daily sessions. Sessions 1-
10 included sequential dose-escalating stimulation of both temporoparietal networks, sessions 11-15 
stimulations of 4 networks (1.5 mA/network), and sessions 16-20 two daily stimulation cycles of 4 
networks/cycle (1.5 mA/network) (Table 1). Side effects, ImpACT scores and EEG power spectra 
were compared before and after HD-tDCS. 
 
Fig 3: A. HD-TDCS devices and HD-cap. B.  Diagram of HD-tDCS stimulation protocol with 4 networks, as applied in the study by 
Turski et al., 2017. Each network will be stimulated for 20 min at 1.5 mA. C. Visualization of current flow modeling using standard MRI 
and head model. It shows the left temporoparietal (TPN) and frontal (FN) networks. Heat map color corresponds to higher field intensity. 
Modeling done using SimNIBS software. Published in Turski et al, 2017. 

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Intensity 
Networks 
stimulated 
Daily 
cycles 
# of stimulation 
sessions 
Duration of 
stimulation 
Interval 
between 
cycles 
Week 1 
1mA 
2 (R+L 
temporooccipital) 
1 
5 
40 min 
N/A 
Week 2 
1.5mA 
2 (R+L 
temporooccipital) 
1 
5 
40 min 
N/A 
Week 3 
1.5mA 
4 
1 
5 
80 min 
N/A 
Week 4-6 
1.5mA 
4 
2 
5 
160 min 
2 hrs 
Table 1: Outline of stimulation schedule in feasibility trial conducted by Turski et al., 2017. 
 
All subjects completed the trial. Adverse events were tingling, transient redness at the stimulation 
site, feeling of being stimulated for 3 hrs and one self-resolving headache. EEG power spectrum 
showed decreased delta power in frontal areas several days after HD-tDCS. While at the group level 
ImpACT scores did not differ before and after stimulations, we found a trend for correlation between 
decreased EEG delta power and individual improvements in ImpACT scores after HD-tDCS. 
We concluded that repeat daily stimulation of multiple brain regions using HD-tDCS is feasible and 
safe in healthy adults. Preliminary EEG results suggest that HD-tDCS may induce long lasting 
changes in excitability in the human brain. 
 
In the proposed pilot trial, we will perform 3 monthly blocks of daily stimulations according to 
schedule applied in week 3 (table 1). 
 
6.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• 
To assess the feasibility of MFE-HD-
tDCS plus simultaneous computerized 
CT as a viable intervention to improve 
cognitive function in patients with MCI. 
 
• 
Treatment completion rates (Primary) 
• 
Consent rates.  
 
 
 
 
Secondary 
• 
To collect preliminary data on the 
efficacy of MFE-HD-tDCS with 
simultaneous computerized CT, 
administered in 15 sessions over a 
period of 3 months, to improve 
cognition in subjects with MCI. 
• 
ADCS PACC score at 3 and 6 months. 
 
• 
To collect preliminary data on the 
efficacy of MFE-HD-tDCS in 
combination with computerized CT, 
administered in 15 sessions over a 
 

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period of 3 months to improve quality 
of life in subjects with MCI. 
• 
To collect preliminary data on the 
effects of MFE-HD-tDCS combined 
with computerized CT on brain 
function and on neurodegeneration. 
• 
Neurite density (intracellular volume fraction) 
at 3 months 
• 
Diffusivity indices: Fractional anisotropy(FA), 
Mean(MD), Axial(AD), Radial(RD) Diffusivity 
at 3 months 
• 
Morphometric indices: Cortical thickness, 
Surface Area, Volume, gyrification index at 3 
months 
• 
ASL perfusion indices: blood flow, blood 
volume, mean transit time, time to peak, at 3 
months 
 
7.0 
STUDY DESIGN 
 General Design  
The study design is a double-blinded, randomized pilot clinical trial of repetitive daily HD-tDCS/sham 
HD-tDCS, administered in combination with CT to subjects with MCI in 3 monthly blocks of 5 daily 
sessions for a total of 15 sessions. The design is outlined in figure 4. 
 
 
Brief Description of Study Groups 
      20 participants with MCI, ages 50-90 years, will be assigned to one of two groups: 
1. Active HD-tDCS + cognitive training (n=10) 
2. Sham-HD-tDCS + cognitive training (n=10) 
 
Figure 4: Design of the HD-tDCS + CT 
trial in subjects with MCI 

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Recruitment outline 
This is a multisite trial. Participating sites are the Medical College of Wisconsin, Milwaukee, and the 
University of Wisconsin, Madison.  
 
 
UW-Madison 
Site 
(n=10) 
     MCW Site (n=10) 
 
Baseline Treatment 
and Follow-
Up 
Baseline 
Treatment 
and 
Follow-Up 
aMCI 
10 
10 
10 
10 
Total 
10 
10 
10 
10 
Table 2: Recruitment outline 
 
Information about subjects will be obtained from medical records, surveys, interview questions, data 
collection forms, and imaging studies. 
Expected duration of intervention is 3 months for each subject and expected duration of 
participation in the trial is 6 months.  
 End of Study Definition 
End of study will occur when 20 subjects have completed this pilot project.  
8.0 
SUBJECT SELECTION 
 Inclusion & Exclusion Criteria   
Eligibility will be determined by inclusion and exclusion criteria below and confirmed by medical 
record review as necessary. 
 
Inclusion Criteria  
1. Age ≥50-90 years 
2. Willing and able to undergo all procedures 
3. Retains decisional capacity at initial visit 
4. Meets criteria for MCI, amnestic type (Petersen, 2004). 
 
Exclusion Criteria 
1. Significant kidney injury requiring hemodialysis 
2. Automatic Internal Cardiac Defibrillator (AICD) or Pacemaker 
3. Significant congestive heart failure 
4. History of clinically significant ischemic or hemorrhagic stroke, or lacune or infarct considered 
by radiologist likely to cause or contribute significantly to cognitive symptoms   
5. History of thalamic lacunar stroke 
6. Modified Hachinski Ischemia Score >4 points 
7. History of seizure disorder requiring medication 
8. History of brain surgery (for seizure disorder, aneurysms, or benign/malignant tumor) 

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9. History of HIV/AIDS 
10. Severe untreated obstructive sleep apnea 
11. Greater than three servings alcohol daily or illicit drug use 
12. Major neurologic disorders other than dementia (e.g., MS, ALS) 
13. Schizophrenia, bipolar disorder, other serious mental illnesses 
14. Other significant medical conditions at investigators’ discretion 
15. Pregnancy 
16. Lack of study partner (Participants are allowed to find a new study partner if the original study 
partner withdraws) 
 Vulnerable Populations 
The consent process is conducted as a face-to-face interview with the patient. No study procedures 
are initiated until the consent process is complete. In all cases, prospective participants with dementia 
will first be assessed for their ability to provide informed consent.  
 
The subject must provide consent himself/herself at screening. We will not enroll any participant 
deemed to have impaired decisional capacity. Participants will be consented at the study sites 
involved using local procedures established by the individual sites. 
 
If any participant appears to have cognitive impairment when they return for their follow up visit, 
capacity to give consent will be assessed in clinical interviews of participants by clinicians 
experienced in clinical dementia research. If it is found the subject no longer has capacity to 
consent, the Legally Authorized Representative will provide consent if appropriate. 
 Subject Identification 
Self-Identification 
Potential subjects may self-identify by responding to IRB-approved recruitment efforts, such as 
web postings, posters/flyers, radio or TV ads, newspaper ads, mass mailings, email blasts, etc. 
IRB-approved screening scripts, eligibility questionnaires, and email response templates will be 
utilized when communicating with potential subjects who respond to these recruitment methods.   
Information collected from the potential subject is to be limited to protect the potential subject’s 
privacy and information collected from potential subjects who fail pre-screening will be destroyed.  
Identification in Clinical Practice 
Potential subjects may be identified during routine visits to the Memory Disorder’s Clinic in the 
Neurology Clinic at the Froedtert and the Medical College of Wisconsin (MCW), Middleton VA 
Hospital Madison, Memory Assessment Clinic [University of Wisconsin (UW) Hospital and Clinics’ 
Memory Clinics and the Wisconsin Alzheimer’s Institute (WAI) Diagnostic Clinic Network, a group 
of diagnostic clinics associated with the WAI experienced in diagnosing and recruiting patients 
with Mild Cognitive Impairment and Alzheimer’s disease. A member of the clinical team will inform 
potential subjects of the research opportunity and provide an IRB-approved consent form. 
Potential subjects will be pre-screened through medical record review and conversation with the 
subject using an IRB-approved script. Information collected from potential subjects who fail pre-
screening will be destroyed. Potential subjects who meet all pre-screening criteria will be invited 
for a formal screening/baseline visit. 

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Department Database 
The Wisconsin ADRC Recruitment Registry, described under a separate UW-Madison protocol 
(2011-0772) may be used to identify eligible subjects. 
 Subject Recruitment 
A total of 20 subjects will be recruited from two sites in the United States. Several recruitment 
strategies may be employed, and sites may use a combination of methods depending on their 
capabilities. Possible recruitment strategies are as follows (non-comprehensive list): 
Recruitment through Clinical Practice 
If the potential subject is agreeable, they will be provided contact information for the study team 
or the research team will initiate contact. 
Posters/Flyers 
Flyers announcing that volunteers are needed for a study may be posted in memory clinics of the 
Wisconsin Alzheimer Institute, UW Health facilities (including UW Hospital and Clinics, The 
American Center, South Park clinics), Meriter Hospital, Middleton Veteran’s Hospital. Several key 
details of the study will be included in the flyer (key eligibility criteria, number and length of visits, 
location of study site, type of remuneration) along with a call back number for people to call in 
case they are interested.   
Telephone Recruitment 
When potential subjects contact the study team, a brief description of the study’s purpose and 
participation requirements will be reviewed. This must also include a statement that participation 
is voluntary. The screener will ask the caller if s/he has any questions and whether they are 
interested in participating. After all questions have been answered, the study team member will 
ask if the potential subject is interested in proceeding to the next step in recruitment for the study 
(e.g., scheduling a visit to learn more and go through the consent process, or answering some 
screening questions). 
 
Letters 
UW Madison will utilize the Wisconsin Alzheimer's Disease Research Center (ADRC) recruitment 
resources to identify individuals who meet inclusion criteria. The ADRC supports researchers in 
their pursuit to identify answers that will lead to improved diagnosis and care for patients, as well 
as those seeking a cure and prevention of Alzheimer's Disease. The ADRC can hold the names 
and eligibility information of potential volunteers, allowing ADRC staff to contact them for 
appropriate research studies.  
 
The ADRC will send the recruitment letters to eligible individuals which contain the reason for 
receiving the letter and outlining the procedures and purpose of the study, signed by Drs 
Hrissanthi Ikonomidou and Sanjay Asthana. If individuals are interested, they can contact Dr. 
Ikonomidou by email or phone. 
 Remuneration and Retention Strategies 
For subjects making trips of 25 miles or more one way, they will be reimbursed at the standard UW 
or MCW travel rate. Remuneration will be offered for specific procedures. 
 
MRI: $50 x 2 scans ($100)   
Neuropsychological Testing: $50 x 3 evaluations ($150)   
Stimulation: $20 x 15 sessions ($300) 

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Study partners will receive $25 for baseline and $25 for both post-treatment follow-up participation. 
The study partner will receive a total of $75 if they complete all visits, even if they participate via 
telephone. 
 
Payments for each completed activity will be processed within 12 weeks from completion. 
 
For MCW subjects only, on a case-by-case basis, subjects may be reimbursed for an overnight stay 
(up to 5 days per week) in a hotel or other form of lodging if necessary to complete a study visit. If 
their visit requires an overnight stay, they will receive a $25 meal reimbursement per night. 
 
To pay subjects, we need their social security number. Any payment may be reportable as income 
on their taxes. 
 
Subject’s enrolled at MCW may be eligible to stay at Kathy’s House as an alternative to a hotel or 
other form of lodging. 
 
Kathy’s House 
 
If subjects reside at a permanent address 50 miles or greater from Milwaukee, they may be eligible 
for lodging at Kathy’s House. Kathy’s House is located on the Froedtert Hospital campus and 
provides housing for research subjects who require a stay greater than 3 days. 
 
Each room includes the following: 
• 
Most rooms have both a queen and a single bed 
• 
Private bathroom with walk-in shower 
• 
Bed and bath linens 
• 
Television, small refrigerator, and telephone (local) 
 
While lodging at Kathy’s House, guests also have access to the following communal amenities: 
• 
Fully equipped kitchen 
• 
Refrigerator, pantry, and freezer storage space 
• 
Free Wi-Fi 
• 
Living Room 
• 
Dining Room 
• 
6 interior & 4 exterior lounge spaces 
• 
Fitness Center 
• 
Meditation Room 
• 
Laundry facilities 
• 
Library, including computer workstations 
 
Food 
• 
Guests are responsible for their own meals 
• 
Each room has designated pantry, refrigerator, and freezer storage space in the kitchen 
• 
A meal from a local restaurant is provided once a week. 
 
Parking and Transportation 
• 
Parking is available for guests on a surface lot. 
• 
Complimentary shuttle service is available during the week on a limited basis due to the COVID-
19 pandemic. 
 

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Guest Responsibilities 
It is important that guests staying at Kathy’s House are comfortable in a communal environment. 
There is no maid service, so guests are asked to clean up behind themselves in the common areas 
and in their rooms. Rooms are thoroughly cleaned upon guest check-out. 
 
Guests staying at Kathy’s House must have a caregiver with them for the duration of their stay. Guests 
must also be able to perform basic mobility and care functions, including: 
• 
do personal laundry as needed 
• 
plan, prepare and clean up following meals 
 
Payment for lodging at Kathy’s House will be arranged and covered by the study team. Care givers 
are expected to lodge with subjects to the extent possible. 
 
With the subject’s verbal consent, a referral can be sent by the study team to Kathy’s House. The 
following personal information will be included in the referral to Kathy’s House: subject and care giver 
name, date of birth, gender, city, state, zip code, phone number, email address, and reason for visit. 
 
Upon reception of the referral, Kathy’s House will conduct a formal background check using 
TruthFinder.com. The subject and caregiver’s names and birthdates will be used to check for any 
criminal charges associated with either person. Kathy’s House has the right to reject any referral 
based on this background check. 
 
Kathys-house.org provides additional information. 
 Early Termination and Withdrawal 
Subjects are free to withdraw from participation in the study at any time upon request. 
 
The Principal Investigator (PI) may discontinue or withdraw a subject from the study for the following 
reasons at his/her discretion: 
• 
Pregnancy 
• 
Subject non-compliance with study requirements (e.g., study intervention non-compliance)  
• 
If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the subject 
• 
If the subject is no longer an appropriate candidate for participation   
• 
There is evidence of progressive disease or unacceptable toxicity 
• 
Subject unable to receive scheduled intervention for 3 weeks 
 
Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention will be replaced. Subjects who sign the informed consent form, are randomized and 
receive the study intervention, then subsequently withdraw, or are withdrawn or discontinued from 
the study, will not be replaced. 
 
The following actions should be taken if a subject withdraws, or fails to return for a required study 
visit: 
• 
The site will attempt to contact the subject and reschedule the missed visit within 6 weeks and 
counsel the subject on the importance of maintaining the assigned visit schedule and ascertain if 
the subject wishes to and/or should continue in the study. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee will make every effort 
to regain contact with the subject where possible, 3 telephone calls and, if necessary, a certified 

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letter to the subject’s last known mailing address or local equivalent methods. These contact 
attempts shall be documented in the subject’s medical record or study file.  
• 
If the subject continues to be unreachable, they will be considered to have withdrawn from the 
study with a primary reason of lost to follow-up. The withdrawn date is the last day of attempted 
contact. 
 
The study team will attempt to obtain the following information from subjects following early 
termination or withdrawal: Adverse events and reason for withdrawal. 
9.0 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, ETC.) AND/OR 
PROCEDURAL INTERVENTION  
 Study Procedural Intervention(s) Description 
• 
For devices: The labeling will contain the statement "CAUTION - Investigational Device. 
Limited by Federal (or United States) Law to Investigational Use."  
HD-tDCS Stimulation protocol 
There will be two groups/arms in this trial,  
 
a. 
A group that will receive HD-tDCS treatments and cognitive training (CT) (n=10),  
b. 
A group that will receive sham HD-tDCS treatments and cognitive training (n=10). 
 
HD-tDCS/sham HD-tDCS sessions combined with CT will be administered in monthly blocks of 5 
consecutive daily sessions for a total of 15 treatments or 3 monthly blocks. For that, treatments 
will be administered at the MCW facilities or the UW Hospital. Study personnel may also visit 
subjects at their homes to administer the intervention if the subjects prefer. The safety and 
feasibility of home delivery of this intervention is supported by the existing literature (Im et al., 
2019). Both HD-tDCS and sham-HD-tDCS treatments will be administered during a cognitive 
training session. The HD-tDCS procedure is described in detail below. We will sequentially 
stimulate or sham stimulate four networks, left and right frontal and left and right temporoparietal 
with 1.5mA. Each network will be stimulated/sham-stimulated for 20 min for a total of an 80 min 
stimulation session. On Mondays prior to CT and Fridays after CT, subjects will be assessed 
on competency and ability to perform the CT. The CT blocks will start after 5 min of stimulation of 
each network and will last 15 min/network (total 60min/session). 
 
 

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Detailed description of the HD-tDCS procedure  
When conducting HD-tDCS, specially designed insets, electrodes, stimulation protocols, and conductive 
gels will be used. Appropriate instrumentation, electrode design, and protocols are considered important 
for HD-tDCS safety and comfort. A flexible cap will be placed on each participant’s head.  
 
The electrode casings or holders will be secured in the cap. The skin prepping guidelines as listed in 
Villamar et al. (2013a) will be followed: separating the hair inside the electrode casings until the scalp is 
exposed, removing hair products and dirt on the scalp using alcohol swabs and then filling the electrode 
casings with 3 mL of Signa Gel (Parker Laboratories, NJ) or HD-GELTM (Soterix Medical) with more 
applied if needed. The electrodes will be placed on a platform inside the casings so that they are 
completely immersed in the gel. More gel will be applied to cover the electrodes if needed, and then they 
will be held in place with the casing caps. Impedance values will be examined for all the electrodes and 
will all be verified to be <2 quality units. 
 
The electrodes will be connected to a Soterix Medical 1x1 
low-intensity DC stimulator (UW-Madison, Figure 5, top 
panel) or a Soterix MxN-9 High-Definition stimulator 
(MCW, Figure 5, bottom panel). Software packages such 
as SimNIBS 2.1 (Saturnino et al., 2018 bioRxiv) and those 
available through Soterix Medical (HD-Targets/HD-
Explore) may be employed for current flow and electric field 
modeling for HD-tDCS. At MCW, we may use patient’s 
structural MRI, (baseline or the one obtained for routine 
clinical standard of care), for modeling and/or for 
navigating to the HD-tDCS electrode positions from the brain surface on to the patient’s scalp, using 
Transcranial Magnetic Stimulation (TMS). 
 
Participants will be randomized to receive real or sham HD-tDCS. For real HD-tDCS, the device will be 
ramped up to 1.5 mA and maintained at this current for 20 minutes. For sham HD-tDCS, the device will 
be ramped up to 1.5 mA, but after 30 seconds, will be ramped back down to 0 mA and stay off for the 
remainder of the 20 minutes for a total of an 80 minutes of stimulation session.  The MxN-9 device allows 
for pre-programming by an unblinded member of the study team that will not be present during the 
Figure 5: HD-tDCS devices and HD-Cap (bottom right) 

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stimulation procedures. The device operator and the study subject will therefore remain blinded to the 
stimulation condition.   
 
In the case of the Soterix Medical 1X1 low-intensity stimulator, an unblinded study member will set-up 
the device and leave the room after covering or hiding the sham button or switch (e.g. using black tape). 
This will guarantee the blinding of both, the study participant and the device operator.    
 
Each cognitive training session will last a total of 60 minutes; This will be achieved by starting cognitive 
training 5 minutes after the initiation of tDCS (i.e. a total of 15 minutes of cognitive training per network).  
 
Method of electrode positioning for HD-tDCS  
There are two approaches that we will explore for HD-tDCS electrode positioning: 1) electrode positioning 
will be the same for all patients and will be based on the International EEG 10-20 system and 2) electrode 
positioning may be different across patients, but guaranteeing the same cortical targets across all 
patients, as determined using the software packages mentioned in the earlier section (Figure 3). For #1, 
according to the diagram presented in figure 6 of the protocol, the positions FP1, FP2, CP3, CP4 will be 
the anodes for each of the four networks and 10 positions P1, PZ, P2, FT9, FT10, FCZ, POZ, PO9, PO10 
will be used as cathodes. The assignment of the electrodes to the 4 different networks is outlined in the 
diagram in figure 3. 
 
The placement of electrodes is based on landmarks on the skull, namely the nasion (Nz), the inion (Iz), 
and the left and right pre-auricular points (LPA or T9 and RPA or T10). The first step is to form the line 
from Nz to Iz, over the vertex (Figure 6).  
To determine the location of the vertex, the contour from LPA (T9) to RPA (T10) is also passed over the 
vertex. These two contours should intersect at 50% of their lengths and the point thus obtained is the 
exact vertex. Along the sagittal Nz-Iz scalp contour over the vertex, the positions Fpz, AFz, Fz, FCz, Cz, 
CPz, Pz, POz and Oz are marked at 10% distances along this antero-posterior contour. With position Cz 
at 50% along this contour, corresponding to the vertex, the position of Oz is at a distance of 90% from 
Nz and 10% from Iz.  
Along the coronal LPA-RPA scalp contour over the vertex, the positions at 10% above the LPA and the 
RPA are marked. These positions are necessary to determine the horizontal contours over the left and 
right temporal lobe.  
A horizontal circumferential contour is determined over the left temporal lobe from Fpz to Oz, through the 
location which was marked at 10% above LPA. 
Along this contour, the positions Fp1, AF7, F7, FT7, 
T7, TP7, P7, PO7 and O1 are determined at 10% 
distances. The circumferential contour over the right 
temporal lobe is determined in the same fashion 
from Fpz to Oz over the location 10% above RPA, and the positions Fp2, AF8, F8, FT8, T8, TP8, P8, 
PO8 and O2 are marked at 10% distances.  
Figure 6: Method of electrode placement 
according to the 10/10 system. 

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A horizontal circumferential contour is determined over the left side of the head between T9 (LPA) and 
Nasion (Nz). Along this contour, the position FT9 is determined at 20% distances. The circumferential 
contour over the right side is determined in the same fashion, this leads to placement of electrode FT10.  
A horizontal circumferential contour is determined over the left side of the head between T9 (LPA) and 
Inion (IZ). Along this contour, the position PO9 is determined at 40% distance from the IZ. The 
circumferential contour over the right side is determined in the same fashion, this leads to placement of 
electrode PO10.  
 
The positions for anodal electrodes Fp1, Fp2, CP3 and CP4 and the cathodal electrodes P1, Pz, P2, 
PO9, PO10, FT10, FT9, FCZ, POZ are marked with a waterproof permanent marker using red color for 
the anodes and black color for the cathodes.  
The markings will be maintained and refreshed from session to session to minimize need for new 
measurements. Whenever the markings fade, new 
measurements using the same landmarks will be 
performed in a stereotypic fashion.  
The devices used are made by Soterix Medical and 
were used in the previous adult studies without 
incident. They are marked as Investigational Use 
Only. The first set of devices are 1) a low-current 
low-voltage tDCS sources; 2) a tDCS splitter box. 
The low-voltage low-current source generates a 
low intensity current for the duration of the 
stimulation. It is powered by 9V batteries and 
limited to 2 mA maximum. In this study we will use 
intensities of 1.5 mA or below as a safety factor. 
The splitter does not actually generate any 
stimulation. It can be thought of as a passive splitter 
box. For #2, we will use the MxN-9 Soterix 
stimulator; note that a splitter box is not needed 
with this device. Modelling will be performed on 
every patient taking into account the size and 
shape of the head and the skull thickness. If the 
anticipated peak electric field at 1.5 mA exceeds 
0.654 V/m in the brain tissue, the current will be 
reduced from 1.5 mA to a lower calculated value, so that the maximal field intensity of 0.654 V/m is not 
exceeded. Peak electric field of 0.654 V/m is observed in adults who receive tDCS with 2mA total current 
(Figure 2; Borckardt et al., 2011).  
 
The output cable of the splitter box or the MxN-9 device connects to the STENs electrodes, which are 
immersed in the SIGNA gel or HD-GEL that is held in place by the plastic insets (or electrode casing 
caps), which are mounted on to the cap.  
 
Dermal abrasion is not typically required for a good contact, however, gentle moving of hair and working 
of gel into skin might be used – Just as done for EEG. 
Cognitive training 
We will use the Posit Science’s brain plasticity-based BrainHQ exercises platform 
(https://www.brainhq.com). The BrainHQ platform consists of more than two dozen exercises 
grouped into six broad categories: Attention, Memory, Brain Speed, Intelligence, People Skills, 
and Navigation. These general categories clearly overlap and the assignment of any given game 
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of absolute specificity (e.g., a game under the ‘Memory’ category will inevitably recruit ‘Attention’ 
and ‘Brain speed’ mechanisms, both cognitive functions necessary for adequate memory 
formation).  
 
All participants will receive active Computerized CT which will be administered for 60 min during 
HD-tDCS or sham HD-tDCS sessions. 
 
Participants will engage in exercises of increasing complexity designed to train attention, memory, 
processing speed, people skills and navigation. To maximize the synergistic effect of HD-tDCS 
and CT on the same brain region, we plan to couple the electric stimulation of a network with a 
game that has a preferential effect on that same network (e.g. left temporoparietal stimulation with 
a verbal memory task, and right temporoparietal stimulation with a non-verbal memory task).  
For this purpose, we will select 12 games (out of an approximate total of 29) and assign each one 
of them to one of the four possible networks that will be stimulated (see table 3).  
 
Table 3: Training Schedule  
 
Choosing 12 games out of a larger pool of 29 will allow us to narrowly select those games better suited 
for the stimulation of the 4 proposed brain networks for every block (3 games/network). The selection 
of 12 games will also facilitate scheduling (3 games/network/day).  
 
The combined HD-tDCS/sham HD-tDCS and CT sessions will be performed monthly on 5 consecutive 
days for 3 months. A study coordinator will visit each participant at their homes or meet them in the 
hospital for a session. The laptop with the appropriate software will be provided by the investigator 
team. 
 
The weekly training schedule is outlined in table 3. A ‘Personalized Trainer’ option will present an 
automated sequence of the chosen exercises. Participants will have identical sessions initially, but 

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later they will be given different sessions based on their individual performance history (3 
games/network will always remain a constraint). The active training blocks will each last 15 min.  
Procedures for Training of Clinicians on Procedural Intervention 
The study interventions will be administered by a research specialist or the study coordinators 
who will be trained by Drs Granadillo, Shah-Basak, Ikonomidou, and Hancock in administering 
HD-tDCS and cognitive training. 
 Method for Assigning to Treatment Groups 
Randomization to the two arms will be the responsibility of an unblinded member of the study team. 
 Unblinding Procedures 
Unblinding will be done in emergent circumstances where the identity of the treatment needs to be 
known. All efforts will be made to maintain blinding except in the case of urgent medical necessity.  
 Study Intervention Compliance 
Threshold adherence/compliance is achieved when the enrolled participant completes all HD-
tDCS/sham HD-tDCS + CT sessions and undergoes cognitive testing at 0, 3 and 6 mo. This degree 
of participation will allow calculation of the primary outcome, i.e. treatment completion rates. 
 Concomitant Therapy 
Permitted Concomitant Therapy 
Subjects will continue all medications and other prescribed treatments during participation in this 
study. No life style changes are necessary.  
Prohibited Concomitant Therapy 
None 

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10.0 
STUDY VISITS AND PROCEDURES 
 
Study Calendar 
The procedures performed at each study visit are listed in the table below. 
 
 
1 
Vitals include: pulse rate, body temperature, blood pressure, respiration rate, height, and weight 
 
MRI will aim to be completed within 6 week window, but can be completed up to 12 months after Visit 16 if scheduling problems arise 
 
Baseline 
Treatment Period 
Month 3 
Month 6 
Early 
Withdrawal 
Visit 
1 
         2-6                        7-11                     12-16 
17 
18 
 
Visit Window 
-6 months 
 
±4 weeks 
 
±4 weeks 
 
Up to  
6 weeks post Visit 
16  
3 months post Visit 
16 
± 8 weeks 
 
Timeframe 
 
Week 1 
(Month 1) 
Week 2 
(Month 2) 
Week 3 
(Month 3) 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Review 
Concomitant 
Medications 
X 
 
 
 
X 
 
X 
Obtain Medical 
History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Vital Signs1 
X 
 
 
 
X 
 
X 
Randomization 
X 
 
 
 
 
 
 
Study Partner 
Questionnaires 
X 
 
 
 
X 
X 
 
Cognitive Battery 
X 
 
 
 
X 
X 
 
MRI 
X 
 
 
 
X2 
 
 
TMS 
Neuronavigation 
(for stimulation 
planning) MCW 
only 
X 
 
 
 
 
 
 
Device 
Administration  
 
X 
X 
X 
 
 
 
Adverse Events 
Review/Assessm
ent 
 
X 
X 
X 
X 
X 
X 

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10.1 Screening and Enrollment 
Subjects may complete study procedures at both sites (e.g., baseline MRI at UW and Month 3 MRI at MCW) 
and any individual subject’s data may be collected between sites depending on subjects’ ability to travel 
between sites, study team availability, and investigator approval. Subjects may be dispersed interchangeably 
and unevenly between sites based on, for instance, subject convenience, study team availability, the site’s 
ability to collect data, and/or the study team’s preference to complete datasets. If a subject is unable to 
complete all study procedures prior to the end of study funding, they may choose to complete remaining 
study procedures at the main site if deemed eligible by the study investigator 
The Screening and Enrollment visits and procedures are described in detail below. 
Pre-screening 
Participants will be screened by telephone for major inclusion and exclusion criteria. Eligibility may be 
determined by screening existing records. Some ineligibility criteria may become known during the course 
of the study, for example, development of new medical conditions or abnormality detected on brain 
imaging that may change the participant’s eligibility.  
Decisional Capacity 
It should be noted that all participants enrolled must retain decisional capacity at their baseline visit. The 
only situation where we indicate a plan to obtain assent from a participant is when a patient with MCI 
loses capacity over the course of the study and has indicated to their legally authorized representative 
that they wish to continue in the study even after losing decisional capacity.  In this case, assent will 
always operate as a veto to the subject’s participation, despite the surrogate’s preference.  Assent will 
always be verified prior to and during any study procedures.   
Baseline Visit 
Prior to any procedures, informed consent will be obtained. Visit procedures may take up to 7 hours but 
may be more or less depending on time needed for breaks, participant comfort, and scanner set-up.  
This baseline visit will likely be completed over 2-3 days but can be completed over multiple days prior 
to Visit 2. 
 
Once consent is obtained, the following assessments will be completed, and information collected for 
study participants. 
 
• 
Document informed consent 
• 
Review eligibility based on inclusion/exclusion criteria 
• 
Demographics (age, sex, race, ethnicity, age, year of birth) 
• 
Medical history 
• 
Physical and Neuro exam including vitals 
• 
Medications  
• 
Cognitive battery 
• 
Structural MRI 
• 
TMS Neuro-navigation (MCW only) 
• 
Study Partner Questionnaires 
Vitals and Medical Evaluation 
Vitals include height and weight measurements, resting blood pressure, body temperature, heart rate, 
and respirations.  Physical and neurological examinations will be conducted by clinicians and include 
a review of systems.  

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Interviews and questionnaires:  
Participants will be interviewed by staff for completion of questionnaires intended to clarify medical 
history and level of awareness of cognitive deficits.  
 
Study partners will complete three questionnaires designed to assess the subject’s cognitive function 
and ability to perform activities of daily living. These questionnaires include: 
• 
Alzheimer’s Disease Cooperative Scale - Activities of Daily Living – Mild Cognitive Impairment 
(ADCS-ADL-MCI)  
• 
Lawton-Brody Instrumental Activities of Daily Living Scale (Lawton IADL) 
• 
Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly (Short 
IQCODE) 
Cognitive Battery 
Participants will complete a broad battery of neuropsychological tests administered by trained 
personnel; this comprehensive battery will include the Alzheimer’s Disease Cooperative Study-
Preclinical Alzheimer Cognitive Composite (ADCS-PACC), which will serve as the primary outcome 
measure for the future phase II trial (see Table 5). The ADCS-PACC is a composite of 4 measures 
with well-established sensitivity for the detection of cognitive decline in prodromal and mild dementia. 
The final score is determined from its components using an established normalization method; the 
four Z scores are then added to form the composite. Consequently, a change of 0.5 standard 
deviations on each component would correspond to a 2-point change on the composite. We will 
alternate between 3 different versions of the test in order to minimize the risk of learning effects 
(Donohue et al., 2014).  
 
The ADCS-PACC emerged as a response to concerns about ceiling effects, and the insensitivity to 
early stage deficits and to cognitive change of more standard Alzheimer’s disease measures (e.g. 
ADAS-Cog). The PACC is currently being used as the primary outcome measure in multiple ongoing 
studies of early or preclinical Alzheimer’s disease (Donohue et al., 2014; Harrison, 2018).  
 
Table 5. ADCS-PACC 
Cognitive Subdomain 
Test 
Episodic Memory 
Rey Auditory Verbal Learning Test (RAVLT) (or Free and Cued 
Selective Reminding Test (FCSRT) (0-48 points) 
 
Logical Memory IIa sub-test from the Wechsler Memory test (0-25 
points).  
Orientation 
Mini Mental Status Examination (MMSE) (0-30 points).  
Executive function 
Digit Symbol substitution test (DSST) from the Wechsler Adult 
Intelligence Scale-Revised (0-93 points).  
 
The neuropsychological test battery will include a multidimensional set of brief measures assessing 
cognitive, emotional, motor and sensory function that can be used as a “common currency” across 
diverse study designs and settings which will be supplemented by measures that are consistent with 
other national studies of Alzheimer’s disease (see Table 6).  
 
Table 6. Cognitive Battery (Secondary Outcome Measures) 
Domain 
Subdomain (measure name) 
Test 
Cognition 
Premorbid Estimate 
Wide Range Achievement Test-4 (WRAT-4) 
 
Attention & Information Processing 
Speed 
Trail Making Test 
 
 
Executive Functioning 
Clock Drawing Test 
Controlled Oral Word Association Test (letter & 
category) 

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Wisconsin Card Sorting Test (WCST) 
 
Language Functioning 
Boston Naming Test (BNT), Language Screen 
 
Motor Skill 
Grooved Pegboard 
 
Visuospatial Skill 
Judgment of Line Orientation (JLO) 
 
Memory 
Benton Visual Memory Test-Revised (BVMT-R) 
Emotion 
(Self-
Report) 
Mood 
Geriatric Anxiety Inventory (GAI) 
Geriatric Depression Scale (GDS) 
Validity 
Effort 
Rey 15 Item Test 
 
Magnetic Resonance Imaging (MRI) 
MRI Safety Screening: Site-specific MR safety screening procedures will be followed. All participants 
will be screened for medical devices, implants, and metal prior to undergoing MRI, first on the 
telephone, and again prior to entering the scanner room. If it is necessary to review medical records 
to confirm contraindication, a review of medical records (e.g. previous surgeries) will take place prior 
to the scheduled visit. Prior to entering the MRI scan room, an x-ray exam may be completed as a 
safety precaution on subjects who might have metal in body (for example, an orbital x-ray, or x-ray of 
another body part).  During the telephone screening process, participants will also be questioned 
about their ability to temporarily remove transdermal patches (such as birth control or nicotine 
patches). Women of child-bearing potential will be asked to confirm that they are not pregnant when 
signing the Informed Consent Form. If a woman has concerns or is uncertain of her pregnancy status, 
she will be excluded, as the risks of an MRI scan to pregnant women are currently unknown. The 
risks are minimal for a properly administered visit. The MR technicians are trained and prepared to 
deal with any problems that may arise.  
 
We will collect a full suite of non-invasive anatomical and blood flow scans using GE 3.0 high-field 
scanners running the newest operating system and a 32-channel head coil. All participants are 
prepped and trained prior to the procedure. The MRI protocol will consist of anatomical and other 
advanced scans including ASL perfusion and DTI. These scans will be conducted over one session 
which will take approximately 60 minutes including set-up and instructions but could take longer 
depending on participant set-up time or need to repeat instructions. The sequences, protocols, 
parameters, and/or scan order may be modified during the study based on new scientific information 
or technical factors. 
 
The MRI scanner is an Investigational Device of Non-Significant Risk: The MRI scanner to be used 
in the study is considered an investigational device due to the investigational software used in the 
study that was developed by the collaborators at both MCW and UW-Madison. However, the 
Magnetic Resonance Imaging (MRI) device is an FDA cleared device for safe and non-invasive 
imaging of the interior of the human body. The MRI scanner is also considered an investigational 
device when the 32-channel head coil is used.  Modified pulse sequences include T1-weighted 
MPnRAGE, pseudocontinuous arterial spin labeling (pcASL), and simultaneous multislice (SMS) 
echo planar imaging for diffusion-weighted imaging (DWI). These pulse sequences were developed 
by medical physics experts using the EPIC pulse sequence development environment provided by 
GE Healthcare, which constrains the pulse sequences to operate within the FDA limits for safe 
operation with respect to gradient switching (dB/dt) and RF power (SAR).  The proposed modified 
MRI pulse sequences (developed at MCW  and UW-Madison), and the 32-channel head coil are not 
implantable devices, are not intended to support or sustain human life; are NOT for a use of 
substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing 
impairment of human health and they do not present a potential for serious risk to the health, safety, 
or welfare of a subject. The scanner also restricts research software from exceeding FDA safety 
levels. The scanner monitors the specific absorption rate (SAR) for research scans just as it does for 

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all other scans. Thus, the scanner with the investigational software fully engaged operates, from a 
technical design and functional standpoint, as a non-significant risk device in accordance with 21 
CFR 812. By staying below these limits, the operating conditions of the MRI device are generally 
deemed, in and of themselves, to make the MRI device a non-significant risk device.  
 
The Nova Medical 32-channel head coil (model number NMSC075-32-3GE-MR750) is an 
investigational device not FDA approved for clinical use.  This coil device includes multiple features 
for safe operation involving human studies.  The 32-channel coil is designed and constructed as a 
receive-only detector of RF signals that are emitted by the brain following the RF excitation generated 
by the GE MRI scanner, which is FDA approved.  During the RF excitation by the scanner, the coil 
device is decoupled (made inactive) through redundant circuitry, thus the coil device never transmits 
RF to the subject, so it has no impact on subject risk or safety.   
 
More specifically, the coil design and construction include the following safety features: (1) High 
voltage breakdown (>2kV) UL-94V0 flame retardant housing. (2) Rugged construction to assure safe 
operation in case of rough handling. (3) Active detuning circuitry providing greater than 35 db isolation 
per element. (4) High power passive detuning circuits in case primary detuning circuitry fails. (5) 
Multiple common mode traps in all receive coil cables. (6) Minimum of 5mm spacing between coil 
conductors and patient contact. 
Additionally, the coil was designed and manufactured under an ISO 13485 certified quality 
management system. As part of this quality system, Nova Medical has conducted a Failure Means 
and Effects Analysis (FEMA) of this product and we feel that it is a non-significant risk under 
foreseeable normal conditions when used on the 3T GE X750 MRI scanners at MCW and UW-
Madison. 
 
Mock Scanner Training. Participants will be offered the option to engage in a mock scanner training 
session. The purpose of this session is to acclimate participants to the scanner and to assess their 
comfort level, minimize any anxiety, and provide practice and training to remain still. Training in the 
mock scanner will take approximately 20 minutes and will occur prior to their imaging sessions. A 
visual feedback system will be employed to inform the subject about her or his performance of 
remaining stationary. Further, contoured padding will be employed to physically ensure subject 
stability throughout the imaging session. After the session, any questions or concerns will be 
discussed. Participants that have been previously engaged in MRI as part of research may be 
excused from the mock scanner training. 
 
Treatment and Follow-up Visits 
After subjects have been enrolled, the On-Study/Follow-up visits and the procedures performed at each 
visit are described in detail below.  
 
Treatment 
 Visits 2-16* 
 
At these visits, the following will occur: 
• 
Cognitive training with HD-tDCS treatment OR 
• 
Cognitive training with sham HD-tDCS treatment 
• 
On Mondays prior to CT and Fridays after CT, subjects will be assessed on competency and 
ability to perform the CT. 

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These visits will likely last about 2.5 to 3 hours. 
*Missed or rescheduled treatment visits: Because there may be a benefit from a single treatment session at 
any point during the study, subjects who miss or need to reschedule treatment visits will be eligible to 
complete their missed visit at any point prior to Month 3 procedures.  
Visit 17 (Month 3) 
At this visit, the following procedures and tests will occur: 
• 
Neuro and physical exam 
• 
Vitals signs 
• 
Cognitive battery 
• 
Study Partner Questionnaires 
• 
Structural MRI (will aim to be completed within 6 week window, but can be completed up to 12 
months after Visit 16 if scheduling problems arise) 
 
This visit will be approximately 6 hours and will likely be completed in 1-2 days but can be completed 
over multiple days.  
Visit 18 (Month 6) 
At this visit, the following procedures and tests will occur: 
• 
Cognitive battery  
• 
Study Partner Questionnaires 
 
This visit will be approximately 4 hours and will likely be completed in 1 day but can be completed over 
multiple days. 
 
Unscheduled Visits 
The reason for an unscheduled visit will be an unexpected or serious adverse event. 
 
Early Termination/Withdrawal Visit 
Subjects who are either withdrawn or terminated early from the study will have one final visit to report 
adverse events. 
11.0 
DATA COLLECTION, HANDLING, SHARING, AND RECORD KEEPING 
 
Data Collection  
Data Collection Forms 
Standardized data collection forms (e.g., source documents, case report forms, standardized assessment 
forms, etc.) are used to ensure data collected are consistent and compliant with the protocol and IRB 
application.  
 
Data collection is the responsibility of study team members under the supervision of the Principal 
Investigator (PI). The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the recorded and reported data. 
 
Data collection forms are maintained in the subject files and retained as described in Section 11.3: 
Records Retention. 

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Confidentiality and Privacy 
Participants’ privacy will be protected with the utmost care. We recognize the diagnosis of MCI or Alzheimer’s 
disease, may cause embarrassment and/or discrimination. We will handle all contacts with participants with 
special attention to privacy. General mailings (not related to specific appointments) will be sent in discrete 
envelopes. Personnel making phone contacts will be trained to protect privacy when leaving messages or 
talking with family members who answer the phone. All research procedures will be conducted in private 
settings, and only information absolutely necessary to conduct our research will be gathered. 
 
Information about study subjects will be kept confidential and managed according to HIPAA requirements. 
All subjects will sign a combined informed consent and HIPAA authorization form that includes specific 
privacy and confidentiality rights. Study data will be maintained per federal, state, and institutional data 
policies. 
 
The investigator(s) will ensure that the identities of subjects are protected by using coded subject information. 
The log of subject identifying information that links subjects to their study-specific identification number will 
be maintained by the investigator. The log and all study records will be maintained in locked spaces and 
access will be limited to the PIs and coordinators. Electronic study records/files will be stored on a dedicated 
server and accessed via networked computers that are password-protected with access provided only to 
authorized study personnel.  
 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for a minimum period of 7 years 
following completion of the study per MCW and UW-Madison institutional policy. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or investigational plan requirements. 
The noncompliance may be either on the part of the subject, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
It is the responsibility of the Principal Investigator/site investigator/study staff to use continuous vigilance to 
identify and report deviations. The Principal Investigator is responsible for assessing whether the deviation 
constitutes noncompliance as defined by the reviewing IRB and if so, reporting it within the required time 
frame(s). The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
12.0 
STUDY ANALYSIS 
 
Statistical Hypotheses 
• 
Primary Efficacy Endpoint(s):  
Treatment completion rates.  
 
• 
Secondary Efficacy Endpoint(s): 
- 
Consent rate.  
- 
ADCS-PACC score at 3 and 6 months 
- 
Neurite density (intracellular volume fraction) at 3 months 
- 
Diffusivity indices: Fractional anisotropy (FA), Mean(MD), Axial(AD), Radial(RD) Diffusivity at 3 months 
- 
Morphometric indices: Cortical thickness, Surface Area, Volume, gyrification index at 3 months 
- 
ASL perfusion indices: blood flow, blood volume, mean transit time, time to peak, at 3 months 

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Sample Size Justification 
Given the pilot nature of this study, two feasibility outcomes will be included: Consent rate and treatment 
completion rate. 20 patients are enough to calculate a 90% exact binomial confidence interval of (.75, 1) if 
all 20 are observed to complete treatment. Thus, this sample size is large enough to potentially exclude 
completion rates of 3/4 or lower. The pilot data from this study will provide initial estimates of the variability 
and the effect sizes; This information will then be used for the formal calculations of power and sample size 
necessary to conduct a future phase II trial. 
 
This pilot study, if successful, would prove the feasibility of the proposed approach. Treatment completion 
rates of less than 75% could be reasonably excluded if all 20 patients are observed to complete treatment. 
Additionally, recruiting and consenting 20 patients over a period of 3 months would support the feasibility of 
conducting a larger-scale, 2-site, phase II trial with 120 MCI patients over a span of 5 years (i.e. approximately 
32 patients/year). This would be the necessary next step in the path to using combined HD-tDCS/CCT as an 
intervention that could lead to tangible clinical improvements. This future trial would use a 2 X 2 factorial 
design that would allow for the inclusion of a ‘true’ control group (i.e. sham HD-tDCS/sham CCT). The 
stimulation period would be extended (six months instead of three) with the hope of inducing longer lasting 
effects that could translate into a slowing of disease progression; Accordingly, we would evaluate the effects 
of the intervention at 6, 12 and 18 months. MRI changes would be assessed at 12 months, as well as the 
effect on cerebrospinal fluid (CSF) AD biomarkers of a subset of patients. Sample size justification for 
future phase II trial (N=120). Driven by the efficacy outcome of change in ADCS-PACC score from baseline 
to 12 months. We presume that 10% of these patients are lost to follow up before one year. We further 
presume that the main aim will be addressed by a two-sided test at the .05 level of the hypothesis that the 
improvement rate in the true HD-tDCS group exceeds that of the sham group.  Under these assumptions 
there is a minimum 90% power to detect a 31% difference in improvement rates. Thus, this design has good 
power to find a moderate effect size of HD-tDCS treatment. 
 
Subject Population(s) for Analysis 
In a future phase II trial, all analyses will be done under the intent-to-treat principle as far as allowed by 
patient consent and follow-up.  All consenting patients will be followed even if they are noncompliant.  
Potentially confounding patterns of loss to follow-up will be investigated via sensitivity analyses [Panel on 
Handling Missing Data in Clinical Trials, Committee on National Statistics Division of Behavioral and Social 
Sciences and Education US National Research Council.   The Prevention and Treatment of Missing Data in 
Clinical Trials.  National Academies Press, 2010]. 
 
Statistical Methods 
In a future phase II trial (and for this feasibility trial as appropriate), baseline clinical and demographic 
characteristics will be tabulated for subjects assigned to the four treatment modes in a future 2 X 2 factorial 
design. Comparison of these characteristics between the four groups will be carried out with t-tests and chi-
square tests. If important differences are found between the groups at baseline, the statistical analyses will 
be repeated after adjusting for these differences. These analyses will be considered to be supportive 
however. 
 
All analyses will be done under the intent-to-treat principle as far as allowed by patient consent and follow 
up.  All consenting patients will be followed even if noncompliant.  Potentially confounding patterns of loss to 
follow up will be investigated via sensitivity analyses. 
The primary outcome variable is efficacy, defined as improvement over time in ADCS-PACC scores from 
baseline to 12 mo. This will be analyzed via a standard 2 x 2 x 2 analysis of covariance,86 where the three 
two-level factors are the two treatments and MCW vs. UW-Madison site, and the continuous covariate is the 
value of the outcome at baseline.  Explicitly, 
µi = β0 + βHD-tDCS x I(HD-tDCSi) + βtrain x I(traini) + βinter x I(HD-tDCSi) x I(traini) + βbase x Yi,base  , 

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where: µi is the mean outcome, indexed by i for subject; β0 is the intercept term, βHD-tDCS is the HD-tDCS main 
effect term, I(HD-tDCSi) is an indicator variable for the ith patient taking the value of 1 if s/he received true 
HD-tDCS and 0 for sham; βtrain is the cognitive training main effect term; I(traini) is an indicator variable for 
true vs. sham cognitive training in the ith patient; βinter is the interaction term between the two treatments, 
measuring their synergy; βbase is the coefficient for baseline outcome level; and Yi,base is the baseline outcome 
level for patient i.  For the primary aim the outcome would be cognitive function measured by ADCS-PACC 
score at 12 mo (since baseline ADCS-PACC score is included, this is formally equivalent to change in 12-
mo ADCS-PACC score from baseline).   
All hypotheses in the primary and secondary aims could be examined by testing appropriate parameters 
using the relevant endpoints in the above model.  The primary aim of examining overall 12-mo HD-tDCS will 
be effected by estimating βHD-tDCS and βinter, accompanied by confidence intervals and a 2-degree-of-freedom 
test that they are both 0.  Rejection of such a test is evidence that HD-tDCS does affect patient’s 12-month 
cognition.  Similarly, therapy’s effectiveness can be examined in this population by estimating βtrain. The 
interaction parameter βinter measures the two treatments’ synergy, the degree to which CT potentiates the 
effects of HD-tDCS.  Since all study outcomes are continuous, models will be fit using ordinary least squares.  
The full 18 mo longitudinal trajectory will be modeled using a repeated measures Laird-Ware formulation 
(Fitzmaurice, GM, Laird, NM, and Ware, J.  Applied Longitudinal Analysis, 2nd Edition.  Wiley; New York, 
NY.  2011), equivalent to that stated above but with intra-subject error terms added and average changes 
modeled instead of single 12 mo values as fixed effects. 
  
Analysis of cognitive data: To analyze the effect of training on outcome measures, a 2 x 4 mixed-
factor analysis of variance (ANOVA) will be employed, including a within-subject factor of test 
performance over time (pre- vs. post-training) and a between-subjects factor of group assignment. 
We will use Bonferroni correction to conservatively control for familywise error. If analyses reveal 
that the groups were not equivalent at baseline, we will employ statistical covariates in order to 
control for group differences.  
 
We will utilize adherence data to determine how many participants follow the training schedule. Threshold 
adherence is achieved when the enrolled participant completes all HD-tDCS/sham HD-tDCS + CT/sham-CT 
sessions and undergoes cognitive testing at 12 mo. This degree of participation will allow calculation of the 
primary outcome, i.e. change in ADCS-PACC at 12 mo. We will exclude data from participants who did not 
meet the minimum threshold of adherence to the interventions.  
 
Finally, if statistically significant improvements in neuropsychological outcome measures are shown, will 
conduct follow-up analyses using reliable change index (RCI) scores.  The RCI allows for an assessment of 
the magnitude of change of scores for an individual that are not susceptible to group means and standard 
deviations. This process has been described in detail elsewhere (Hinton-Bayre, 2010; Maassen et al., 2009). 
We will use the Jacobson–Truax method with a 0.90 confidence interval, which indicates a 95% chance of 
true improvement for anyone who passes the threshold (Jacobson & Truax, 1991). 
Neuroimaging: In a future larger-scale phase II trial We will perform Kruskal- Wallis tests, to 
determine if there are significant between group differences at 12 mo, on each of the NODDI 
(neurite orientation dispersion (OD) index, neurite density (or intracellular volume fraction) (Vic),) 
and diffusivity (FA, MD, RD) measures, as well as measures of neurodegeneration measured by 
cortical thickness and ASL perfusion (cerebral blood volume, mean transit time, time to peak etc). 
Post-hoc analyses comparing the sham group to each of the three remaining groups will be done 

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using Mann-Whitney U tests. All analyses will be done with and without controlling for possible 
confounding factors such as age, intracranial volume, family history of AD or other dementias. 
 
Planned Interim Analysis 
There will not be an interim analysis. 
13.0 
RISK/BENEFIT ASSESSMENT 
 
Potential Benefits to the Subjects 
There are no direct benefits to participating in the study. The scientific benefits are great and include a better 
understanding of the associations between the planned interventions and brain/biomarker/cognitive changes 
associated with MCI and Alzheimer’s disease and possible mechanisms underlying these associations. 
Study completion may provide evidence in support of HD-tDCS + CT as an efficacious approach to the 
prevention of Alzheimer’s disease and related neurodegenerative disorders in midlife. 
 
Known Potential Risks 
MRI:  Participants are screened by study staff prior to the scan to verify they do not have any 
contraindications for MRI. Potential side effects of the scan include anxiety due to claustrophobia and/or 
noise. Participants with known anxiety or claustrophobia will not be recommended to participate since 
the head must be placed fully inside the MRI scanner tube. If a participant experiences anxiety, they will 
be removed from the scanner and offered reassurance by study staff.  To minimize the level of noise, all 
subjects will be fitted with disposable earplugs.  Communication with the participant is possible during 
the scan. In addition, fatigue and physical discomfort due to the length of the scan session are possible. 
Participants will be reminded that the procedure is optional.   
   
The MRI scanner to be used in the study is considered an investigational device due to the investigational 
software and equipment used in the study (for blood flow imaging), which is being supplied by GE; 
however, the baseline Magnetic Resonance Imaging (MRI) device is an FDA cleared device for safely 
and non-invasively imaging the interior of the human body. The scanner restricts research software from 
exceeding FDA safety levels. Thus, the scanner with the investigational software and equipment fully 
engaged operates, from a technical design and functional standpoint, as a non-significant risk device 
in accordance with 21 CFR 812. 
 
Risks of extended neuropsychological testing: Extended neuropsychological testing may cause 
embarrassment, sadness when asked about personal feelings. The subject may feel bored, nervous, 
embarrassed with some of the tests or when answering questions about how he/she feels.  
 
Risk of Breach of Confidentiality: Because personal information will be retained in a computer 
database, there is a small possibility that this information could become available to unauthorized 
persons.  This study involves protections to minimize the chance of any such breach. 
Known Interventional Risks 
Risks of HD-tDCS include redness and skin irritation at the site of stimulation. When current flow is 
initiated the subject may perceive a tingling sensation on his/her scalp. In one study, fatigue was reported 
as a side effect of tDCS. Turski et al (2017) reported that one subject developed a headache during one 
session, which resolved when stimulation was stopped. Another subject reported poor sleep one night, 
which however resolved and was judged to not be caused by the stimulation. 

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Risk/Benefit Analysis 
The risks of the proposed procedures are minimal, and the potential knowledge gains are substantial, making 
the risk/benefit ratio low. These experiments will provide a unique opportunity to determine the potential for 
HD-tDCS and CT to benefit participants with MCI. 
14.0 
DATA AND SAFETY MONITORING  
 
Adverse Event (AE) Definition 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. 
 
Serious Adverse Event (SAE) Definition 
An adverse event is considered "serious" if, in the view of either the investigator or sponsor, it meets any of 
the following criteria: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires an inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in persistent or significant disability or incapacity.  
• 
Results in a congenital anomaly/birth defect. 
• 
A medical event, based on appropriate medical judgment, that is believed to jeopardize the subject 
and/or requires medical or surgical intervention to prevent one of the outcomes defining a SAE. For 
example: allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
convulsions that may not result in hospitalization 
 
Classification of an Adverse Event 
Severity of Event 
All AEs will be assessed by the clinician using the Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0, each event searchable using the Safety Profiler website (https://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). For AEs not included in the protocol-defined grading system, the 
following guidelines will be used to describe severity. 
 
Mild 
(Grade 1) 
Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate 
(Grade 2) 
Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference 
with functioning. 
Severe 
(Grade 3) 
Events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
potentially life-threatening or incapacitating. 
Life Threatening 
(Grade 4) 
The subject was at risk of death at the time of the event. 
Fatal 
(Grade 5) 
The event caused death. 
 

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Relationship to Study, Study Procedure(s) and/or Study Intervention(s) 
For all collected AEs, the clinician who examines and evaluates the subject will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
 
Definitely Related 
Clearly related to the study procedures/intervention and other 
possible contributing factors can be ruled out. 
Probably Related 
Likely related to the study procedures/intervention and the influence 
of other factors is unlikely. 
Possibly Related 
Possibly related to the study procedures/intervention and there are 
other factors that could be equally likely. 
Unlikely to be related Doubtfully related to the study procedures/intervention and there is 
another likely cause. 
Unrelated 
Clearly not related to the study procedures/intervention and/or 
evidence exists that the event is definitely related to another cause. 
 
Expectedness for Study, Study Procedure(s) and/or Study Intervention(s) 
The PI will be responsible for determining whether an AE is expected or unexpected in relation to the 
study procedures and intervention(s) (as applicable).  
 
For device studies: An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the risk information previously described in the clinical protocol, device manual, 
investigator’s brochure, the package insert(s), the IRB application, or the informed consent document. 
Expectedness is recorded for both study procedures and interventions. 
 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study subject presenting for medical care, or upon review by a study monitor. All AEs including 
local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate CRF. 
Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the subject is screened will be considered as baseline 
and not reported as an AE. However, if the study subject’s condition deteriorates at any time during the study, 
it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode.  
 
The PI will record all reportable events with start dates occurring any time after the administration of the study 
drug and for up to 30 days after the date of the last dose of study drug. At each study visit, before and after 
each interventional session, the investigator will inquire about the occurrence of AE/SAEs since the last 
contact. Events will be followed for outcome information until resolution, stabilization, or completion of study 
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Reporting AEs and SAEs  
The investigator will immediately report to the coordinating site PI any SAE, whether or not considered study 
intervention-related, including those listed in the protocol and must include an assessment of whether there 
is a reasonable possibility that the study intervention caused the event. Study endpoints that are SAEs (e.g., 
all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a 
causal relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, 
the investigator must immediately report the event to the sponsor. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the subject is stable.  
 
Unanticipated Problems 
An unanticipated problem (UP), as defined by the DHHS Office for Human Research Protection (OHRP), is 
any incident, experience, or outcome that meets all of the following criteria:  
• 
The incidence, experience, or outcome is unexpected given the research procedures described in 
protocol-related documents (e.g., the study protocol, the informed consent documents, the Investigator’s 
Drug Brochure) and the characteristics of the subject population being studied. An event may be 
considered unexpected if it exceeds the nature, severity, or frequency described in the study-related 
documents, Investigator’s Device Brochure, product labeling, or package insert. 
• 
The incidence, experience, or outcome is related or probably related to participation in the research study. 
“Probably related” means the incidence, experience, or outcome is more likely than not to be caused by 
the research study procedures. 
• 
The occurrence of the incidence, experience, or outcome suggests that the research places subjects or 
others at a greater risk of harm (physical, psychological, economic, or social) than was previously known 
or recognized. 
 
The investigator will report UPs to the reviewing IRB. The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP;  
• 
A description of any changes to the protocol, informed consent documents, or other corrective actions 
that have been taken or are proposed in response to the UP. 
 
Report UPs within the timeframe(s) specified by the IRB(s) of record. 
 
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect means any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
An investigator shall submit to the reviewing Institutional Review Board (IRB) a report of any unanticipated 
adverse device effect occurring during an investigation as soon as possible, but in no event later than 5 
working days after the investigator first learns of the effect. 

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Incidental Findings 
MR image clinical abnormality 
 
If there are any clinically relevant adventitious findings from the baseline or follow-up visits, subjects will 
be informed; however subjects may not be informed of findings of questionable significance. Participants 
will be contacted directly (either on the phone or in person) if the results of an imaging study are clinically 
significant. The clinician will confer with the subject about whether they would like their primary care 
provider to be notified about any clinically significant findings and contact them if desired.   
 
Study Monitoring 
The Principal Investigators (PIs) will be responsible for ensuring participants’ safety on a daily basis.  
In addition, the PI, Co-Is and core research staff will meet every two months to monitor study progress and any 
data and safety issues will be reviewed.  
All unanticipated problems and complications will be discussed during regular staff meetings (attended by PI, 
supervisors, and coordinators) during which a plan of action will be formulated and implemented. 
 Study Stopping Rules 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the investigators. If the study is prematurely terminated or suspended, the 
PI will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to subjects  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy 
the applicable federal and institutional regulatory authorities. 
15.0 
STUDY FEASIBILITY  
 
Economic Burden to Subjects 
Subjects will not have to pay for study procedures.  
 
Feasibility of Recruiting the Required Number of Subjects 
Recruitment sources: Participants may be recruited by several methods. Major sources are summarized below: 
1) Physician Referrals (e.g. from a Memory Assessment Clinic [University of Wisconsin (UW) Hospital and 
Clinics’ Memory Clinics and the Memory Disorder’s Clinic in Neurology at Froedtert and the Medical College 
of WI, Middleton VA Hospital Madison, Froedtert Hospital, MCW Memory Disorders Clinics and the Geriatric 
Psychiatry Clinic]; the Wisconsin Alzheimer’s Institute (WAI) Diagnostic Clinic Network. 
2) Participants from the community (through advertisements, brochures, educational /outreach events, etc.) 
3) From existing large studies such as the Wisconsin Alzheimer’s Disease Research Center clinical core. In 
addition, we will approach participants who have provided permission to be contacted for future research as 
part of their participation in Wisconsin ADRC-affiliated studies.  

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4) WI ADRC Recruitment Registry (REGGIE, 2011-0772) and the Alzheimer’s Association Trial Match website. 
  
 
To maximize retention, study personnel may travel to participants’ homes to perform interventions. 
16.0 
MULTISITE RESEARCH CONSIDERATIONS  
 
Single IRB (sIRB) Communication Plan 
Study Team Communication Plan  
Study initiation conference calls will include a presentation by the reliance site’s PI to inform all sites about the 
reliance arrangement as well as the review processes and reporting requirements of the Reviewing IRB  
Dr. Granadillo or his delegate will be responsible for ensuring ongoing communication with all participating study 
teams via teleconferences and regular emails throughout the study. Key communication points will occur to: 
• 
Disseminate IRB determinations and IRB-approved documents 
• 
Educate study teams regarding the approved study and amendments to the study 
• 
Alert study teams to problems that may affect the conduct of the study or the rights and welfare of 
research participants, such as unanticipated problems and serious noncompliance 
• 
Inform study teams of any changes in study status (e.g., temporary suspensions of recruitment) or new 
information 
• 
Facilitate submissions to the Reviewing IRB, including:  
o Inclusion of site-specific requirements in consent documents 
o Identification of any variability in study implementation across sites that must be communicated 
to the Reviewing IRB 
o Collection of information from participating sites to include in continuing review reports to the 
Reviewing IRB 
o Site-specific amendments 
o Personnel updates (as required by the Reviewing IRB) 
o Reportable events (e.g., noncompliance, unanticipated problems) 
o Closure reports 
• 
Ensure revisions to applicable conflict of interest management plans are provided to the Reviewing IRB 
17.0 
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