Assessing the Feasibility and Acceptability of a Time Restricted Feeding Intervention Among Older Adults With Mild Cognitive Impairment
Phase: NA
Conditions: Mild Cognitive Impairment, Obesity
Sponsor: University of North Carolina, Chapel Hill

 
PROTOCOL TEMPLATE: INTERVENTIONAL STUDY 
 
 
Complete Title: Assessing the feasibility and acceptability of a Time Restricted Feeding intervention among 
older adults with Mild Cognitive Impairment 
 
 
 
Short Title: Time Restricted Eating for Metabolic and Psychological Optimization (TEMPO) 
Drug or Device Name(s): N/A 
FDA IND/IDE (if applicable): N/A  
Sponsor: National Institute of Aging  
Protocol Date: 7/1/2025 
NCT#:   
NCT05997316 
 
 
 
 
 
 
Study Principal Investigator: 
 
UNC Center for Health Promotion and Disease Prevention 
Office # 237 
1700 Martin Luther King Jr Blvd 
Chapel Hill NC 27599 
Phone 919-966-9812 
email: Patrick_smith@med.unc.edu 
 
EXAMPLE: Protocol Signature page for Multicenter research where the PI at UNC is the overall PI.  
 
PROTOCOL TITLE:  
Assessing the feasibility and acceptability of a Time Restricted Feeding intervention 
among older adults with Mild Cognitive Impairment 
 
 
 
 
Short Title:  
Time Restricted Eating for Metabolic and Psychological Optimization (TEMPO) 
 
Lead Investigator: 
Patrick Josey Smith, PhD, MPH  
University of North Carolina at Chapel Hill 
Version Date: 7/1/2025 
 
I confirm that I have read this protocol and understand it.    
Principal Investigator Name:  
 
 
Patrick J. Smith, PhD, MPH 
 
 
 
 
 
Principal Investigator Signature:  
 
 
Date:   
 
 
 
 
 
7/1/2025 
 
 
 
 

 
Title: Assessing the feasibility and acceptability of a Time Restricted Feeding intervention among older adults 
with Mild Cognitive Impairment 
 
 
 
 
Protocol Date: 7/1/2025 
NCT#:  
NCT05997316 
 
PROTOCOL SYNOPSIS: Obesity and related metabolic comorbidities have been associated with more than a 
4-fold increased risk of incident cognitive impairment, including Alzheimer’s disease and related dementias 
(ADRD). Dysfunctional metabolic flexibility is increasingly recognized as a critical mechanism linking metabolic 
risk factors to risk of cognitive impairment, although few studies portable behavioral strategies to enhance 
metabolic function among individuals at risk for ADRD. The TEMPO trial examined the feasibility and 
acceptability of a 12-week time restricted feeding intervention among individuals with mild cognitive impairment 
(MCI), as well as assessing changes in cognitive and metabolic function. 
BACKGROUND AND RATIONALE: 
A.1. Public Health Significance of Mild Cognitive Impairment and Alzheimer’s and Related Dementias. 
The United States population is increasingly older and overweight, with nearly 50% of adults projected to meet 
criteria for obesity by 2030.38 In parallel, older adults (aged > 65 years) will represent an increasingly high 
proportion of the American population, at an estimated 73 million individuals. As a corollary, the prevalence of 
Alzheimer’s and Related Dementias (ADRD) is also projected to increase from 26.6 million to over 106 million 
worldwide by mid-century.39-41 In addition, many more older adults will develop subclinical cognitive 
impairments that substantially impair quality of life and independent functioning without reaching criteria for 
dementia, including mild cognitive impairment (MCI).52 Recent estimates have suggested that ADRD may 
account for up to $215 billion annually in public health expenditures42 and is projected to increase.  
A.2 Metabolic Function, MCI, and ADRD. Metabolic dysfunction is increasingly recognized as a ‘a key 
[causal] player in dementia pathology’, increasing the risk of disease progression and cognitive impairment.43 
Obesity and associated metabolic risk factors are associated with increased risk of MCI,44,45 elevated ADRD 
biomarkers, 46-48 and faster progression from MCI to ADRD.1,48-50 The adverse impact of obesity on the brain is 
not surprising, given that obesity is associated with an array of cardiovascular and metabolic abnormalities,51 
including hypertension,52 insulin resistance, and dyslipidemia; all of which increase ADRD risk,53-61 worsen 
ADRD biomarker profiles,62 and are modifiable with weight loss.63,64 The presence of obesity appears to 
increase ADRD risk independent of comorbid vascular risk factors 65 or genetic risk.66  
Despite the robust association demonstrated between peripheral metabolic dysfunction and cognitive 
impairment, primary prevention efforts have been hampered by a lack of mechanistic insight delineating the 
pathways by which peripheral impairments in metabolic function impair central nervous system (CNS) 
metabolic function. This is particularly important as neurocognitive benefits following exercise-based lifestyle 
modification appear to be age-dependent,67-71 with larger benefits in middle-aged relative to older samples, 
leading some investigators to hypothesize a metabolic ‘tipping point’ for intervention efficacy.72-74 In addition, 
the beneficial effects of weight loss on cognition do not appear to correlate consistently with improved aerobic 
fitness or weight loss from prior behavioral trials, 75,76 strongly suggesting that the beneficial effects of such 
interventions may be transmitted through alternative metabolic pathways.37,77 This could explain why recent 
trials among participants with metabolic risk factors, such as the Diabetes Prevention Program (DPP)78 and 
LOOK-AHEAD trials, found that behavioral weight loss may not improve cognition.79-84 Elucidating metabolic 
pathways that enhance cognition is a critical knowledge gap.  
A.2 Metabolic Switching, Ketone Metabolism, and MCI. An emerging line of research suggests that the 
brain’s ability to shift between metabolic energy substrates is a critical, understudied mechanism linking obesity 
to cognitive impairment. The ability to metabolically switch between peripheral energy resources between 
times of negative energy balance and positive energy balance (i.e. excess energy intake relative to output) 
appears to play an important role in healthy aging, systemic metabolic function, and CNS metabolic 
efficiency.85 In addition, experimental evidence linking dietary changes to neuroimaging biomarkers suggests 
that greater time spent utilizing ketones as the brain’s primary fuel supply has a stabilizing effect on brain 
network connectivity and improves cognitive function, whereas the opposite pattern is observed for glucose.86 
The capacity for the brain to change fuel sources, referred to as ‘metabolic switching’, declines with age86,87 
and is impaired among those with metabolic conditions, such as diabetes.88 Despite constituting only 2% of 
body mass, the brain disproportionately utilizes 20% of systemic energy resources and decreases in metabolic 

 
efficiency with older age. Systemic insulin resistance has a well-documented, deleterious effect on brain 
glucose utilization, blunting the effects of CNS energy resources, accelerating cognitive aging, and increasing 
the likelihood of ADRD by 2-3 fold.14 Despite the profound effects of systemic metabolism on brain function, 
ketogenic energy resources appear relatively spared from the effects of biological aging and appear to remain 
efficient among older adults.16 Notably, although CNS hypometabolism is a cardinal feature of ADRD brain 
function, utilization of ketone bodies appears unaffected by this ongoing neurodegenerative process and 
chronic engagement in hypocaloric dietary patterns appears to preserve synaptic plasticity and cognitive 
function in animal models.89 Few studies have attempted to examine the effects of ketone manipulation on 
neurocognitive function15,90,91 or the potentially mediating role of increased ketone production for 
neurocognitive improvement in the context of lifestyle modification interventions.  
Available evidence is therefore consistent with alterations in ketones playing a critical mechanistic role by 
which lifestyle improves cognitive function. Ketones are the preferred fuel source for cerebral functions and are 
over-represented in the prefrontal cortex,92 consistent with the effects of behavioral weight loss on executive 
functions and learning / memory consolidation.69,70,72,73 A recent pilot study among older adults with memory 
complaints or impairments demonstrated that dietary modification increased cerebral ketone metabolism and 
memory performance.93 In addition, recent meta-analytic studies suggest that trials eliciting even mild ketosis 
result in moderate cognitive improvements among individuals with mild cognitive impairment or ADRD.90  
A.3  Time Restricted Feeding to Improve Metabolic Function. A rapidly emerging body of literature 
suggests that time restricted feeding (TRF) / intermittent fasting is a 
feasible intervention to enhance metabolic function32 among older 
adults.30,35,94 Recent pilot studies have demonstrated that even a 
one-month TRF intervention among older adults (aged > 65 years) 
with metabolic risk factors results in substantial weight loss (~5lbs) 
and was associated with high levels of treatment adherence 
(meeting goals on 84% of days).35 Importantly, available data from 
both human and animal studies suggests that TRF is unique from 
other ‘whole diet’ interventions in its impact on metabolic 
mechanisms, mitochondrial biogenesis, and cellular plasticity, 
resulting in overall enhanced metabolic efficiency. 95 TRF has also 
been suggested play an important protective role in protecting 
against cognitive decline both by increasing overall cerebral health 
and by enhancing the brain’s ability to adapt during acute metabolic 
fluctuations by recruiting additional energy resources, such as 
ketones.19 Recent thought leaders in the field of TRF have 
advocated for “Future randomized controlled IF trials should use 
biomarkers of the metabolic switch (e.g., ketone levels) as a 
measure of compliance and of the magnitude of negative energy 
balance during the fasting period”. 85 Our overarching conceptual 
hypothesis is that chronic metabolic dysfunction results in an 
impaired CNS metabolic efficiency and cognitive function, both of 
which may be improved by TRF (Figure 1).  
B. INNOVATION. The proposed project has a number of innovative 
features. First, the project is innovative in its focus on using a 
potentially portable, low-cost intervention approach for a highly prevalent, very costly public health problem. 
Despite the prevalence and lack of treatments to stabilize MCI, no studies have examined experimentally 
manipulated fasting or its mechanisms in this vulnerable patient group. Second, our focus on temporal 
patterns of eating behavior is unique and represents a critical departure from prior work examining either 
caloric restriction or modifying overall dietary patterns. Prior multimodal interventions have suggested that 
dietary interventions have among the lowest adherence rates when compared to other behavioral intervention 
components, such as exercise or vascular risk modification.96,97 Recent evidence among older adults suggests 
that TRF is more feasible and therefore represents a more portable intervention approach. Therefore, if the 
proposed intervention is successful, it holds great importance as a first-line strategy to enhance prevention 
efforts among individuals with MCI. Third, our focus on multiple markers of metabolic switching is novel and an 
important innovation that diverges from conventional ‘whole diet’ or single nutrient approaches, which target 
Figure 1. Conceptual model linking metabolic 
inflexibility, cognitive function, and obesity in MCI. 

 
basal metabolic function. Fourth, Duke is among leading institutions in the United States in its examination of 
metabolic mechanisms linking lifestyle factors, such as physical activity and eating patterns, with metabolic 
disease processes. The present proposal solidifies new collaborations between investigators within the Duke 
Molecular Physiology Institute (DMPI: Huffman and Muoio) and investigators within aging and behavioral 
interventions in MCI (PI Smith and co-I Strauman).  
C. PRELIMINARY STUDIES. Our team has conducted research in three broad areas relevant to the proposed 
study, including 1) dietary modification and weight loss, 2) MCI trials, and 3) metabolic mechanisms: 
1) Metabolic Mechanisms of Caloric Restriction: Drs. Huffman, Parker, and Muoio have conducted and/or 
evaluated metabolic responses to multiple translational studies linking lifestyle modification to therapeutic 
mechanisms. In young, normal to slightly overweight (BMI 22-27.9 kg/m2) adults, 12 months of ~12% CR 
(versus ad libitum (AL)) increased NMR- assessed fasting acetone and, after 24 months, fasting β-
hydroxybutyrate (both groups, P<0.04) (Figure 2).98 In CALERIE Phase 1, six months of 25% CR, 12.5% CR 
plus 12.5% caloric deficit from exercise training, and weight maintenance control diet were compared. Despite 
being matched for caloric deficit with confirmation by similar weight loss and body composition changes, CR 
alone and CR displayed unique metabolic responses for amino acids, acylcarnitines (fatty acid oxidation by 
products), and fatty acids. For CR alone, acylcarnitine concentrations increased and were consistent with 
greater amounts of complete fatty acid oxidation.99  Additionally, CR alone improved metabolic flexibility, 
assessed as a greater ability to shift substrate utilization from the fasting to fed state with post-prandial 
reductions in fatty acids and acylcarntines, exceeding improvements in CR + exercise.100  
 
2) Lifestyle Trials, Metabolism, and Cognitive Function: Our investigative team has conducted numerous 
RCTs examining the associations between improved metabolic function and cognitive function.37,70,101-107 Dr. 
Patrick Smith’s previously published findings from the ENCORE trial of middle-aged adults with obesity and 
hypertension demonstrated that 4 months of weight loss program improved executive functioning, memory, 
and learning, and these results were strongest when weight loss was enhanced using the DASH diet (d = 0.56, 
P = .008).37 Dr. Smith was also instrumental to the 
design106 and implementation of the ENLIGHTEN 
trial of aerobic exercise and the DASH diet among 
older adults with vascular comorbidities and 
cognitive impairment,12,102,108,109 many of whom had 
MCI. Results demonstrated that exercise 
participants exhibited significant improvements in 
executive function (d = 0.32, P = .046), with smaller 
improvements among DASH participants (d = 0.30, 
P = .059), and the largest improvements among 
participants randomized to receive both (d = 0.40; p 
= 0.046)109 that were sustained at 18-months.110  
3) Peripheral metabolic mechanisms of ADRD 
risk:  We have published numerous studies 
examining metabolic mechanisms of cognitive 
change.102,104,105,111,112 Our research group has 
focused primarily on examining the overlap between 
cardiometabolic risk factors (CMRFs), subclinical 
carotid atherosclerosis, and endothelial dysfunction 
on cognition,102,111,112 demonstrating that these subclinical risk markers may mediate the associations between 
clinical CMRFs (e.g. hypertension) and neurocognitive impairment.112 We examined mechanisms linking 
physical activity, aerobic fitness, the DASH diet, and cognition, focusing on CMRFs and inflammatory 
biomarkers.102 We found that higher levels of fitness and the DASH diet were associated with better cognition 
among individuals with CIND, and that these associations were partially mediated by CMRFs, suggesting that 
these interrelated factors were additively associated with outcomes.102 In addition, we found that obese 
participants exhibited worse executive function at baseline and that this association was mediated by impaired 
metabolic biomarkers, including insulin and leptin resistance.36 Similar findings emerged from baseline 
assessments of our ongoing behavioral weight loss trial among treatment-resistant hypertensives, the majority 
Figure 2: CALERIE Phase 1 group differences for circulating ketone 
concentrations. Ketones were measured use nuclear magnetic 
resonance-based methods.  

 
of whom are obese. We found that greater obesity (β = -0.19, P = .029) and HOMA-IR (β = -0.46, P <.001) 
associated with worse executive function,36 with HOMA-IR mediating this association.113                      
Co-Investigators’ Expertise. The proposed R21 integrates work from several areas to provide an integrated 
behavioral approach to enhance metabolic functioning through TRF among individuals with MCI. 
Dr. Patrick Smith completed postdoctoral fellowships in both behavioral medicine and clinical neuropsychology 
and has served as the PI or co-I on multiple MCI studies, including lifestyle trials (HL109219)12,106,109,110,113 and 
identification of MCI patients using functional connectivity metrics (AG042599). Dr. Smith also serves as one of 
two core clinical neuropsychologists on the recently funded Duke-UNC Alzheimer’s Disease Research Center. 
His work has focused on enhancing neurocognition using behavioral weight loss, such as dietary modification 
and exercise,12,36,37,70,104,113-117 most of which integrated Dr. Krista Ingle, our study interventionist, as the primary 
behavioral weight loss interventionist. Dr. Smith recently served as the PI for a trial examining the effects of 
behavioral weight loss on cerebrovascular and endothelial mechanisms of cognitive enhancement 
(HL130237).36,118 Drs. Kim Huffman and Deborah Muoio have performed extensive work examining metabolic  
and inflammatory mechanisms of lifestyle modification.100,119-124 Dr. Huffman has also mentored Dr. Daniel 
Parker, a geriatrician focusing on biomarkers and mechanistic treatment targets for ADRD-related dementias. 
Finally, Dr. Timothy Strauman is an expert in interventions to enhance self-regulatory function across multiple 
clinical populations.125-132 He has collaborated extensively with Dr. Smith on prior trials37 and related reviews.70  
 
RESEARCH STRATEGY: D. R21 APPROACH  
Methodological Features: Our intervention approach has been informed both by contemporary pilot studies in 
healthy older adults,35,133,134 adults with cardiometabolic risk factors,135-138 and our own work among adults with 
cardiometabolic risk factors37,115,139-141 and cognitive impairment.12,36,109,110,113,142 In terms of our behavioral 
intervention approach for TRF, our primary conceptual underpinning is therefore based on temporal self-
regulation theory,143-148 in which adults with MCI participate in TRF using behavioral (e.g. hunger) and 
environmental context (e.g. home and time of day) to enhance context-specific responsivity for self-regulation. 
Several key features were prioritized in developing the initial treatment approach for the proposed intervention, 
including 1) appetite awareness training,37,139,149 2) enhanced psychological flexibility and experiential 
acceptance of aversive hunger cues,150-152 3) stimulus control through environmental modification,153-155 and 4) 
cognitive control techniques derived from the Motivationally Enhanced Compensatory Cognitive Training for 
Mild Cognitive Impairment (ME-CCT-MCI) protocol (see details in Human Subjects).156-158 Although our a priori 
focus be on intervening on an individual level 
with the participants, we recognize that many 
participants will have social support members 
who may wish to participate. We will therefore 
allow but not require participation by study 
partners, consistent with our prior intervention 
approaches.12,142,159,160 For participants with 
study partners, we will incorporate elements 
from Multi Contextual Treatment Approach, 
which focuses on strategy generation and 
metacognitive process components to enhance 
transfer of behavioral skills.161-166 
We anticipate that early sessions will focus on motivational and organizational factors, including 1) 
identifying motivational factors leading to study enrollment through values clarification and self-discrepancy 
exercises129,167,168 to enhance the personal salience of TRF goals, 2) collaborative goal-setting using SMART 
(Specific, Measurable, Achievable, Relevant, and Time-bound),169 and 3) organizational strategies to enhance 
self-monitoring and success with early TRF sessions. The intervention will then shift to focus on coping skills 
to enhance affect regulation and inhibitory control. Approaches will include 1) appetite awareness training 
with mindfulness,37 2) relaxation and distress tolerance techniques,170 and 3) cognitive defusion approaches.171 
Following the deployment of affect regulation strategies, we will then shift to cultivating cognitive 
compensatory strategies to enhance 1) attention modulation, 2) encoding of TRF information, and 3) 
problem-solving approaches. In the final stage of the trial, we plan to focus on relapse prevention training 
through 1) self-reinforcement strategies, 2) contingency management, and 3) stimulus control.150 Throughout 
the intervention, we will deploy behavioral intervention strategies known to be efficacious among individuals 
with MCI, in which environmental cues and other aspects of implementation intentions are leveraged to 

 
encourage initiation of target behaviors. Environmental modifications will therefore be recommended to 
enhance automatic cues for TRF success in the participant’s home, such as using a centralized white board. 
Common barriers to organization will be discussed, with potential self-management strategies offered for 
participants to choose a personalized strategy to enhance adherence. Intervention approaches will be 
personalized using baseline executive function profiles with a particular focus on individual differences in 
inhibitory control. We note that the proposed intervention components above and detailed in the Human 
Subjects section will serve as a general template or ‘roadmap’ for intervention development, which will be 
iteratively adapted based on participant feedback in order to optimize acceptability.  
TRF intervention components: Prior studies have demonstrated the greatest feasibility using a 16-hour based 
fasting period (16:8), deployed twice per week (5:2). Initial TRF recommendations will be to fast during two 
days during the next week, at least two days apart, with a fasting period of 14 hours and eating period of 10 
hours. This will gradually be titrated up to a 16 hour fast with 8 hours of unrestricted eating (16:8) on two days 
per week, consistent with the prevailing 5:2 trial approaches. Participants typically place their 16-hr fasting 
period as beginning following dinner (e.g. 8pm) and ending at lunch the following day (e.g. 12pm). We will a 
priori target the 16:8 fasting on a 5:2 schedule to maximize acceptability. A minimum of 14-hrs will be used 
during the early stages of fasting training, as needed. During the fasting periods, participants will be allowed to 
drink water but will be instructed to refrain from eating, snacking, or consuming sugar-sweet beverages.  
Importance of Executive Functioning: Executive functioning is a key driver of self-regulatory behaviors and 
is highly predictive of habitual behavioral modifications. Participants with greater inhibitory control, working 
memory, and mental flexibility should have greater ability to both make and sustain behavioral changes over 
time. Baseline levels of executive functioning will therefore play a major role in personalization of intervention 
techniques. Individuals with poorer inhibitory control, for example, will be preferentially trained to increase the 
amount of behavioral ‘friction’ for dietary indiscretions during fasting periods. This could include 1) engaging in 
activities away from their home (and easily accessible food sources) during fasting periods, 2) removing all 
easily accessible snacks from their kitchen and/or pantry in order to reduce their primacy, and 3) substituting 
pleasurable distractions such as spending time with others, watching a movie, or engaging in other value-
consistent activities to help distract them from hunger cues.   
Phasic Intervention Approach: Recent behavioral intervention development approaches have placed an 
emphasis on the use of phased intervention approaches to enhance acquisition and extension of new 
behavioral skills. Our intervention team was persuaded by recent data from the Science of Behavior Change 
(SOBC)172 initiative demonstrating that behavioral intervention strategies are most effective when tailored to 
intervention stage, with strategies to improve self-efficacy yielding the largest benefits in behavioral adoption / 
initiation phase, self-regulatory and stimulus control strategies to modify contextual cues yielding the largest 
benefits in the implementation phase, and strategies to modify self-monitoring and expectations in the 
maintenance phase. Reinforcement frequency and potency as well as self-monitoring techniques, have been 
found to be optimally utilized when deployment varies by the phase of treatment, with more frequent 
reinforcement during skills acquisition (e.g. adoption phase [1-3]) and variable reinforcement during skills 
implementation and maintenance phases (e.g. implementation phase [4-8]). This dual-process intervention 
approach maximizes habitual elements of behavior changes by modifying contextual cues, emphasizing 
behavioral rehearsal, and reducing behavioral friction to the initiation of healthy behaviors in early intervention 
phases to reduce the amount of intentional effort required in later intervention phases.  
The present TRF intervention was designed using components successfully utilized in our prior trials, 
including enhanced tolerance of satiety cues, mindful appetite awareness, and self-monitoring of target behaviors. 
In developing the proposed intervention approach, In addition, 
recognizing that participants will differ in their prior training 
experiences and behavioral compliance with exercise and diet at 
baseline, early content-focused sessions will be tailored to the 
individual needs of the participant. The proposed intervention 
schedule below is therefore intended to provide a basic overview of 
the intervention schedule, which will be tailored to individual 
participants using baseline behavioral data and background 
information to personalize training targets based on their individual 
needs. Consistent with contemporary intervention practices 
emphasizing processes elements as critical to behavior change,172-

 
174 our research team sought to integrate process-based components from several frameworks targeting 
enhanced self-regulatory skills,172 including social cognitive theory,175 relational frame theory,176,177 self-
systems theory,130 and Habit Theory.178  
 
D.2. ASSESSMENT PROCEDURES 
Assessment of Feasibility and Acceptability. Study feasibility will be assessed by examining attrition (i.e., 
study completion) and adherence (i.e., completed intervention sessions and assessments). Consistent with 
prior TRF trials, adherence to the intervention will be assessed using daily diaries, with additional verification 
through calls by the study coordinator. Acceptability will be assessed using by participant satisfaction using the 
Client Satisfaction Questionnaire 10-item version.179  
Assessments of Cognitive Function.  The primary focus of the proposed study will be on cognitive 
performance within domains known to be most sensitive to early metabolic disruptions, including executive 
function / complex processing speed64,180 and learning efficiency under interference conditions.181-184 These 
domains of performance are also highly prognostic of future impairments in instrumental activities of daily 
living, development of MCI and ADRD. Our test battery chosen for its sensitivity to subclinical disruptions in 
metabolic function and its prognostic association with future cognitive decline and ADRD. The tasks are 
streamlined with standard discontinuation rules applied to reduce subject frustration and overall burden. The 
battery will consist of Executive Function / Processing Speed (Trail Making Test,185 Stroop Test,186 Controlled 
Oral Word Association Test,187 Animal Naming Test,188 Digit Span Forward and Backwards,189 Digit Symbol 
Substitution Test, and the Ruff 2 & 7 Test190). We will also assess Learning / Memory (Loewenstein-Acevedo 
Scales Semantic Interference and Learning,183,184 California Verbal Learning Test-II [CVLT-II], 191 and the 
Benton Visual Memory Test – Revised [BVMT-R]).192  
Assessments of Metabolic and Inflammatory Function. Metabolic function and flexibility will be assessed 
using a diverse array of outcomes, including glucose, insulin, insulin-like growth factor, HbA1c, lipids, 
triglycerides, non-esterified fatty acids, total ketones, brain derived neurotrophic factor (BDNF), beta-
hydroxybutyrate, lactate, amino acids, plasma kynurenine, kynurenic acid, and tryptophan.  
non-esterified fatty acids, total ketones, beta-hydroxybutyrate, lactate, amino acids, and acylcarnitines. We will 
also measure conventional clinic markers of metabolic function, including blood pressure, body mass index, 
and metabolic syndrome severity score. Inflammatory markers will also be obtained, including IL-6, TNF-alpha, 
high sensitivity C-reactive protein (CRP), IL-1β, IL-8, IL-10, myostatin, and glial fibrillary acidic protein (GFAP). 
Finally, samples will be obtained for the purposes of assessing gene expression profiles.124,193  
Fasting-Dependent Changes in Cognitive and Metabolic Functions. In order to assess state-dependent 
changes in cognitive and metabolic functions, we will conduct ancillary assessments at pre- and post-treatment 
following an 18-hr fasting period. In contrast to the assessments above, this will allow us to better delineate 
cognitive and metabolic changes occurring in the context of elevated metabolic demand, providing a ‘metabolic 
stress test’. In order to assess subtle changes in tests most sensitive to early decline, a brief assessment of 
cognition will be obtained using the Trail Making185 and Stroop Tests186 for Executive Function / Processing 
Speed and the Loewenstein-Acevedo Scales Semantic Interference and Learning183,184 for Learning / Memory. 
We will also repeat our markers of metabolic function, as described above.   
Select Methodological Issues: 
Study Sample: We discussed various study samples at length, including selecting individuals with metabolic 
syndrome, central adiposity instead of BMI, or using alternative measures of excess weight, as well as 
potentially selecting a wider age range for inclusion. We elected to use overweight and obesity based on 
recent reviews suggesting that alternative measures of adiposity have measurement limitations and would 
further limit the external validity of any findings.194 Study Intervention: Our choice of study intervention to 
improve metabolic function was a topic of considerable discussion in our investigative team, because the 
proposed metabolic mechanisms may also be impacted by exercise. We elected to focus on TRF because of 
its portability and specific impact on ketones and other markers of ‘metabolic switching’. We also feel the 
proposed study intervention will lessen overall participant burden by focusing on TRF as the target behavior. 
  
RESEARCH STRATEGY: Data Management and Analysis  
Data will be entered into a centrally managed Redcap database. Assessments of TRF feasibility and 
acceptability will be assessed by carefully characterizing accrual, adherence, and retention for the 12-week 
TRF trial (Aim 1). Feasibility will be assessed by accrual in the study timeline, 90% adherence to study 
procedures, and 90% of participants completing the protocol. For our analyses of cognitive and metabolic 
changes following TRF (Aim 2) we will use repeated measures, linear mixed effect models in which cognitive 

 
performance is modeled using mean rank approach with in each cognitive domain,106 as recommended by 
O’Brien.243 Within these analyses, we will adjust for age, biological sex, and pretreatment levels of the 
respective outcome, with the time effect as our variable of interest. This composite approach has several 
advantages over testing multiple individual endpoints, including increased reliability, enhanced precision of the 
treatment estimates, improved power, and minimization of Type I Error.244, 245 Analyses are powered to detect 
differences in the primary ‘gatekeeper’ model at the P = .05 level.195,196 If significant, examination of 
components of the global score are examined in secondary, explanatory analyses in which the significance 
level is propagated forward.197 A parallel model will be used to examine changes in metabolic function, in which 
diverse measures of metabolic function and flexibility are combined into a global mean-rank score. For our 
analyses of fasting-dependent changes in cognitive and metabolic function (Aim 3), we will explore fasting-
dependent changes utilizing a parallel, mixed effect modeling strategy with fasting state (non-fasted vs. fasted) 
as an additional categorical predictor, with the time X fasting state interaction as our predictor of interest. 
Patterns of missing data will be characterized using Rubin’s198 criteria and managed accordingly using Harrell’s 
multiple imputation (mult.impute) procedure in R. We will supplement our primary regression analyses with an 
examination of the treatment effect among completers199 using Rubin’s Complier Average Causal Effect 
(CACE) model200 using SAS (Cary, NC) or R. Power Analysis: Power for Aim 2 was based previous 
estimates from our lifestyle trials.37,109 We conducted our power analyses with the following assumptions: 1) an 
initial sample size of 40 participants with 15% attrition at 4-months, 2) alpha of 0.05, and 3) an R2 of 0.50 
between model covariates and the outcome of interest. Based on these assumptions, we anticipate power to 
detect improvements of d = 0.70 between baseline and post-treatment assessments, paralleling improvements 
from our recent behavioral weight loss trial in adults with resistant hypertension.36  
 
E.  PROTECTION OF HUMAN SUBJECTS  
1.  RISKS TO HUMAN SUBJECTS  
 
1a.  Human Subjects Involvement, Characteristics and Design  
Subjects will include 40 men and women aged 65-85 years with amnestic Mild Cognitive Impairment (Montreal 
Cognitive Assessment Battery score [MoCA] total score 19-25 or a phonemic fluency score of <12 with MoCA 
> 25 or semantic fluency score < 15 with MoCA score > 25;201 and score of > 1.0 on the Mail-in Cognitive 
Function Screening Instrument)202, obese (body mass index 27.5-40 kg/m2), sedentary, and be willing to 
participate in all aspects of the proposed intervention. Reasons for participant exclusion will include secondary 
causes of obesity, evidence of clinical dementia (MoCA score < 18), severe CKD (eGFR <45 ml/min/1.73m2), 
heart failure, high grade arrhythmias, severe valvular heart disease, severe asthma or chronic obstructive lung 
disease, diabetes requiring insulin, musculoskeletal or neurologic problems that would preclude participation in 
aerobic exercise training, a major psychiatric disorder, a history of drug abuse, alcohol consumption >14 
drinks/week, gastric bypass surgery, non-English speaking, or a life-limiting comorbid medical condition such 
as cancer.  
 
1b.  Sources of Materials  
Medical, clinical, and questionnaire data will be provided by participants for research purposes.   
 
1c.  Potential Risks  
Risks of serious injury during the trial is considered negligible.  TRF has been shown to have adequate 
acceptability and a low prevalence of adverse events in older adults with obesity.35 Participants may 
occasionally experience headaches, light-headedness, or nausea, which occur infrequently and appear to 
peak approximately two weeks into treatment. 135  Although unlikely, there is the possibility that changes in 
dietary behavior could result in excessive metabolic derangements in some participants, which we will monitor 
and manage as needed. Participants also will be carefully monitored for clinically significant changes in 
neurocognitive function and Dr. Daniel Parker, a board-certified behavioral neurologist, will assess participants 
exhibiting significant neurocognitive change to make additional referrals as needed. There is also some risk of 
loss of confidentiality of cognitive performance data.  
 
2.  ADEQUACY OF PROTECTION AGAINST RISKS  
 
2a.  Recruitment and Informed Consent 

 
If the volunteer clearly meets all of the study eligibility criteria, he/she will be asked to read and sign a 
Duke University Medical Center IRB-approved informed consent form.  A research assistant will confirm a 
statement in the consent form that to qualify for participating in the study, additional weight measurements will 
be made to verify eligibility criteria. If overweight / obesity criteria are met, then the participant will be 
administered the Montreal Cognitive Assessment Battery203 in order to determine if his or her cognitive status 
meets criteria for the proposed study.  Physician approval will be required for participants to enroll in this study.  
Potential participants will be recruited from physician referrals at Duke, the Durham VA, Duke Raleigh Hospital 
and their affiliated community-based clinics, as well as the Durham Veterans Affairs Hospital.  
The Duke / UNC Alzheimer’s Research Center has recently been awarded, with a focus on recruiting 
diverse older adults with cardiometabolic risk factors at risk for ADRD. Dr. Smith is one of only two core 
neuropsychologists working on the ADRC project, which will afford unique opportunities to leverage emerging 
recruitment opportunities to enhance enrollment efforts.  
The Duke Family Medicine Clinic follows about 13,000 participants annually, with more than 50% 
being African American and 65% women.  Duke Family Medicine received recognition from the National 
Committee for Quality Assurance (NCQA) as a Level 3 Patient-Centered Medical Home in June 2012 under 
the PCMH 2011 Standards. In 2018, the clinic was actively following 5,121 individuals with BMIs 25-40 kg/m2.  
The Durham VA is a large, high complexity facility that provides primary care to 40,000 veterans in 3 
main sites (two hospital-based clinics in Durham and a community-based clinic in Raleigh). Of these registered 
participants, previous estimates have suggested up to 80% are overweight or obese.204 We have previously 
used VA recruitment to achieve 100% of our enrollment targets for behavioral intervention studies.109  
 
2b.  Protection Against Risk 
A number of special precautions will be taken to ensure participant safety:   
Prospective study participants will be carefully screened before initiating the proposed TRF program.  
Potential subjects with clinical evidence of ischemic heart disease, heart failure, or other major medical or 
psychiatric problems will be excluded.  In addition, subjects who have evidence of severe valvular disease, 
ECG evidence of ischemia on recent exercise testing, an abnormal BP response, or complex ventricular 
ectopy will be excluded from the study and referred for appropriate treatment.  At the conclusion of the trial, 
participants will be referred back to their treating physicians.  In the event that participants do not have a 
physician, several well-established outpatient programs at Duke University Medical Center, Duke Raleigh, or 
UNC are equipped to receive referrals from our research program.  We believe that these facilities, in addition 
to private practitioners in the community, provide a comprehensive range of appropriate referral sources for 
participants needing further treatment.  We are confident that careful screening and monitoring of all 
participants entered into our protocol, and tracking of all participants following the completion of the 
interventions, will minimize risk to study participants.  The study personnel, including physicians, psychologists, 
internal medicine physicians, and the physician’s assistant, have the training and experience to provide the 
necessary safeguards for participation. 
Participants included in our clinical databases contribute clinical information based on their 
neuropsychological assessment, biomarker assessments, clinical history, laboratory results, and 
cerebrovascular risk factor information pertinent to their neurocognitive function. The data are used specifically 
for research purposes. Release of patient information is carefully controlled through the Institutional Review 
Board (IRB).  All project staff will have fulfilled Duke University's mandatory HIPAA training requirements. All 
aspects of the study protocol will meet HIPAA requirements specified by the Human Studies Committee and 
the Privacy Office at Duke University. The protocol will be approved by the Duke University Medical Center IRB 
and University of North Carolina Hospitals before it is implemented. All investigators have completed the 
required education and certification in the protection of human research participants.  
In the unlikely event of an adverse medical event during assessment or any other on-site phase of 
study participation, the patient’s attending physician and/or the emergency services at DUMC will be contacted 
immediately. In addition, the principal investigator and medical director of the study will be notified of all such 
events. Any patient who develops new cardiac symptoms or experiences a significant deterioration of cognitive 
function will be referred for additional evaluation at the discretion of the study neurologist (Dr. Parker). Also, if 
any patient exhibits significant psychopathology or becomes acutely suicidal they will be escorted to the Duke 
emergency room for immediate treatment. 
 
3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS   

 
This study will likely have several important potential benefits. First, participants receiving the TRF 
intervention will very likely experience weight loss, may achieve improved metabolic function, reduced 
cerebrovascular risk factors, and potentially improved neurocognition. We will also explore treatment response 
in relationship to age, pre-treatment neurocognitive function, cerebrovascular burden, and phospholipid 
metabolism. This may make it possible to identify participants who are especially likely to respond well to TRF. 
The information gathered could enhance health care professionals' ability to advise participants about the 
effects of voluntary weight loss and may enable health care providers to identify, in a timely fashion, 
participants who might benefit most from an intensive lifestyle intervention.  
Potential benefits to society include the identification of an effective strategy to reduce the incidence of 
neurocognitive decline, elucidate metabolic mechanisms of neurocognitive improvement, and gain a better 
understanding of the mechanisms underlying the relationship between obesity and Alzheimer’s Disease and 
Related Dementias (ADRD). If the TRF intervention shows preliminary benefits in improving neurocognitive 
and metabolic function, it could be used as a potential preventive strategy among individuals at risk for ADRD 
and implemented as part of conventional rehabilitation approaches. In addition, because there are no current 
pharmacological treatments to reduce the prevalence and development of neurocognitive decline, interventions 
that improve neurocognition have significant implications for the management and treatment of individuals with 
obesity, who may be at particularly higher risk for the development of ADRD. 
 
4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
Our prior work has highlighted the efficacy of lifestyle change to enhance metabolic and neurocognitive 
function. What is not yet known is the degree to which older adults at risk for ADRD may be able to utilize TRF 
as a strategy to maintain brain health and reduce ADRD risk. The proposed intervention therefore introduces a 
portable and potentially impactful behavioral approach to mitigate the progression of cognitive decline and 
reduce ADRD risk in a highly vulnerable and increasingly common patient population.  
Dissemination of our findings involves the transfer of our research results to participants, health care 
providers, and decision makers to modify the lifestyle behaviors of participants and inform health care 
providers about optimal ways to manage participants with risk factors for cognitive decline. A major strategy 
will be the presentation of the study design and results at various national meetings including the International 
Neuropsychological Society, the American Psychiatric Association, the American Psychological Association, 
and the American Heart Association. Another key strategy will be the rapid publication of the study design and 
results in major journals. We hope to publish our findings in the best journals available to both the general 
medical community (e.g., JAMA, NEJM, Lancet), as well as to specialty journals in neurology, 
neuropsychology, internal medicine, and psychiatry. 
 
5. Data and Safety Monitoring Plan:   
 
Adverse events will be systematically monitored at the time of enrollment, initiation of the study 
intervention, and at the conclusion of the 4-month TRF program.  Although we anticipate few adverse events, we 
note that any intervention-related adverse events in metabolic or cognitive change will be reviewed by Drs. 
Parker and Huffman on a regular basis. For the purposes of the present, an adverse event is defined as any 
undesired, noxious, or pathological change in a participant, as indicated by symptoms or laboratory changes that 
occur in association with our additional assessments.  In addition, as noted above, participants exhibiting a 
MoCA < 18 during baseline assessments will be excluded and participants reporting or exhibiting clinically 
worrisome cognitive changes during the 4-month intervention or post-treatment assessments will be referred 
for additional neurological evaluation at the discretion of Dr. Parker. Pre-existing conditions that worsen during 
a study are considered adverse events. Serious Adverse Events (SAE) are defined as any adverse event that 
results in any of the following outcomes: 
 
• 
Death or a life-threatening illness including active suicidal ideation/attempt (such as drug overdose) 
• 
A persistent or significant disability/incapacity 
• 
A requirement for hospitalization ≥24 hours 
 
After careful screening, patients who are judged at risk (e.g., because participation in the treatment is 
medically contraindicated) will be excluded from the study and referred for appropriate treatment. Participants 
who exhibit significantly abnormal metabolic functioning suggesting clinically significant instability or who 
cannot otherwise participate in the TRF program also will be excluded from the study and referred to their 

 
primary care physician for treatment. Drs. Huffman and Parker will be fully apprised of this information on a 
regular basis. All staff involved in the design or conduct of the study will receive the required education on the 
protection of human research participants prior to funding of the project. Dr. Smith will be available 24/7 for 
emergent and/or urgent study-related issues. 
 
6. Data Sharing Plan: An anonymized dataset with key study-related data will be made available to 
investigators upon request one-year after the publication of the primary study findings. Investigators will be 
able to make requests through Drs. Smith and Pieper, who can facilitate such data management tasks. In 
addition, we will plan to provide a complete, anonymized dataset for deposition into online data repositories 
within three years of publication, for use in subsequent follow-up analyses or meta-analytic studies. We will 
also make annotated statistical analytical code available for public usage, in order to increase the 
reproducibility of our findings for future studies. 
 
7. Protocol Development: Source Materials for Behavioral Intervention  
The behavioral portion of our TRF intervention was developed using source materials from our prior behavioral 
interventions,12,37 strategies to enhance self-regulatory functioning,125,126,129 and behavioral intervention 
components with previously demonstrated efficacy among individuals with MCI.205,206 An example of a TRF 
protocol is provided below. We note that the proposed intervention schedule below is intended to provide a 
roadmap for development and will be enhanced with feedback from participants throughout the trial. We also 
anticipate that our intervention approach will be flexibly implemented, with personalization based on individual 
participant characteristics, background profile of cognitive impairments, and individual goals.  
 
WEEK 1: Overview of TRF training, review the pathophysiology of TRF on metabolic function and cognition, 
and an introduction to the relation between self-regulatory function and TRF success. The importance of self-
monitoring techniques and environmental modifications will be emphasized. In addition, the importance of self-
regulatory coping techniques will be emphasized as self-management skills that can be mastered through 
regular practice.  The patient will also be asked to describe their MCI and medical history, as well as identifying 
underlying values motivating them to participate. An autobiography, which we have used in our prior work also 
will be employed as a way of allowing the patient to tell his or her own “story” and identify key motivational 
factors and personal barriers that will need to be addressed during treatment. Participants will also undergo a 
values clarification and self-discrepancy exercise to enhance the personal salience of TRF goals. Finally, 
patients will be instructed in the use of self-monitoring tools, which will be monitored. Participants will also be 
asked to engage in collaborative goal setting for the first week of TRF by first identifying the best days of the 
week for establishing their 5:2 routine. Initial TRF recommendations will be to fast during two days during the 
next week, at least two days apart, with a fasting period of 14 hours and eating period of 10 hours. This will 
gradually be titrated up to a 16 hour fast with 8 hours of unrestricted eating (16:8) on two days per week, 
consistent with the prevailing 5:2 trial approaches. 
WEEK 2: Self-Monitoring and Organizational Strategies. Participants will engaged in discussion of activities to 
cultivate TRF routines, both as a method to enhance TRF adherence and also to reduce cognitive burden. 
Using weekly calendars, reminder strategies, and other compensatory techniques to cue participants to 
prepare and engagement in TRF. For example, cultivating a routine for the night before TRF begins. 
Environmental modifications will be recommended to enhance automatic cues for TRF success in the 
participant’s home, such as using a centralized white board. Common barriers to organization will be 
discussed, with potential self-management strategies offered for participants to choose a personalized strategy 
to enhance adherence. For those successfully adhering to the intervention, behavioral goals will be titrated 
towards their 16:8 fasting goal. For those who have not yet achieved their initial goals, a focus on identifying 
and managing barriers will remain the treatment target focus to ensure success. Intervention approaches will 
be personalized using baseline executive function profiles with a particular focus on individual differences in 
inhibitory control.  
WEEK 3: Appetite Awareness Training with Mindfulness. Participants will be trained in mindfulness exercises 
modified from the Motivationally Enhanced Compensatory Cognitive Training for Mild Cognitive Impairment 
(ME-CCT-MCI). Participants will engage in mindfulness training exercises to enhance attention control, 
increase cognitive flexibility, and to develop a take-home practice routine. Process targets will include 
enhancing awareness and cognitive defusion of hunger pangs, redirecting attention away from food cues using 
distraction techniques, and to build insight regarding automatic thoughts related to satiety cues. Use of 
experiential acceptance techniques, paradox of control, self-soothing techniques, suffering in the service of 
health and other values. Participants will be encouraged to cultivate and practice distraction techniques during 

 
fasting periods to enhance tolerability of hunger cues.  
WEEK 4: Relaxation and Distress Tolerance Techniques. Participants will be instructed on relaxation 
techniques to help manage anxiety and elevated distress. Techniques will include mini-practices, distress 
tolerance techniques, and progressive muscle relaxation. An explicit focus on using these techniques as a way 
of managing hunger pangs and when experiencing impulses to over-eat. Relaxation and distress tolerance will 
be framed as affective self-regulatory skills to help manage transient increases in distress, frustration, hunger, 
and impulsive feelings.  Techniques will include distraction, self-soothing, and imagery. 
WEEK 5: Attention and Concentration. Strategies for enhancing attention and concentration will be introduced 
to enhance TRF compliance, including the STEP BACK energy conservation principles. Behavioral strategies 
to enhance participants’ ability to modulate attention will also be deployed, including ‘spotlight’ attention 
strategies (e.g. detailed observation of a painting) and LEAP principles to enhance conversational attention. 
Consistent with temporal self-regulation theories, attention and concentration resources will be characterized 
as a ‘muscle’ that can be strengthened over time and that will fatigue with overuse. Focused periods of 
attention during TRF will be cultivated and strengthened through the intervention, with an intentional focus on 
periods of more active attention and periods of rest and recovery. 
WEEK 6: Learning and Memory. Participants will be trained in memory techniques to help augment their 
adherence to TRF. Strategies will be linked to deployment of self-monitoring and organizational skills from 
session 2, as well as attention strategies in session 5. External memory strategies will include reminder 
systems, calendars, and timers. Internal reminder enhancements will include dual-mode encoding, visual 
imagery, self-talk, internal rehearsal, chunking, and ‘overlearning’ approaches. Retrieval strategies will also be 
discussed, such as mental retracing, recreating the context, and using previously learned organization and 
relaxation skills. 
WEEK 7: Problem-Solving Techniques. Participants will collaboratively with an emphasis on active problem-
solving of barriers to PA. Problem-solving will be modeled and encouraged in all subsequent sessions. 
participants will be instructed in systematic ways to approach daily problems (e.g., defining the problem, 
identifying elements of the problem, brainstorming, selecting approach, evaluating effectiveness). 
WEEK 8: Self-Reinforcement Techniques. Participants will collaboratively discuss different self-reinforcement 
approaches, including both intrinsic and external reinforcers. Intrinsic reinforcement will be cultivating using 
self-monitoring of self-reported fatigue and energy levels, weight loss, enhanced sense of self-efficacy, and 
improvements in body image. External reinforcement strategies will include selecting pleasurable activities to 
engage in after meeting behavioral compliance targets. These might include getting new clothes, watching a 
movie of interest, or participating in other pleasurable activities. 
WEEK 9: Contingency Management Techniques. Participants will collaboratively develop approaches for 
anticipating and managing relapse behaviors, such as missing a day of TRF or accidentally eating during TRF. 
Goals will include processing behavioral antecedents of relapse behaviors, identifying alternative coping 
strategies, and using organizational aids to anticipate future barriers to relapse over the next several weeks. 
Behavioral analysis will be reviewed closely to 1) identify potential discrepancies between short-term goals and 
TRF engagement and 2) highlight potential behavioral patterns contributing to TRF non-compliance. As in our 
prior intervention studies, identification of problematic behavioral patterns will be discussed in order to manage 
potential TRAPs (Trigger, Response, and Avoidance Pattern) in order to cultivate adaptive response patterns 
(TRACs [Trigger, Response, Alternative Coping response]). Review will focus on value engagement and not 
on avoidance of aversive symptoms. 
WEEK 10: Stimulus Control / Committed Action: This session will focus on any additional modifications to 
environment or within participants’ social support system to enhance sustained compliance with TRF. 
Strategies for both groups will include increasing behavioral friction for impulsive eating, visual stimuli to 
increase the salience of long-term valued action, and eliciting social support to increase accountability to TRF 
goals. This could include placing a picture of one’s children or grandchildren near workout gear (family as 
value) or prominently placed quotes embracing struggle as a means of spiritual enhancement (religious value). 
WEEK 11-12: Remediation and Review: This session will focus on review of previous intervention materials 
and remediation of any coping skills deficits. The interventionist will also spend time revisiting the participants’ 
personal values, long term goals, areas of strength observed during the intervention, and individualized TRAPs 
and TRACs. 
 
8. Assessment of Neurocognitive Performance: The primary outcome of interest from the present study will 
be from assessments of neurocognitive performance. While neurocognitive changes observed in obese 

 
individuals have been documented in multiple domains,207,208 impairments are most common on tests of frontal 
lobe functioning, including “executive functions”,209-212 such as slowed information processing, set-shifting, and 
working memory.213-216 However, we also recognize that impairments in episodic and declarative memory 
performance are prototypically observed among individuals at risk for ADRD and also are common among 
individuals with obesity.217-222 We therefore adopted a 45-60 minute test battery as recommended by the 
Neuropsychological Working Group for vascular cognitive disorders,180 which provides an assessment of both 
executive functioning, memory, and processing speed across multiple subtests. We have used similar test 
batteries in our prior studies with success.37,107-109,223,224 The neuropsychological test battery will be 
administered in a fixed order with alternative forms, and we will alternate the order of test versions using a 
counterbalanced sequence in order to minimize practice effects. Tests will be streamlined with standard 
discontinuation rules applied to reduce subject frustration and overall burden. The neuropsychological test 
battery will be administered in a fixed order with alternative forms. We also will alternate the order of test 
versions using a counterbalanced sequence in order to minimize practice effects. The battery will consist of:  
 
Executive Function / Processing Speed 
Trail Making Test:185 This test is used to measure visuomotor attention and executive function. For Part 
A of the test, participants draw lines to connect consecutively number circles; for Part B, participants connect 
consecutively numbered and lettered circles by alternating between the two sequences (1-A-2-B-3-C, etc).   
Stroop Test:186 This test assesses executive function and set-shifting ability.  The standardized version 
of the Stroop test used in the proposed study consists of three sections: word, color, and color-word.   
Controlled Oral Word Association Test:187 This tests verbal flexibility and executive function as 
demonstrated by rapidly generating words to a particular letter (C-F-L; P-R-W; F-A-S) in 60 seconds.  
Animal Naming Test:188 This tests semantic fluency and verbal flexibility/executive function as 
demonstrated by rapidly generating words a specified category (in this case, animals) within a 60 seconds.   
Digit Symbol Substitution Test:189 This test from the Wechsler Adult Intelligence Scale measures 
executive functioning and attention.  Participants are asked to draw symbols that match one of 10 digits copied 
from a key.  Scores on this task are the number of correct symbols drawn in a 120-second time period.   
Digit Span Forward and Backwards:189 This test from the Wechsler Adult Memory Scale – IV assesses 
auditory attention and working memory. Participants repeat digits of increasing length, first in the forward 
direction as they have heard the numbers and then in reverse order. 
 
Memory 
Hopkins Verbal Learning Test – Revised: One of three equivalent forms of the HVLT-R will be used to 
assess verbal memory, retention, and recognition.  
Brief Visual Memory Test – Revised (BVMT-R):192,219,225 One of three equivalent alternate forms of the 
BVMT-R will be used to measure nonverbal learning, recognition, and delayed recall.  
 
Cognitive Complaints 
 
Everyday Cognition Scale (ECog): Detailed information regarding subjective cognitive compliants will 
be obtained using the ECog at both baseline and post-treatment assessments. The ECog measures an 
individual’s ability to perform everyday tasks relative to their reported ability 10 years ago. This instrument has 
been widely validated in MCI samples234 and correleates with the degree of underlying neuropathological 
burden.235 The ECog consists of 39 items rated from 1 (‘no change or actually performs better than 10 years 
ago’) to 4 (‘performs the task much worse than 10 years ago’). A Global Cognition score is calculated by 
averaging score ratings on all 39 items. Scores are also provided within six subdomains corresponding to 
Memory, Language, Visuospatial function, Planning, Organization, and Divided Attention.  
 
 
9. Ancillary Markers of Behavioral and Psychosocial Process Measures 
The following assessment procedures will be conducted on all participants at baseline and following 
completion of the intervention. These measures are designed to assess psychological processes that may 
have important, mechanistic associations with participant uptake and engagement of intervention materials.  
Acceptance and Action Questionnaire-II (AAQ-II):236 The AAQ-II is a 7-item measure of psychological 
inflexibility or the degree to which participants are able to remain mentally present and fully accepting of the 

 
present moment, without interference from distracting thoughts and feelings. Participants respond to items 
using a 7-point Likert scale from 1 (not at all true) to 7 (completely true).236  
Brief Experiential Avoidance Questionnaire (BEAQ):237 The BEAQ is a 15-item measure of experiential 
avoidance. Experiential avoidance provides an assessment of participants’ tendency to engage in cognitive or 
behavioral strategies to avoid uncomfortable internal experiences, including  behavioral avoidance, distress 
aversion, procrastination, distraction and suppression, repression and denial, and distress endurance. Sample 
items include: “The key to a good life is never feeling any pain” and “I would give up a lot not to feel bad”. 
 
General Self-Efficacy Scale (GSE):238 The GSE is a widely used instrument for measuring general 
levels of self-efficacy, a key psychological mechanistic marker within behavioral interventions. The GSE 
assesses individuals’ ability to maintain a broad and stable sense of personal competence and deal effectively 
with a variety of stressful situations.  
 
Perceived Stress Scale (10-item Version; PSS-10):239 The PSS is one of the most widely used 
psychological instruments for assessing participants’ perception of stress or the degree to which individuals 
appraise their life as stressful. Items assess the degree to which individuals feel their life is unpredictable, 
uncontrollable, and how overloaded they experience their lives to be.  
 
10. Ancillary Markers of Metabolic Risk Factors and Function 
Metabolic Function and Flexibility Markers:  Lipids, triglycerides, glucose, insulin, insulin-like 
growth factor, HbA1c, non-esterified fatty acids, total ketone bodies, brain derived neurotrophic factor, 
beta-hydroxybutyrate, lactate, amino acids, plasma kynurenine, kynurenic acid, tryptophan, non-esterified 
fatty acids, and acylcarnitines will all be assayed from fasting blood samples drawn between 0800 and 
0900 hr at a local LabCorp facility, which we have used in prior research.  
Inflammatory Markers: Inflammatory markers will be obtained using similar methodology as described 
above for our metabolic outcomes. Inflammatory markers will include IL-6, TNF-alpha, high sensitivity C-
reactive protein (CRP), IL-1β, IL-8, IL-10, myostatin, and glial fibrillary acidic protein (GFAP). We will also 
obtain samples for the purposes of assessing gene expression profiles.124,193   
Clinic Blood Pressure: Clinic SBP and DBP will be obtained during participant screening using 
standardized procedures. BP assessments will be repeated following completion of the 4-month protocol. 
BP assessments will be obtained following Joint National Committee (JNC 8) guidelines,240 in which BP is 
assessed in a quiet, temperature-controlled room within our clinical research facility. Participants will have 
been asked to refrain from smoking or ingesting caffeine for at least 30 minutes prior to their appointment 
time. BP measurements will be standardized for cuff size, position, environment, time of day, and 
medication dosing. After 5 minutes of quiet rest, four seated BP readings, each 2 minutes apart. The last 
three readings will be averaged to define clinic BP.  
Metabolic Syndrome Severity: Metabolic syndrome severity will be quantified using previously 
published z-score methods, in which metabolic syndrome components are aggregated using sex- and 
race-specific risk formulae, including waist circumference, triglycerides, HDL-C, SBP, and glucose.241 
Body Weight and Nutritional Habits:  Baseline and post-intervention body weight will be determined by 
a calibrated medical balance beam scale. We will assess dietary changes using widely validated report 
measures, including a 4-day food diary242,243 and a standard Food Frequency Questionnaire.  
 
Framingham Stroke Risk Profile: To quantify the degree of cerebrovascular risk in the sample, stroke 
risk factors will be aggregated using the revised Framingham Stroke Risk Profile Score,244 which incorporates 
data on SBP, antihypertensive medication use, diabetes status, prevalent CVD, atrial fibrillation, and left 
ventricular hypertrophy using gender-specific risk estimates.  
Cardiometabolic Medication Burden: To facilitate assessment and quantification of commonly used 
cardiometabolic medications that may influence the interpretation of metabolic outcomes data, we will quantify 
total cardiometabolic medication burden using the Daily Defined Dose (DDD), a standardized methodology 
developed by the World Health Organization.245,246  The DDD is a system for quantification of drug amount 
designed to enable comparison across drug classes (e.g., 1×DDD=150 mg irbesartan or 5 mg amlodipine),246 
which we have previously used in the context of behavioral trials.109,139 We will specifically explore the influence 
of statins on any observed associations, given their possible influence on markers of phospholipid change.  
 
  
 
 
 

 
Title: Assessing the feasibility and acceptability of a Time Restricted Feeding intervention among older adults 
with Mild Cognitive Impairment 
 
 
 
 
Protocol Date: 7/1/2025 
NCT#:  
NCT05997316 
 
Data Management and Analysis  
Data will be entered into a centrally managed Redcap database. Assessments of TRF feasibility and 
acceptability will be assessed by carefully characterizing accrual, adherence, and retention for the 12-week 
TRF trial (Aim 1). Feasibility will be assessed by accrual in the study timeline, 90% adherence to study 
procedures, and 90% of participants completing the protocol. For our analyses of cognitive and metabolic 
changes following TRF (Aim 2) we will use repeated measures, linear mixed effect models in which cognitive 
performance is modeled using mean rank approach with in each cognitive domain, as recommended by 
O’Brien. Within these analyses, we will adjust for age, biological sex, and the pretreatment level of the 
respective outcome, with the time effect as our variable of interest. Biological sex will be addressed both by 
adjusting for biological sex in our regression analyses and testing for potential moderation of any observed 
changes in cognitive or metabolic outcomes by biological sex. This composite approach has several 
advantages over testing multiple individual endpoints, including increased reliability, enhanced precision of the 
treatment estimates, improved power, and minimization of Type I Error. Within this modeling framework, 
analyses are powered to detect differences in the primary ‘gatekeeper’ model at the P = .05 level. If the primary 
model is found to be significant, examination of individual components of the global score are examined in 
secondary, explanatory analyses in which the significance level is propagated forward. A parallel model will be 
used to examine changes in metabolic function, in which diverse measures of metabolic function and flexibility 
are combined into a global mean-rank score. For our analyses of fasting-dependent changes in cognitive and 
metabolic function (Aim 3), we will explore fasting-dependent changes utilizing a parallel, mixed effect 
modeling strategy with fasting state (non-fasted vs. fasted) as an additional categorical predictor, with the time 
X fasting state interaction as our predictor of interest. Patterns of missing data will be characterized using 
Rubin’s criteria and managed accordingly using Harrell’s multiple imputation (mult.impute) procedure in R. We 
will supplement our primary regression analyses with an examination of the treatment effect among 
completers199 using Rubin’s Complier Average Causal Effect (CACE) model200 using SAS (Cary, NC) or R. 
Power Analysis: Power for Aim 2 was based previous estimates from our lifestyle trials. We conducted our 
power analyses with the following assumptions: 1) an initial sample size of 40 participants with 15% attrition at 
4-months, 2) alpha of 0.05, and 3) an R2 of 0.50 between model covariates and the outcome of interest. Based 
on these assumptions, we anticipate power to detect improvements of d = 0.70 between baseline and post-
treatment assessments, paralleling improvements from our recent behavioral weight loss trial in adults with 
resistant hypertension.36 
 
 

 
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