Ignite Creation Date:
2024-10-25 @ 8:05 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06588946
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-05
Brief Title:
Brain Effects of Exogenous β-OHB Supplementation in Older Adults
Sponsor:
None
Organization:
None
Study Overview
Official Title:
The Effect of Exogenous β-OHB Supplementation on Cerebral Blood Flow and Functional Brain Characteristics in Adults With Subjective Cognitive Decline
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Interventions that reduce dementia risk are urgently needed for our aging Canadian population In particular people with subjective cognitive decline SCD have a greater risk of developing dementia than cognitively normal individuals Impaired cerebral blood flow CBF and cerebral glucose hypometabolism are leading mechanisms underlying dementia that could be ideal interventional targets Literature and our recent work have shown that oral consumption of ketone monoesters KME can improve CBF and cerebral metabolism which in turn can improve cognition
Our multidisciplinary project will examine changes in 60 older adults 50 female aged 55-75 30group acutely after a single KME dose and following a 14-day oral supplementation of either placebo or KME The primary objectives are to measure changes to cognition CBF functional brain connectivity vascular function and blood-borne factors This novel study aims to advance our understanding of how combatting vascular impairments could improve CBF and cognition in older adults
Our multidisciplinary project will examine changes in 60 older adults 50 female aged 55-75 30group acutely after a single KME dose and following a 14-day oral supplementation of either placebo or KME The primary objectives are to measure changes to cognition CBF functional brain connectivity vascular function and blood-borne factors This novel study aims to advance our understanding of how combatting vascular impairments could improve CBF and cognition in older adults
Detailed Description:
BACKGROUND
Alzheimers Disease and related dementias are debilitating health conditions that can cause individuals to lose their ability to communicate take care of themselves and remember people places or eventsAlzheimers Association 2019 Alzheimers Society of Canada 2010 GBD 2019 Dementia Forecasting Collaborators 2022 By 2031 dementia is expected to affect nearly 1 million people in Canada with associated healthcare costs in excess of 166 billionAlzheimers Society of Canada 2010 Delaying dementia onset by two years could reduce the total economic burden of dementia by 25 over 30 yearsAlzheimers Society of Canada 2010 GBD 2019 Dementia Forecasting Collaborators 2022 People who report subjective cognitive decline SCD have a 3 to 6 times greater risk of progressing to clinical dementia compared to cognitively normal adultsCunnane et al 2020 SCD refers to the subjective experience of worsening cognitive abilities like attention flexible thinking and memory in the absence of objectively measured cognitive impairmentJack et al 2010 Nation et al 2019 SCD is considered the first clinical manifestation on the dementia continuum and represents the critical intervention period to prevent or delay dementia progressionJessen et al 2010 Iadecola 2013 McCrimmon et al 2012
Impaired cerebral glucose metabolism and cerebral blood flow CBF are putative mechanisms underlying dementia pathogenesis that can precede other clinical biomarkers by decadesCunnane et al 2020 Iadecola 2013 McCrimmon et al 2012 Cerebral hypometabolism and impaired CBF in SCD negatively impact neuronal function specifically in modelling the Default Mode Network DMN from functional magnetic resonance imaging fMRI dataLi et al 2017 The DMN is activated during wakeful rest reciprocally inhibited during cognitive engagement and directly impacts attention future planning and memoryPetrella et al 2011 Changes in DMN activity can predict eventual conversion to dementia in people with SCD or mild cognitive impairment Accordingly mitigation of cerebral hypometabolism and impaired CBF are critical interventional targets to reduce the risk of conversion to dementia from SCD Despite this knowledge pharmacological interventions eg anti-amyloid agentsMujica-Parodi et al 2020 are largely ineffective highlighting the need for innovation to protect brain health in those with SCD
Emerging evidence suggests that dietary interventions that increase plasma ketone bodies eg ketogenic diets can improve cerebral metabolism and enhance CBF in SDCKrikorian et al 2012 Roy et al 2022 Cunnane et al 2016 Svart et al 2018 Ketogenic diets have poor adherence given that they are highly restrictive and gastrointestinal complaints are common Emerging work from our lab shows that ingesting oral ketone monoester KMEeg beta-hydroxybutyrate β-OHB supplements can mimic the beneficial effects of a ketogenic diet on brain health without dietary restriction or gastrointestinal complaints KME supplementation has been shown to increase CBF and cognition in healthy adults those with impaired glucose metabolism Type 2 DiabetesNeudorf et al 2024Jensen et al 2020 and obesityWalsh et al 2021ab Although not entirely understood the improved stability of cerebral energy metabolism provided by elevated KME levels through supplementation may increase CBFWalsh et al 2021a KME supplementation has also shown improved cerebrovascular function and an increase in neuroprotective proteins eg brain-derived neurotrophic factor BDNF suggesting that β-OHB may signal neuroprotective properties with elevated concentrationsWalsh et al 2021b Shimazu et al 2013 Han et al 2018 Promisingly KME supplementation could be a multi-pronged therapeutic to prevent SCD progression to dementia during this critical intervention window
Purpose The purpose and primary outcome of this study is to investigate the effects of a 14-day KME supplementation intervention on indices of CBF and cognitive brain function in older adults with SCD in a fasted non-supplemented state AIM 1 The secondary outcome is to investigate if the 14-day intervention alters the acute response to a single KME supplement dose with respect to CBF and cognitive brain function relative to pre-intervention AIM 2 We hypothesize that compared to pre-intervention and placebo a 14-day KME supplementation intervention will increase CBF increase DMN functional connectivity improve cognitive performance AIM 1 and produce an elevated response to a single dose AIM 2
METHODS
Recruitment We will obtain permission from potential participants to contact them via email Participants will be asked to contact the research team to confirm their interest in participating in this study A phone call or virtual meeting ie Zoom will be scheduled for participants to confirm their interest in participating and to book Study Visit 1 to obtain written informed consent perform the cognitive screening tests MoCA and PRMQ MRI safety screening and have body metrics height weight waist circumference measured
We will invite SCD participants enrolled in our current Alzheimers Society funded study to participate We work closely with the MacSeniors Exercise Program at the Physical Activity Centre of Excellence PACE and recruitment posters will be placed within PACE and the Ivor Wynne Centre of McMaster University We will obtain consent from the staff at PACE before posting any recruitment posters We will place an ad in Coffee News a popular newspaper column local to Hamilton newspapers as well as various social media websites We also work closely with the McMaster Institute on Research in Aging MIRA geriatricians eg Dr Papaioannou at the Geras Centre for Aging Research and the local Alzheimers society of Brant Haldimand Norfolk Hamilton Halton httpsalzdaca to engage with older adults in the Hamilton community Dr Mbuagbaw will oversee the random allocation of eligible participants to a group Recruitment posters will also be placed in local physician offices adult community centres and recreation centres throughout the Hamilton region with permission
Sample Size Determination Our previous study of global CBF changes in middle-to-older adults with obesity following a 14-day KME supplementation informed our sample size calculation which found that global CBF was increased by 12 in adults with obesity as measured by duplex ultrasound of the extracranial arteriesWalsh et al 2021a corresponding to a large effect size Using GPower v3194 we conservatively estimated a required sample size of 24group n48 total based on a medium effect size 90 power and alpha level of 005 two-tailed t-test of the null hypothesis that there is no difference between groups Importantly this sample size also provides adequate power for secondary outcomesMujica-Parodi et al 2020 Walsh et al 2021a To account for 10 drop out and data quality concerns 60 participants 30group 50 female will be recruited We expect 4 to 6 eligible participants per month based on the recruitment rate of our current Alzheimers Society funded KME supplementation study in older adults allowing a conservative timeline of 20-months for recruitment screening and data collection activities Data processing and statistical analyses will be performed within the following 6-months
Study Design In total the study will involve 3 visits at the Imaging Research Centre located in St Josephs Hospital in Hamilton During Visit 1 all interested individuals will complete an eligibility screening study visit to establish inclusionexclusion Participants will also be introduced to the lab the different tests that we will run and will be given the chance to practice the tests that will be completed during the experimental visits Visits 2 and 3 Data will be collected at two time points 1 Pre-intervention Visit 2 baseline and post-intervention Visit 3 following 14-day intervention All outcome measures will be collected at the Imaging Research Center at St Josephs Healthcare Hamilton 3T GE MRI with the estimated total time commitment of 5 hours 25 hours per visit Participants will be provided with a standardized dinner and breakfast before both study visits Energy 50 carbohydrate 30 fat 20 proteinHarris and Benedict 1918 to control for potential dietary influences on brain function Meals will be provided via a local meal preparation service Heart to Home Meals Hamilton Participants will be asked to refrain from alcohol and structured exercise and limit physical activity to their activities of daily living on the day before each trial
Eligible participants will complete two identical study visits for prepost-intervention comparisons Written informed consent will be obtained before data collection at the first study visit Participants will arrive at the MRI suite in the morning for about 8am or 9am following an 8-hour overnight fast Both study visits will include outcome measures collection ie brain MRI scanning cognitive testing venous blood samples at a fasted non-supplemented state and repeated 30-minutes after a single dose of placebo or KME All participants will then receive a 14-day supply of placebo or KME doses to consume one dose thrice daily Between Visits 2 and 3 participants will consume a placebo or KME dose 3x daily aligning with breakfast lunch and dinner A study Visit 3 will occur 14-days later to repeat the data collection protocol
Demographic information will also be collected at the beginning of the first study visit to obtain information regarding medication use medical history age years of education and sex and gender-based variables This information will be collected using a participant history questionnaire
Statistical Analysis Plan Descriptive statistics means SD and frequencies and Q-Q plots of residuals will be used for normality and skewness testing to assess model assumptions Linear- mixed effects models with fixed effects of time pre vs post condition placebo vs KME and time by condition interaction and random effects of participants will be used to compare all primary and secondary outcome data We will recruit equal numbers of males and females report data disaggregated by sex and explore potential sex differences for all outcomes in sub-analyses We will also explore potential influences of gender identity in a sub-analysis All data will be reported following the 2010 CONSORT guidelines for RCTsMoher et al 2010
Alzheimers Disease and related dementias are debilitating health conditions that can cause individuals to lose their ability to communicate take care of themselves and remember people places or eventsAlzheimers Association 2019 Alzheimers Society of Canada 2010 GBD 2019 Dementia Forecasting Collaborators 2022 By 2031 dementia is expected to affect nearly 1 million people in Canada with associated healthcare costs in excess of 166 billionAlzheimers Society of Canada 2010 Delaying dementia onset by two years could reduce the total economic burden of dementia by 25 over 30 yearsAlzheimers Society of Canada 2010 GBD 2019 Dementia Forecasting Collaborators 2022 People who report subjective cognitive decline SCD have a 3 to 6 times greater risk of progressing to clinical dementia compared to cognitively normal adultsCunnane et al 2020 SCD refers to the subjective experience of worsening cognitive abilities like attention flexible thinking and memory in the absence of objectively measured cognitive impairmentJack et al 2010 Nation et al 2019 SCD is considered the first clinical manifestation on the dementia continuum and represents the critical intervention period to prevent or delay dementia progressionJessen et al 2010 Iadecola 2013 McCrimmon et al 2012
Impaired cerebral glucose metabolism and cerebral blood flow CBF are putative mechanisms underlying dementia pathogenesis that can precede other clinical biomarkers by decadesCunnane et al 2020 Iadecola 2013 McCrimmon et al 2012 Cerebral hypometabolism and impaired CBF in SCD negatively impact neuronal function specifically in modelling the Default Mode Network DMN from functional magnetic resonance imaging fMRI dataLi et al 2017 The DMN is activated during wakeful rest reciprocally inhibited during cognitive engagement and directly impacts attention future planning and memoryPetrella et al 2011 Changes in DMN activity can predict eventual conversion to dementia in people with SCD or mild cognitive impairment Accordingly mitigation of cerebral hypometabolism and impaired CBF are critical interventional targets to reduce the risk of conversion to dementia from SCD Despite this knowledge pharmacological interventions eg anti-amyloid agentsMujica-Parodi et al 2020 are largely ineffective highlighting the need for innovation to protect brain health in those with SCD
Emerging evidence suggests that dietary interventions that increase plasma ketone bodies eg ketogenic diets can improve cerebral metabolism and enhance CBF in SDCKrikorian et al 2012 Roy et al 2022 Cunnane et al 2016 Svart et al 2018 Ketogenic diets have poor adherence given that they are highly restrictive and gastrointestinal complaints are common Emerging work from our lab shows that ingesting oral ketone monoester KMEeg beta-hydroxybutyrate β-OHB supplements can mimic the beneficial effects of a ketogenic diet on brain health without dietary restriction or gastrointestinal complaints KME supplementation has been shown to increase CBF and cognition in healthy adults those with impaired glucose metabolism Type 2 DiabetesNeudorf et al 2024Jensen et al 2020 and obesityWalsh et al 2021ab Although not entirely understood the improved stability of cerebral energy metabolism provided by elevated KME levels through supplementation may increase CBFWalsh et al 2021a KME supplementation has also shown improved cerebrovascular function and an increase in neuroprotective proteins eg brain-derived neurotrophic factor BDNF suggesting that β-OHB may signal neuroprotective properties with elevated concentrationsWalsh et al 2021b Shimazu et al 2013 Han et al 2018 Promisingly KME supplementation could be a multi-pronged therapeutic to prevent SCD progression to dementia during this critical intervention window
Purpose The purpose and primary outcome of this study is to investigate the effects of a 14-day KME supplementation intervention on indices of CBF and cognitive brain function in older adults with SCD in a fasted non-supplemented state AIM 1 The secondary outcome is to investigate if the 14-day intervention alters the acute response to a single KME supplement dose with respect to CBF and cognitive brain function relative to pre-intervention AIM 2 We hypothesize that compared to pre-intervention and placebo a 14-day KME supplementation intervention will increase CBF increase DMN functional connectivity improve cognitive performance AIM 1 and produce an elevated response to a single dose AIM 2
METHODS
Recruitment We will obtain permission from potential participants to contact them via email Participants will be asked to contact the research team to confirm their interest in participating in this study A phone call or virtual meeting ie Zoom will be scheduled for participants to confirm their interest in participating and to book Study Visit 1 to obtain written informed consent perform the cognitive screening tests MoCA and PRMQ MRI safety screening and have body metrics height weight waist circumference measured
We will invite SCD participants enrolled in our current Alzheimers Society funded study to participate We work closely with the MacSeniors Exercise Program at the Physical Activity Centre of Excellence PACE and recruitment posters will be placed within PACE and the Ivor Wynne Centre of McMaster University We will obtain consent from the staff at PACE before posting any recruitment posters We will place an ad in Coffee News a popular newspaper column local to Hamilton newspapers as well as various social media websites We also work closely with the McMaster Institute on Research in Aging MIRA geriatricians eg Dr Papaioannou at the Geras Centre for Aging Research and the local Alzheimers society of Brant Haldimand Norfolk Hamilton Halton httpsalzdaca to engage with older adults in the Hamilton community Dr Mbuagbaw will oversee the random allocation of eligible participants to a group Recruitment posters will also be placed in local physician offices adult community centres and recreation centres throughout the Hamilton region with permission
Sample Size Determination Our previous study of global CBF changes in middle-to-older adults with obesity following a 14-day KME supplementation informed our sample size calculation which found that global CBF was increased by 12 in adults with obesity as measured by duplex ultrasound of the extracranial arteriesWalsh et al 2021a corresponding to a large effect size Using GPower v3194 we conservatively estimated a required sample size of 24group n48 total based on a medium effect size 90 power and alpha level of 005 two-tailed t-test of the null hypothesis that there is no difference between groups Importantly this sample size also provides adequate power for secondary outcomesMujica-Parodi et al 2020 Walsh et al 2021a To account for 10 drop out and data quality concerns 60 participants 30group 50 female will be recruited We expect 4 to 6 eligible participants per month based on the recruitment rate of our current Alzheimers Society funded KME supplementation study in older adults allowing a conservative timeline of 20-months for recruitment screening and data collection activities Data processing and statistical analyses will be performed within the following 6-months
Study Design In total the study will involve 3 visits at the Imaging Research Centre located in St Josephs Hospital in Hamilton During Visit 1 all interested individuals will complete an eligibility screening study visit to establish inclusionexclusion Participants will also be introduced to the lab the different tests that we will run and will be given the chance to practice the tests that will be completed during the experimental visits Visits 2 and 3 Data will be collected at two time points 1 Pre-intervention Visit 2 baseline and post-intervention Visit 3 following 14-day intervention All outcome measures will be collected at the Imaging Research Center at St Josephs Healthcare Hamilton 3T GE MRI with the estimated total time commitment of 5 hours 25 hours per visit Participants will be provided with a standardized dinner and breakfast before both study visits Energy 50 carbohydrate 30 fat 20 proteinHarris and Benedict 1918 to control for potential dietary influences on brain function Meals will be provided via a local meal preparation service Heart to Home Meals Hamilton Participants will be asked to refrain from alcohol and structured exercise and limit physical activity to their activities of daily living on the day before each trial
Eligible participants will complete two identical study visits for prepost-intervention comparisons Written informed consent will be obtained before data collection at the first study visit Participants will arrive at the MRI suite in the morning for about 8am or 9am following an 8-hour overnight fast Both study visits will include outcome measures collection ie brain MRI scanning cognitive testing venous blood samples at a fasted non-supplemented state and repeated 30-minutes after a single dose of placebo or KME All participants will then receive a 14-day supply of placebo or KME doses to consume one dose thrice daily Between Visits 2 and 3 participants will consume a placebo or KME dose 3x daily aligning with breakfast lunch and dinner A study Visit 3 will occur 14-days later to repeat the data collection protocol
Demographic information will also be collected at the beginning of the first study visit to obtain information regarding medication use medical history age years of education and sex and gender-based variables This information will be collected using a participant history questionnaire
Statistical Analysis Plan Descriptive statistics means SD and frequencies and Q-Q plots of residuals will be used for normality and skewness testing to assess model assumptions Linear- mixed effects models with fixed effects of time pre vs post condition placebo vs KME and time by condition interaction and random effects of participants will be used to compare all primary and secondary outcome data We will recruit equal numbers of males and females report data disaggregated by sex and explore potential sex differences for all outcomes in sub-analyses We will also explore potential influences of gender identity in a sub-analysis All data will be reported following the 2010 CONSORT guidelines for RCTsMoher et al 2010
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None