- Email: [email protected]
Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study
Accepted Manuscript Title: Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of Mild Cognitive Impairment: A case study Authors: Kelly J. Gibas, Kaitlyn Dahlgren PII: DOI: Reference:
S1871-4021(18)30116-4 https://doi.org/10.1016/j.dsx.2018.04.031 DSX 979
To appear in:
Diabetes & Metabolic Syndrome: Clinical Research & Reviews
Please cite this article as: Gibas KJ, Dahlgren K, Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of Mild Cognitive Impairment: A case study, Diabetes and Metabolic Syndrome: Clinical Research and Reviews (2010), https://doi.org/10.1016/j.dsx.2018.04.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Ketogenic diet, high intensity interval training (HIIT) and memory training in the
Dr. Kelly J. Gibas
SC RI PT
treatment of Mild Cognitive Impairment: A case study
Doctorate of Behavioral Health Sciences
Human Bioenergetics & Applied Health Science Bethel University, Minnesota, USA
N
U
[email protected]
A
Kaitlyn Dahlgren (Corresponding Author)
CC
EP
TE
D
M
Human Bioenergetics & Applied Health Science Bethel University, Minnesota, USA
Abstract
A
Alzheimer’s disease (AD) deaths have increased by 89% since 2000 (CDC, 2016). This alarming trajectory of neurological disease highlights the failure of current best practice. Deteriorating brain fuel supply is the nemesis of intact neurological health. Cerebral hypometabolism associated with AD occurs years before onset. Both the ketogenic diet and calorie restriction (fasting) lead to a compensatory rise in ketones to improve energy deficits in the brain derived from cerebral insulin resistance. Two forms of ketone bodies, -hydroxybutyrate and
acetoacetate, fuel the brain during starvation, fasting and strenuous exercise. Ketones are neuroprotective agents that shelter the aging brain from memory loss and neurodegeneration. Induced ketone production has been shown to ameliorate mitochondrial function, reduce the expression of apoptotic and inflammatory mediators and provide neuroprotection to cells (Lange et al., 2017). This case study highlights an innovative research design aimed at attenuating
SC RI PT
memory decline in a 57 year old female previously diagnosed with comorbid mild cognitive
impairment (MCI) and metabolic syndrome (MetS). Mild cognitive impairment is a predementia syndrome known to precede AD (Michaud et al, 2017). The 12-week intervention included
ketogenic nutrition protocol, high intensity interval training (HIIT) and memory training using the PEAK brain training app. Memory function was assessed via the MoCA (Montreal
Cognitive Assessment) pre/post intervention. Physiological biomarkers for MetS including
U
HOMA-IR(homeostatic model assessment of insulin resistance), triglyceride/HDL ratio, HgA1c,
N
fasting triglycerides and HDL were measured pre/post intervention. MoCA baseline score was 22/30 (MCI); post intervention score: 30/30 (normal). MetS biomarker improvements also
M
A
reflected statistical significance.
Keywords
Introduction
TE
diet; MoCA; memory loss
D
Alzheimer’s disease; Mild Cognitive Impairment (MCI); Metabolic Syndrome (MetS); ketogenic
EP
Every 66 seconds, someone in the United States develops Alzheimer’s disease. It kills more than breast cancer and prostate cancer combined. The current 5.5 million cases of AD is projected to
CC
reach 16 million by 2050, costing the nation 1.1 trillion dollars (CDC, 2016). Neuroprotective strategies are critical to reversing this pandemic disease. Demetrius & Driver (2014) posit that
A
elucidating the origin of the disease is fundamental to prevention. The predominant amyloid cascade model contends that the imbalance in the production and clearance of beta-amyloid is responsible for the pathogenesis and progression of AD. An opposing bioenergetic theory posits that the primary cause of AD is age-induced mitochondrial dysregulation resulting in hypometabolic brain circuitry (Demetrius & Driver, 2014; Gibas, 2017). Supplying the brain with alternative fuel through nutritional treatments designed to raise plasma ketone levels, particularly
in the early stages of AD, may not only prevent further degeneration but reverse the condition altogether (Cunnane et al., 2016; Gibas, 2017). Ketone delivery to the brain alleviates hypometabolism and ameliorates neuronal capacity. Ketone bodies protect neurons against neuronal injury caused by starvation and 1-42, an amyloid precursor protein (Kashiwaya, et al., 2000). 1-42 is toxic to hippocampal cells. Kashiwaya et al. exposed cultured hippocampal neurons
SC RI PT
to 1-42, which reduced the number of cells as well as the neurite number and length
compared control. The cells were simultaneously exposed to -hydroxybutyrate. The surviving cell number doubled and the cell size and neurite outgrowth increased compared to the cells
exposed exclusively 1-42. The researchers exposed the surviving hippocampal neurons to ketone bodies for 14 additional hours. The cells increased in number and neurite number
compared to control cells (Kashiwaya et al., 2000). This finding suggests that ketones can act as
U
growth factors to hippocampal neurons and protect against mitochondrial defects that contribute
N
to the pathogenesis of AD. The therapeutic potential of -hydroxybutyrate for improving and
M
A
restoring memory function is the topic of this case study.
Methods
A 57-year old female previously diagnosed with comorbid MCI and MetS completed a 12-week
D
therapeutic intervention designed to restore memory loss and reverse MetS biomarkers. A
TE
nutrition protocol purposed at raising plasma ketones through low a carbohydrate/high fat diet, calorie restriction (fasting) and high intensity interval training was administered by health care
EP
professionals and the student researcher for 12 consecutive weeks. The patient was instructed to play the PEAK brain training games on a mobile device five days per week. PEAK brain training
CC
domains utilized were language, problem solving, mental agility, memory and focus. The PEAK application is designed to strengthen the frontal, parietal, occipital, prefrontal cortex, temporal, angular gyrus, posterior cingulate cortex and hippocampus (Whiteford, 2014). Biomarkers for
A
MetS were measured via blood serum pre/post intervention and include fasting insulin, blood lipids, blood ketones and risk ratios: HOMA-IR and the triglyceride/HDL. Memory function was assessed via MoCA at baseline and post intervention by a licensed professional clinical counselor (LPCC). Nutritional monitoring and blood ketones were measured each week by healthcare professionals. Twenty minutes of high intensity interval training was administered by the student researcher every other week for a total of six sessions. The high intensity exercise
involved alternating periods of vigorous exercise with periods of recovery. Research has shown that HIIT can promote substantial improvements in insulin sensitivity, glucose control, and improvement in the biomarkers of a multitude of metabolic diseases (Francois & Little, 2015).
Case Report
SC RI PT
The patient, a 57-year-old female presenting with comorbid mild cognitive impairment and
metabolic syndrome is employed full-time as a pediatric respiratory nurse and stays active by swimming and participating in a multitude of exercise classes despite her measured cognitive
and metabolic deficits. She joined the treatment program to prevent further cognitive decline.
The memory complaints were related primarily to tasks of daily living such as remembering a
grocery list or people’s names. She also experienced problems with staying focused on the task
U
at hand or forgetting why she entered a room. The patient was previously diagnosed with MetS
N
and MCI. Although she is a breast cancer survivor and taking thyroid medication, the patient is
A
in good health. There is no family history of Alzheimer’s disease.
M
Results
One adult female was enrolled in the 12-week intervention program. Within three weeks, the
D
patient entered into physiological ketosis at 1.1 mg/dL, as measured by the Abbott Precision Xtra
TE
ketone meter (normal range 0.5-2.0 mg/dL). Triglycerides decreased by nearly 50% by the fourth week of the intervention. The MoCA score increased by 26% from baseline; 22/30 to 30/30 (normal range 26-30). The improvement in memory is statistically significant and
EP
clinically relevant to this case. The significant MetS biomarker improvements are also pertinent, as the triglyceride/HDL ratio and VLDL are directly correlated with increased cerebral
CC
metabolism and marked reductions in cognitive decline (Cunnane et al., 2016). See Table 1
A
below for results summary.
The patient experienced a corollary increase in all domains of the PEAK brain training application suggesting improved brain metabolism. See Table 2 below.
Data
Statistically significant results were recorded in all aspects of the intervention including memory, MetS biomarkers and PEAK brain training domains relevant to brain metabolism. See Figures
M
A
N
U
SC RI PT
1-4 below.
A
CC
EP
TE
D
Fig. 1. The patient’s HDL increased by 26% after the 12-week intervention with an adjusted Rsquared of 0.97 reflecting statistical significance.
N
U
SC RI PT
Fig. 2. The patient’s PEAK brain training overall total score increased by 83 points after the 12week intervention with an adjusted R-squared of 0.96 reflecting statistical significance.
A
CC
EP
TE
D
M
A
Fig. 3. The patient’s PEAK brain training score in the area of FOCUS increased by 115% after the 12-week intervention with an adjusted R-squared of 0.93 reflecting statistical significance.
Fig. 4. The patient’s MoCA score increased 26% after the 12-week intervention with an adjusted R-squared of 0.89 reflecting statistical significance. Discussion
Early stages of AD induce region-specific declines in brain glucose metabolism. A vicious cycle ensues ultimately leading to AD and dementia. Brain hypo-metabolism leads to chronic brain energy deprivation, deteriorating neuronal mitochondrial function, further decline in glucose demand and finally progression of cognitive impairment (Lange et al., 2017). According to the bioenergetic model, AD is governed by the dynamics of the mitochondria in neurons (Demetrius
SC RI PT
& Driver, 2014; Gibas, 2017). Ketone bodies have neuroprotective features that not only feed the starving brain but also favor cell growth and regeneration (Lange, et al, 2017). Several
clinical studies demonstrate that nutritional treatments designed raise plasma ketones improve brain metabolism and restore mitochondrial integrity (Cunanne et al, 2016; Henderson et al., 2009; Hertz & Chen, 2015; Lange et al, 2017; Paoli et al., 2014; & Reger et al., 2004).
This case study of a patient with comorbid MCI and MetS suggests that a ketogenic diet, high
U
intensity interval exercise, and memory training may reverse early stage memory loss (MCI) and
N
improve/normalize MetS biomarkers. The results of this case study are consistent with the aforementioned clinical trials. Elucidating the pathogenesis of AD through the lens of metabolic
A
disease will help promote metabolic interventions aimed at glucose regulation, restoration of
M
insulin sensitivity and improved brain metabolism.
Limitations of this study include the specific and small population. In future studies, it would be
D
beneficial to expand the sample to include males as well as a variety of ages.
TE
Conclusion
Nutritional ketogenic treatment approaches for brain hypo-metabolism seem to yield the best results in early stage memory loss in AD. Ketone bodies have been shown to have
EP
neuroprotective features that preserve mitochondrial integrity, cerebral energy circuits and promote healthy neuronal growth. Several clinical trials have demonstrated the neurological
CC
efficacy of high fat, low carbohydrate ketogenic diets. This novel approach of changing nutrition status for those with early stage memory loss warrants further clinical investigations based on the
A
promising results produced in this case study and recent clinical trials.
Statement of Ethics
Conflict of Interest The authors declare that there is no conflict of interest. Disclosure Statement
U
Sources of support (funding): No funding was required.
SC RI PT
The study was approved by an ethics committee. All the participants gave their written informed consent before taking part in the study.
N
Author Contributions
M
A
All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept.
D
Research in Context
EP
TE
1. Systematic Review: The authors reviewed the literature using traditional (e.g., google scholar) sources. While the role of a ketogenic diet applied to Alzheimer's disease is not yet as widely studied as other aspects of AD physiology, there have been several recent publications describing the clinical aspects of a ketogenic diet. These relevant citations are appropriately cited.
CC
2. Interpretation: Our findings led to an integrated hypothesis describing the role of the high fat ketogenic diet. This hypothesis is consistent with nonclinical and clinical findings currently in the public domain.
A
3. Future Directions: The manuscript proposes a framework for the generation of new hypotheses and the conduct of additional studies regarding this area of study. Examples include further understanding: (a) the role of MCT oil in treatment of AD; (b) the potential reversibility of neuronal damage in the AD brain.
References
SC RI PT
Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimers disease. Annals of the New York Academy of Sciences. 2016;1367(1):12-20. doi:10.1111/nyas.12999. Demetrius LA, Driver JA. Preventing Alzheimer’s disease by means of natural selection. Journal of The Royal Society Interface. 2014;12(102):20140919-20140919. doi:10.1098/rsif.2014.0919. Francois ME, Little JP. Effectiveness and Safety of High-Intensity Interval Training in Patients With Type 2 Diabetes. Diabetes Spectrum. 2015;28(1):39-44. doi:10.2337/diaspect.28.1.39.
N
U
Gibas MK, Gibas KJ. Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2017;11. doi:10.1016/j.dsx.2017.03.022.
M
A
Gibas KJ. The starving brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimers disease (AD). Neurochemistry International. 2017;110:5768. doi:10.1016/j.neuint.2017.09.004.
TE
D
Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimers disease: a randomized, double-blind, placebocontrolled, multicenter trial. Nutrition & Metabolism. 2009;6(1):31. doi:10.1186/1743-7075-631.
EP
Hertz L, Chen Y, Waagepetersen HS. Effects of ketone bodies in Alzheimers disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. Journal of Neurochemistry. 2015;134(1):7-20. doi:10.1111/jnc.13107.
CC
Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta Hydroxybutyrate protects neurons in models of Alzheimers and Parkinsons disease. Proceedings of the National Academy of Sciences. 2000;97(10):5440-5444. doi:10.1073/pnas.97.10.5440.
A
Lange KW, Lange KM, Makulska-Gertruda E, et al. Ketogenic diets and Alzheimer’s disease. Food Science and Human Wellness. 2017;6(1):1-9. doi:10.1016/j.fshw.2016.10.003. Michaud TCAL, Su D, Siahpush M, Murman DL. The Risk of Incident Mild Cognitive Impairment and Progression to Dementia Considering Mild Cognitive Impairment Subtypes . Dementia and Geriatric Cognitive Disorders Extra. 2017;7(1):15-29. doi:10.1159/000452486.
Paoli A, Bosco G, Camporesi EM, Mangar D. Ketosis, ketogenic diet and food intake control: a complex relationship. Frontiers in Psychology. 2015;6. doi:10.3389/fpsyg.2015.00027. Reger MA, Henderson ST, Hale C, et al. Effects of β-hydroxybutyrate on cognition in memoryimpaired adults. Neurobiology of Aging. 2004;25(3):311-314. doi:10.1016/s01974580(03)00087-3.
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TE
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Whiteford, K.M. (2014). Testing the Validity of the PEAK Relational Training System in Assessing Language & Cognition after Brain Injury (Unpublished doctoral dissertation). Southern Illinois University Carbondale, Illinois.
Table 1: Percent Improvement MetS Biomarkers Percent Improvement
Triglycerides
56%
HDL
26%
SC RI PT
Variable
Triglyceride/HDL ratio
51%
VLDL
37%
U
Table 2: Improvement in PEAK brain training scores Percent
114%
Focus
115%
Memory
27%
Mental Agility
105%
Language
A
CC
EP
TE
30%
M
A
Problem Solving
N
Improvement
D
Variable
S1871-4021(18)30116-4 https://doi.org/10.1016/j.dsx.2018.04.031 DSX 979
To appear in:
Diabetes & Metabolic Syndrome: Clinical Research & Reviews
Please cite this article as: Gibas KJ, Dahlgren K, Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of Mild Cognitive Impairment: A case study, Diabetes and Metabolic Syndrome: Clinical Research and Reviews (2010), https://doi.org/10.1016/j.dsx.2018.04.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Ketogenic diet, high intensity interval training (HIIT) and memory training in the
Dr. Kelly J. Gibas
SC RI PT
treatment of Mild Cognitive Impairment: A case study
Doctorate of Behavioral Health Sciences
Human Bioenergetics & Applied Health Science Bethel University, Minnesota, USA
N
U
[email protected]
A
Kaitlyn Dahlgren (Corresponding Author)
CC
EP
TE
D
M
Human Bioenergetics & Applied Health Science Bethel University, Minnesota, USA
Abstract
A
Alzheimer’s disease (AD) deaths have increased by 89% since 2000 (CDC, 2016). This alarming trajectory of neurological disease highlights the failure of current best practice. Deteriorating brain fuel supply is the nemesis of intact neurological health. Cerebral hypometabolism associated with AD occurs years before onset. Both the ketogenic diet and calorie restriction (fasting) lead to a compensatory rise in ketones to improve energy deficits in the brain derived from cerebral insulin resistance. Two forms of ketone bodies, -hydroxybutyrate and
acetoacetate, fuel the brain during starvation, fasting and strenuous exercise. Ketones are neuroprotective agents that shelter the aging brain from memory loss and neurodegeneration. Induced ketone production has been shown to ameliorate mitochondrial function, reduce the expression of apoptotic and inflammatory mediators and provide neuroprotection to cells (Lange et al., 2017). This case study highlights an innovative research design aimed at attenuating
SC RI PT
memory decline in a 57 year old female previously diagnosed with comorbid mild cognitive
impairment (MCI) and metabolic syndrome (MetS). Mild cognitive impairment is a predementia syndrome known to precede AD (Michaud et al, 2017). The 12-week intervention included
ketogenic nutrition protocol, high intensity interval training (HIIT) and memory training using the PEAK brain training app. Memory function was assessed via the MoCA (Montreal
Cognitive Assessment) pre/post intervention. Physiological biomarkers for MetS including
U
HOMA-IR(homeostatic model assessment of insulin resistance), triglyceride/HDL ratio, HgA1c,
N
fasting triglycerides and HDL were measured pre/post intervention. MoCA baseline score was 22/30 (MCI); post intervention score: 30/30 (normal). MetS biomarker improvements also
M
A
reflected statistical significance.
Keywords
Introduction
TE
diet; MoCA; memory loss
D
Alzheimer’s disease; Mild Cognitive Impairment (MCI); Metabolic Syndrome (MetS); ketogenic
EP
Every 66 seconds, someone in the United States develops Alzheimer’s disease. It kills more than breast cancer and prostate cancer combined. The current 5.5 million cases of AD is projected to
CC
reach 16 million by 2050, costing the nation 1.1 trillion dollars (CDC, 2016). Neuroprotective strategies are critical to reversing this pandemic disease. Demetrius & Driver (2014) posit that
A
elucidating the origin of the disease is fundamental to prevention. The predominant amyloid cascade model contends that the imbalance in the production and clearance of beta-amyloid is responsible for the pathogenesis and progression of AD. An opposing bioenergetic theory posits that the primary cause of AD is age-induced mitochondrial dysregulation resulting in hypometabolic brain circuitry (Demetrius & Driver, 2014; Gibas, 2017). Supplying the brain with alternative fuel through nutritional treatments designed to raise plasma ketone levels, particularly
in the early stages of AD, may not only prevent further degeneration but reverse the condition altogether (Cunnane et al., 2016; Gibas, 2017). Ketone delivery to the brain alleviates hypometabolism and ameliorates neuronal capacity. Ketone bodies protect neurons against neuronal injury caused by starvation and 1-42, an amyloid precursor protein (Kashiwaya, et al., 2000). 1-42 is toxic to hippocampal cells. Kashiwaya et al. exposed cultured hippocampal neurons
SC RI PT
to 1-42, which reduced the number of cells as well as the neurite number and length
compared control. The cells were simultaneously exposed to -hydroxybutyrate. The surviving cell number doubled and the cell size and neurite outgrowth increased compared to the cells
exposed exclusively 1-42. The researchers exposed the surviving hippocampal neurons to ketone bodies for 14 additional hours. The cells increased in number and neurite number
compared to control cells (Kashiwaya et al., 2000). This finding suggests that ketones can act as
U
growth factors to hippocampal neurons and protect against mitochondrial defects that contribute
N
to the pathogenesis of AD. The therapeutic potential of -hydroxybutyrate for improving and
M
A
restoring memory function is the topic of this case study.
Methods
A 57-year old female previously diagnosed with comorbid MCI and MetS completed a 12-week
D
therapeutic intervention designed to restore memory loss and reverse MetS biomarkers. A
TE
nutrition protocol purposed at raising plasma ketones through low a carbohydrate/high fat diet, calorie restriction (fasting) and high intensity interval training was administered by health care
EP
professionals and the student researcher for 12 consecutive weeks. The patient was instructed to play the PEAK brain training games on a mobile device five days per week. PEAK brain training
CC
domains utilized were language, problem solving, mental agility, memory and focus. The PEAK application is designed to strengthen the frontal, parietal, occipital, prefrontal cortex, temporal, angular gyrus, posterior cingulate cortex and hippocampus (Whiteford, 2014). Biomarkers for
A
MetS were measured via blood serum pre/post intervention and include fasting insulin, blood lipids, blood ketones and risk ratios: HOMA-IR and the triglyceride/HDL. Memory function was assessed via MoCA at baseline and post intervention by a licensed professional clinical counselor (LPCC). Nutritional monitoring and blood ketones were measured each week by healthcare professionals. Twenty minutes of high intensity interval training was administered by the student researcher every other week for a total of six sessions. The high intensity exercise
involved alternating periods of vigorous exercise with periods of recovery. Research has shown that HIIT can promote substantial improvements in insulin sensitivity, glucose control, and improvement in the biomarkers of a multitude of metabolic diseases (Francois & Little, 2015).
Case Report
SC RI PT
The patient, a 57-year-old female presenting with comorbid mild cognitive impairment and
metabolic syndrome is employed full-time as a pediatric respiratory nurse and stays active by swimming and participating in a multitude of exercise classes despite her measured cognitive
and metabolic deficits. She joined the treatment program to prevent further cognitive decline.
The memory complaints were related primarily to tasks of daily living such as remembering a
grocery list or people’s names. She also experienced problems with staying focused on the task
U
at hand or forgetting why she entered a room. The patient was previously diagnosed with MetS
N
and MCI. Although she is a breast cancer survivor and taking thyroid medication, the patient is
A
in good health. There is no family history of Alzheimer’s disease.
M
Results
One adult female was enrolled in the 12-week intervention program. Within three weeks, the
D
patient entered into physiological ketosis at 1.1 mg/dL, as measured by the Abbott Precision Xtra
TE
ketone meter (normal range 0.5-2.0 mg/dL). Triglycerides decreased by nearly 50% by the fourth week of the intervention. The MoCA score increased by 26% from baseline; 22/30 to 30/30 (normal range 26-30). The improvement in memory is statistically significant and
EP
clinically relevant to this case. The significant MetS biomarker improvements are also pertinent, as the triglyceride/HDL ratio and VLDL are directly correlated with increased cerebral
CC
metabolism and marked reductions in cognitive decline (Cunnane et al., 2016). See Table 1
A
below for results summary.
The patient experienced a corollary increase in all domains of the PEAK brain training application suggesting improved brain metabolism. See Table 2 below.
Data
Statistically significant results were recorded in all aspects of the intervention including memory, MetS biomarkers and PEAK brain training domains relevant to brain metabolism. See Figures
M
A
N
U
SC RI PT
1-4 below.
A
CC
EP
TE
D
Fig. 1. The patient’s HDL increased by 26% after the 12-week intervention with an adjusted Rsquared of 0.97 reflecting statistical significance.
N
U
SC RI PT
Fig. 2. The patient’s PEAK brain training overall total score increased by 83 points after the 12week intervention with an adjusted R-squared of 0.96 reflecting statistical significance.
A
CC
EP
TE
D
M
A
Fig. 3. The patient’s PEAK brain training score in the area of FOCUS increased by 115% after the 12-week intervention with an adjusted R-squared of 0.93 reflecting statistical significance.
Fig. 4. The patient’s MoCA score increased 26% after the 12-week intervention with an adjusted R-squared of 0.89 reflecting statistical significance. Discussion
Early stages of AD induce region-specific declines in brain glucose metabolism. A vicious cycle ensues ultimately leading to AD and dementia. Brain hypo-metabolism leads to chronic brain energy deprivation, deteriorating neuronal mitochondrial function, further decline in glucose demand and finally progression of cognitive impairment (Lange et al., 2017). According to the bioenergetic model, AD is governed by the dynamics of the mitochondria in neurons (Demetrius
SC RI PT
& Driver, 2014; Gibas, 2017). Ketone bodies have neuroprotective features that not only feed the starving brain but also favor cell growth and regeneration (Lange, et al, 2017). Several
clinical studies demonstrate that nutritional treatments designed raise plasma ketones improve brain metabolism and restore mitochondrial integrity (Cunanne et al, 2016; Henderson et al., 2009; Hertz & Chen, 2015; Lange et al, 2017; Paoli et al., 2014; & Reger et al., 2004).
This case study of a patient with comorbid MCI and MetS suggests that a ketogenic diet, high
U
intensity interval exercise, and memory training may reverse early stage memory loss (MCI) and
N
improve/normalize MetS biomarkers. The results of this case study are consistent with the aforementioned clinical trials. Elucidating the pathogenesis of AD through the lens of metabolic
A
disease will help promote metabolic interventions aimed at glucose regulation, restoration of
M
insulin sensitivity and improved brain metabolism.
Limitations of this study include the specific and small population. In future studies, it would be
D
beneficial to expand the sample to include males as well as a variety of ages.
TE
Conclusion
Nutritional ketogenic treatment approaches for brain hypo-metabolism seem to yield the best results in early stage memory loss in AD. Ketone bodies have been shown to have
EP
neuroprotective features that preserve mitochondrial integrity, cerebral energy circuits and promote healthy neuronal growth. Several clinical trials have demonstrated the neurological
CC
efficacy of high fat, low carbohydrate ketogenic diets. This novel approach of changing nutrition status for those with early stage memory loss warrants further clinical investigations based on the
A
promising results produced in this case study and recent clinical trials.
Statement of Ethics
Conflict of Interest The authors declare that there is no conflict of interest. Disclosure Statement
U
Sources of support (funding): No funding was required.
SC RI PT
The study was approved by an ethics committee. All the participants gave their written informed consent before taking part in the study.
N
Author Contributions
M
A
All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept.
D
Research in Context
EP
TE
1. Systematic Review: The authors reviewed the literature using traditional (e.g., google scholar) sources. While the role of a ketogenic diet applied to Alzheimer's disease is not yet as widely studied as other aspects of AD physiology, there have been several recent publications describing the clinical aspects of a ketogenic diet. These relevant citations are appropriately cited.
CC
2. Interpretation: Our findings led to an integrated hypothesis describing the role of the high fat ketogenic diet. This hypothesis is consistent with nonclinical and clinical findings currently in the public domain.
A
3. Future Directions: The manuscript proposes a framework for the generation of new hypotheses and the conduct of additional studies regarding this area of study. Examples include further understanding: (a) the role of MCT oil in treatment of AD; (b) the potential reversibility of neuronal damage in the AD brain.
References
SC RI PT
Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimers disease. Annals of the New York Academy of Sciences. 2016;1367(1):12-20. doi:10.1111/nyas.12999. Demetrius LA, Driver JA. Preventing Alzheimer’s disease by means of natural selection. Journal of The Royal Society Interface. 2014;12(102):20140919-20140919. doi:10.1098/rsif.2014.0919. Francois ME, Little JP. Effectiveness and Safety of High-Intensity Interval Training in Patients With Type 2 Diabetes. Diabetes Spectrum. 2015;28(1):39-44. doi:10.2337/diaspect.28.1.39.
N
U
Gibas MK, Gibas KJ. Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2017;11. doi:10.1016/j.dsx.2017.03.022.
M
A
Gibas KJ. The starving brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimers disease (AD). Neurochemistry International. 2017;110:5768. doi:10.1016/j.neuint.2017.09.004.
TE
D
Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimers disease: a randomized, double-blind, placebocontrolled, multicenter trial. Nutrition & Metabolism. 2009;6(1):31. doi:10.1186/1743-7075-631.
EP
Hertz L, Chen Y, Waagepetersen HS. Effects of ketone bodies in Alzheimers disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. Journal of Neurochemistry. 2015;134(1):7-20. doi:10.1111/jnc.13107.
CC
Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta Hydroxybutyrate protects neurons in models of Alzheimers and Parkinsons disease. Proceedings of the National Academy of Sciences. 2000;97(10):5440-5444. doi:10.1073/pnas.97.10.5440.
A
Lange KW, Lange KM, Makulska-Gertruda E, et al. Ketogenic diets and Alzheimer’s disease. Food Science and Human Wellness. 2017;6(1):1-9. doi:10.1016/j.fshw.2016.10.003. Michaud TCAL, Su D, Siahpush M, Murman DL. The Risk of Incident Mild Cognitive Impairment and Progression to Dementia Considering Mild Cognitive Impairment Subtypes . Dementia and Geriatric Cognitive Disorders Extra. 2017;7(1):15-29. doi:10.1159/000452486.
Paoli A, Bosco G, Camporesi EM, Mangar D. Ketosis, ketogenic diet and food intake control: a complex relationship. Frontiers in Psychology. 2015;6. doi:10.3389/fpsyg.2015.00027. Reger MA, Henderson ST, Hale C, et al. Effects of β-hydroxybutyrate on cognition in memoryimpaired adults. Neurobiology of Aging. 2004;25(3):311-314. doi:10.1016/s01974580(03)00087-3.
A
CC
EP
TE
D
M
A
N
U
SC RI PT
Whiteford, K.M. (2014). Testing the Validity of the PEAK Relational Training System in Assessing Language & Cognition after Brain Injury (Unpublished doctoral dissertation). Southern Illinois University Carbondale, Illinois.
Table 1: Percent Improvement MetS Biomarkers Percent Improvement
Triglycerides
56%
HDL
26%
SC RI PT
Variable
Triglyceride/HDL ratio
51%
VLDL
37%
U
Table 2: Improvement in PEAK brain training scores Percent
114%
Focus
115%
Memory
27%
Mental Agility
105%
Language
A
CC
EP
TE
30%
M
A
Problem Solving
N
Improvement
D
Variable