Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05207397 |
| Other study ID # |
STUDY00144303 |
| Secondary ID |
1R01AG062548 |
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
April 12, 2023 |
| Est. completion date |
January 2025 |
Study information
| Verified date |
April 2024 |
| Source |
University of Kansas Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The investigator has shown that improved cardiorespiratory fitness following an aerobic
exercise program elicits cognitive benefit in elderly subjects and memory improvement in
Alzheimer's disease (AD). The physiological mechanism may be related to exercise-mediated
change in circulating factors that permeate the brain. The response to each individual bout
of exercise (i.e. the acute exercise response) may differ between subjects and be key to
driving brain benefit. In young populations, the acute response to exercise can last hours
and affect brain glucose metabolism. However, the field knows little about this acute
exercise response in AD. Most exercise intervention trials designed to prevent and slow AD,
including our own (AG033673; AG034614; AG043962; AG049749; AG053952), assess biomarkers at
two fasting time points: pre- and post-intervention. The acute exercise response in the brain
and periphery likely varies between subjects and diagnoses and provide key information
regarding mechanisms of benefit. Our primary goals are to characterize the acute exercise
response to exercise in the brain (glucose metabolism) and periphery (biomarker response) in
aging and AD. The investigator will identify relationships between exercise-related factors
(i.e. heart rate, biomarkers) and change in brain metabolism and cognition. Understanding
these mechanistic relationships will provide specific targets that can be used in future
trials to develop individualized exercise prescriptions and maximize benefit.
Accumulating evidence suggests that the exercise-related metabolite lactate is an
understudied effector of brain health. Lactate is an essential fuel for neuronal function. It
is supplied to neurons through glucose metabolism in nearby glia and from peripheral blood,
since the brain is permeable to lactate. A drop in cerebral glucose metabolism is a marker of
AD. Thus, supplying neurons directly with lactate for oxidation may supplement energy
requirements in AD, as has been suggested with ketones. Importantly, circulating lactate
levels rise during exercise. Repeated increases in systemic lactate (acute exercise response)
may transiently spare glucose by providing an alternative fuel. With routine exercise, acute
responses may elicit adaptations that facilitate the use of lactate beyond that which occurs
during acute exercise and contribute to brain benefits observed during chronic exercise
interventions. In younger populations, higher exercise intensity evokes a greater lactate
response compared to lower intensities and elicits cognitive benefit. The investigator will
achieve these goals through the following aim:
Aim 1. Examine differences in lactate metabolism between diagnosis groups and the effect of
lactate on cognitive performance. Increased blood lactate can reflect increased production or
decreased uptake. This has never been compared in ND and AD. The investigator will use a
"lactate clamp" procedure, where lactate is infused to concentrations that match those found
during exercise, to characterize lactate turnover. The investigator will characterize
cognitive performance following lactate infusion, independent of exercise factors. The
investigators hypothesize that ND subjects (n=12) will use lactate more efficiently (greater
uptake) than AD individuals (n=12). The investigator further hypothesize that cognitive
performance will acutely improve after lactate infusion in ND and AD subjects.
The overall goal is to characterize lactate metabolism, and its relationships with cognition.
The KU ADC is a recognized leader in the study of exercise and metabolism in aged and AD
populations, and puts the investigator in a strong position to successfully achieve these
aims.
Description:
Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting over 5
million Americans, with this number expected to balloon to nearly 14 million by 2050. Annual
health care costs associated with AD exceed 200 billion dollars which has led to the
formation National Alzheimer's Project Act (NAPA). Goals of NAPA include the creation of a
national plan to overcome AD, development of treatments to prevent, halt, or reverse AD, and
improvements in early diagnosis and care of AD patients.
Our team has been at the forefront research to characterize the impact of exercise on AD
prevention and progression. The investigator has shown that an exercise program improves
cognitive (primarily executive) function in nondemented (ND) subjects in an exercise
dose-dependent manner. The investigator has further shown that there is a positive
relationship between cardiorespiratory fitness change and memory change in individuals with
AD who participate in 6 months of aerobic exercise and are currently investigating these
effects in subjects with preclinical AD (ClinicalTrials.gov ID NCT02000583). However, not all
individuals benefit from exercise, and the precise mechanisms by which exercise elicits a
beneficial effect are unclear. The investigator is currently exploring a variety of
approaches ranging from molecular to neuroimaging studies to investigate these effects. One
of the great knowledge gaps, however, is how little the field knows about the acute effects
of exercise in AD. Most clinical trials, including our own, have been designed to assess
metabolic outcomes at two fasting timepoints, before and after the intervention. However, the
effects of each acute exercise bout on brain metabolism, and potential mechanisms by which
cognition and memory may be affected, remain unclear. The investigator will explore these
factors in the current application. Few groups are as well-positioned as ours to integrate
cardiorespiratory fitness measures, acute exercise interventions, and advanced neuroimaging
techniques.
Exercise benefits the brain: rationale for understanding the acute exercise response in AD
Longitudinal observational studies show a relationship between self-reported exercise and
cognitive decline, and higher physical activity in midlife and late life is associated with a
reduced risk of developing late-onset AD. Furthermore, intervention studies have shown
cognitive improvement following exercise in ND and MCI subjects. Cardiorespiratory fitness
decline tracks with brain atrophy and progression of dementia severity in AD and hippocampal
volume has improved with a physical activity intervention in some studies of older adults. In
our recent study of exercise in AD subjects, the investigator did not see an overall
improvement in memory in the intervention group but change in cardiorespiratory fitness was
positively correlated with change in memory. The finding that cardiorespiratory fitness
change is important in achieving memory effects in AD is consistent with work that shows a
positive relationship between exercise-related cardiorespiratory fitness change and markers
of cortical thickness and brain volume in ND, MCI, and AD subjects. It is also consistent
with work from our group and others that shows physical activity and fitness levels are
associated with larger brain volume.
Importantly, the investigator postulate that cardiorespiratory fitness change is likely
driven by the repeated, acute effects of each single, acute exercise bout that is additive
over time. These acute effects include changes in peripheral biomarkers that readily cross
the blood brain barrier but return to normal within a few hours. However, the effects of
acute exercise on the brain are not well understood, especially in aged and AD populations,
and at the intensities that are often used in exercise intervention programs. This presents a
knowledge gap in the study of the beneficial effects of exercise in aging and dementia
populations.
Why study lactate? The terms "lactate" and "lactic acid" are often used interchangeably and
differ by only one proton. Lactic acid is still considered by some to be a waste product
generated during exercise, and although controversy still remains regarding the role of
lactic acid in muscle acidification, there is substantial evidence that lactate plays a
critical and beneficial role in a variety of tissues. The production of lactate from pyruvate
generates NAD+, a necessary intermediate for glycolysis. Peripheral lactate is transported to
the liver for regeneration of pyruvate via the Cori cycle; however, lactate is transported
throughout the entire body, and during physical exercise, lactate provides a key source of
energy for muscle and brain. Because lactate is used efficiently by the brain even at rest,
the investigator hypothesize that lactate is a critical energy source for the brain, and that
generation of lactate during acute exercise directly impacts glucose metabolism in the brain.
The investigator will explore the effects of acute exercise on brain glucose metabolism as
well as the dynamics of acute exercise biomarkers, including lactate and related substances
that may affect brain metabolism.
In 1994, it was shown that that glucose use, lactate production, and lactate release
increased with brain activation. This spurred the "lactate shuttle hypothesis" which posits
that astrocytes primarily metabolize glucose to lactate, which is shuttled to neurons for use
in oxidative phosphorylation. The concept of metabolic compartmentalization between brain
cells is supported by expression of specific monocarboxylate transporter (MCT) isoforms,
which transport lactate, in neurons compared to glia. Neurons express MCT2, which is
characterized by a high affinity for lactate and limited expression profile, while astrocytes
primarily express MCT4, which has low lactate affinity and is implicated in efflux of
lactate. It is suggested that astrocytes rely more heavily on glycolysis than neurons.
Glycolytic enzyme fructose biosphosphatase is degraded in neurons, suggesting a limited
ability of neurons to increase glycolysis and further suggests increased shunting of glucose
metabolism towards the pentose phosphate pathway. In short, glycolysis in neurons may be more
critical for regeneration of antioxidants like glutathione, rather than generation of
pyruvate for oxidation within mitochondria. Finally, studies of mice using FRET technology
have shown that lactate can permeate both astrocytes and neurons, with evidence of an
astrocyte-neuron lactate gradient. Lactate injection has been shown to increase neuronal
lactate uptake relative to astrocytes. Taken together, this molecular evidence suggests that
interventions which increase peripheral lactate, such as aerobic exercise, may increase flux
into neuronal cells.
Lactate dynamics and exercise In humans, there is a linear relationship between systemic
lactate concentration and brain lactate uptake at physiological concentrations and lactate
can contribute to as much as 60% of cerebral metabolism when transporters are saturated. The
kinetics of lactate entry into brain indicate the blood brain barrier is about half as
permeable to lactate as glucose, but that intracellular uptake of lactate is greater. Recent
evidence suggests that the FDG signal is driven by glial glucose use, and that increased
supply of peripheral lactate may reduce the FDG-PET signal. Regardless of source, increased
lactate supply should drop the FDG signal due to increased availability to both cell types.
Human studies: To date, most human studies of lactate and the brain have used lactate
infusion and/or exercise, and were performed in healthy young men. A study using a lactate
clamp and exercise showed that lactate oxidation during moderate exercise was improved by
increasing lactate levels, sparing glucose and decreasing glucose production. Two other
studies demonstrated that acute exercise improved cognition, and the cognitive improvement
positively correlated with cerebral lactate uptake. Finally, exercise at an intensity which
increased circulating lactate levels decreased cerebral glucose metabolism (FDG-PET signal),
while lower intensity exercise that did not increase peripheral lactate did not. Although the
decrease in cerebral glucose metabolism is proposed to be due to glucose sparing, as energy
needs are met by lactate, the cellular fates of glucose and lactate have not been measured
directly in humans due to technological limitations. Nonetheless, the acute changes in
cerebral glucose metabolism may represent an important measure of cerebral responsiveness to
exercise. It may also predict changes in resting cerebral glucose metabolism that have been
observed in longer exercise intervention studies. However, the effects of acute exercise on
brain glucose metabolism have not been assessed in ND elderly or AD populations.
Potential roles of related exercise biomarkers Although a lactate-specific relationship with
cerebral glucose metabolism will be our focus for Aim 1, the investigator will also examine
five additional exercise-related biomarkers that affect the brain. These biomarkers will
include brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF),
transforming growth factor beta (TGF), irisin, and glucose. Our rationale for the selection
of these specific exercise-related biomarkers follows. BDNF is a potential mediator of
exercise-related brain benefit, but its acute response has not been analyzed in AD. Studies
in human cell lines suggest that short-term lactate exposure increases BDNF expression in
both cortical astrocytes and SY5Y cells. Lactate is positively linked to both BDNF and VEGF
levels following exercise, although it is unclear whether lactate drives these responses. In
addition, in rodents, exercise-induced elevation of blood lactate increases TGF in brain CSF.
This may be of relevance as TGF is implicated in the mobilization of fat-related energy
substrates. The investigators have indirect evidence that energy substrate use during fitness
tests may differ based on AD diagnosis, which is discussed later. Furthermore, in rodents,
inhibition of TGF signaling decreased memory performance and long-term potentiation. Another
modulator of fat metabolism and signaling is irisin. Irisin is a relatively newly-recognized
hormone that is induced during moderate intensity exercise and has been linked to cognition
in older adults at risk for dementia. The investigators and others have linked glucose to
progression of AD and AD-related neuropathology, and in pilot studies the investigators have
observed that glucose and insulin are both acutely responsive to exercise, with large
variation between individuals. Quantification of these important exercise- and cognition-
related biomarkers will enhance our understanding of the acute exercise response in aged and
AD populations. The investigators will quantify them during the lactate clamp procedure. This
will allow the investigator to determine if lactate itself is performing a function as a
signaling molecule and affecting levels of other exercise related biomarkers, or if
exercise-mediated change in these biomarkers occurs through other pathways.
