Ketogenic Diet, Aging, and Neurodegeneration

2016 ◽  
Author(s):  
Kui Xu ◽  
Joseph C. LaManna ◽  
Michelle A. Puchowicz
Keyword(s):  
Oxidative Stress ◽  
Energy Source ◽  
Blood Flow ◽  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Neurovascular Unit ◽  
Cerebral Metabolic Rate ◽  
Downstream Effects ◽  
Atp Supply ◽  
The Brain

The brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α‎) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α‎.

Abstract 2381: Aneurysmal Subarachnoid Hemorrhage: Metabolic and Blood Flow Patterns

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
parham moftakhar ◽  
Thomas C Glenn ◽  
John Boscardin ◽  
Neil A Martin
Keyword(s):  
Blood Flow ◽  
Phase Ii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Phase Iii ◽  
Entire Study ◽  
Cerebral Metabolic Rate ◽  
Study Population ◽  
Blood Flow Patterns ◽  
The Brain ◽  
Oxygen Difference

Objective: The purpose of this study is to classify and describe the clinically distinct metabolic and hemodynamic phases post-ASAH. Methods: 224 patients who suffered an ASAH (mean age 55±14; 74% female, 26% male) were examined. Patients underwent daily transcranial Doppler (TCD) and cerebral blood flow (CBF) studies (using 133 Xe clearance). Due to the paucity of data on post-hemorrhage day (PHD) 0, the internal carotid artery end-diastolic (ICA ED ) velocity, a surrogate for CBF, was used for the first 24 hours. The brain arteriovenous oxygen difference (AVDO 2 ) was recorded for each patient and the cerebral metabolic rate of oxygen (CMRO 2 ) was calculated. Clinical outcome was evaluated based on the Glasgow Outcome Scale (GOS) 6 months after rupture. Results: Following ASAH, 3 distinct hemodynamic phases arose for the entire study population. Phase I (hypoperfusion phase), occurs on the day of rupture (PHD 0) and is defined by a low ICA ED velocity (mean 17.8±1.1 cm/s), normal middle cerebral artery (MCA) velocity (mean V MCA 58.0±23.4 cm/s), and normal Lindegaard Ratio ([LR], mean 1.66±0.50). Phase II (relative hyperemia), (PHD 1–3), is characterized by an increasing ICA ED (mean 35.4±1.0 cm/s, p<0.0001), a relative hyperemia (mean CBF 15 40.1±1.5 ml/100g/minute, CMRO 2 1.17±0.41 ml/100g/min), a rising V MCA (mean 71.5±5.8 cm/sec, p<0.0001), and a rising but normal LR (mean 2.21±0.19, p<0.0001). During phase III (vasospasm phase, PHD 4–21), both the ICA ED and CBF decrease (mean ICA ED 19.9±0.9 cm/s, p<0.0001; mean CBF 15 36.8±0.7 ml/100g/minute, p=0.04), V MCA continues to rise (mean 107.6±2.9cm/sec, p<0.0001), and the LR is further increased (mean 3.25±0.08, p<0.0001). The CMRO 2 remains low (mean 1.17±0.40 ml/100g/min, p=1). Based on the GOS up to 90% of patients who experienced either a relative or absolute hyperemia had good outcomes. Conclusions: After an ASAH, 3 discrete metabolic and hemodynamic phases arise each with the potential for its own unique phase-specific management and therapy. Relative hyperemia, or “luxury perfusion,” during Phase II in the setting of non-elevated ICPs may provide some type of benefit for patients.

Ketogenic Diet and PPARgamma

2016 ◽  
Author(s):  
Timothy A. Simeone
Keyword(s):  
Ketogenic Diet ◽  
Refractory Epilepsy ◽  
Ketone Bodies ◽  
Peroxisome Proliferator ◽  
Potential Therapeutic Target ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Transcription Factor ◽  
Inflammatory Processes ◽  
The Brain

The ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial function, which is thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. This chapter focuses on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews what is known concerning PPARgamma in the brain, the evidence that PPARgamma has neuroprotective and antiseizure properties, and the evidence suggesting that PPARgamma may be involved in the antiseizure mechanisms of the ketogenic diet.

Generalized decrease in brain glucose metabolism during fasting in humans studied by PET

1989 ◽  
Vol 256 (6) ◽  
pp. E805-E810 ◽  
Author(s):  
C. Redies ◽  
L. J. Hoffer ◽  
C. Beil ◽  
E. B. Marliss ◽  
A. C. Evans ◽  
...  
Keyword(s):  
Blood Flow ◽  
Blood Volume ◽  
Ketone Bodies ◽  
Oxygen Metabolism ◽  
Whole Body ◽  
Transfer Coefficients ◽  
Oxygen Utilization ◽  
Whole Brain ◽  
Brain Glucose ◽  
The Brain

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

2020 ◽  
Vol 16 (5) ◽  
pp. 502-515 ◽  
Author(s):  
Patrícia Quelhas ◽  
Graça Baltazar ◽  
Elisa Cairrao
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Blood Vessels ◽  
Neurovascular Unit ◽  
Muscle Cells ◽  
Cerebral Blood Vessels ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain

The neurovascular unit is a physiological unit present in the brain, which is constituted by elements of the nervous system (neurons and astrocytes) and the vascular system (endothelial and mural cells). This unit is responsible for the homeostasis and regulation of cerebral blood flow. There are two major types of mural cells in the brain, pericytes and smooth muscle cells. At the arterial level, smooth muscle cells are the main components that wrap around the outside of cerebral blood vessels and the major contributors to basal tone maintenance, blood pressure and blood flow distribution. They present several mechanisms by which they regulate both vasodilation and vasoconstriction of cerebral blood vessels and their regulation becomes even more important in situations of injury or pathology. In this review, we discuss the main regulatory mechanisms of brain smooth muscle cells and their contributions to the correct brain homeostasis.

scholarly journals Overview of Monitoring of Cerebral Blood Flow and Metabolism after Severe Head Injury

1994 ◽  
Vol 21 (S1) ◽  
pp. S6-S11 ◽  
Author(s):  
J. Paul Muizelaar ◽  
Marc L. Schröder
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Severe Head Injury ◽  
Cerebral Metabolism ◽  
Jugular Bulb ◽  
Cerebral Metabolic Rate ◽  
Venous Oxygen Saturation ◽  
Arteriovenous Difference ◽  
The Brain ◽  
Pressure Autoregulation

AbstractThe relationships between cerebral blood flow (CBF), cerebral metabolism (cerebral metabolic rate of oxygen, CMRO2) and cerebral oxygen extraction (arteriovenous difference of oxygen, AVDO2) are discussed, using the formula CMRO2 = CBF × AVDO2. Metabolic autoregulation, pressure autoregulation and viscosity autoregulation can all be explained by the strong tendency of the brain to keep AVDO2 constant. Monitoring of CBF, CMRO2 or AVDO2 very early after injury is impractical, but the available data indicate that cerebral ischemia plays a considerable role at this stage. It can best be avoided by not "treating" arterial hypertension and not using too much hyperventilation, while generous use of mannitol is probably beneficial. Once in the ICU, treatment can most practically be guided by monitoring of jugular bulb venous oxygen saturation. If saturation drops below 50%, the reason for this must be found (high intracranial pressure, blood pressure not high enough, too vigorous hyperventilation, arterial hypoxia, anemia) and must be treated accordingly.

Neuroprotection in hypothermia linked to redistribution of oxygen in brain

2003 ◽  
Vol 285 (1) ◽  
pp. H17-H25 ◽  
Author(s):  
Masaharu Sakoh ◽  
Albert Gjedde
Keyword(s):  
Blood Flow ◽  
Oxygen Consumption ◽  
Energy Metabolism ◽  
Brain Tissue ◽  
Traumatic Injury ◽  
Oxygen Extraction Fraction ◽  
Physiological Variables ◽  
Cerebral Metabolic Rate ◽  
Extraction Fraction ◽  
The Brain

Hypothermia improves the outcome of acute ischemic stroke, traumatic injury, and inflammation of brain tissue. We tested the hypothesis that hypothermia reduces the energy metabolism of brain tissue to a level that is commensurate with the prevailing blood flow and hence allows adequate distribution of oxygen to the entire tissue. To determine the effect of 32°C hypothermia on brain tissue, we measured the sequential changes of physiological variables by means of PET in pigs. Cerebral blood flow and oxygen consumption (cerebral metabolic rate of oxygen) declined to 50% of the baseline in 3 and 5 h, respectively, thus elevating the oxygen extraction fraction to 140% of the baseline at 3 h. The results are consistent with the claim that cooling of the brain to 32°C couples both energy metabolism and blood flow to a lower rate of work of the entire tissue.

scholarly journals Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

2021 ◽  
Vol 118 (51) ◽  
pp. e2112561118
Author(s):  
Samuel A. Mills ◽  
Andrew I. Jobling ◽  
Michael A. Dixon ◽  
Bang V. Bui ◽  
Kirstan A. Vessey ◽  
...  
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Vascular Function ◽  
Immune Cell ◽  
Neurovascular Unit ◽  
Retinal Blood Flow ◽  
Proper Function ◽  
Early Diabetes ◽  
Vascular Regulation ◽  
The Brain

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial–capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial–vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

scholarly journals Effect of Adenosine on Total and Regional Cerebral Blood Flow of the Newborn Piglet

1990 ◽  
Vol 10 (3) ◽  
pp. 392-398 ◽  
Author(s):  
Nicole Laudignon ◽  
Kae Beharry ◽  
Joan Rex ◽  
Jacob V. Aranda
Keyword(s):  
Blood Flow ◽  
Regional Cerebral Blood ◽  
Cerebral Metabolic Rate ◽  
Newborn Brain ◽  
Total Brain ◽  
Adenosine Concentration ◽  
Potent Vasodilator ◽  
Periventricular Area ◽  
Dose Dependent ◽  
The Brain

The effect of adenosine on total and regional CBF, measured by radiolabeled microspheres, was assessed in 16 anesthetized and ventilated newborn (1–3 days old) piglets. They received a ventriculocisternal perfusion containing either CSF alone (controls, n = 5) or CSF mixed with two different concentrations of adenosine (15 min each) randomly assigned using the following doses: 0.1 μ M, 10 μ M, 100 μ M, 1 m M (n = 4), or 10 m M (n = 6). Mean CSF adenosine concentration (by HPLC) before perfusion was 0.6 ± 0.4 μ M. Total and regional CBF were not altered by the perfusion of CSF alone. All adenosine concentrations, except at low doses, increased total and regional CBF, without altering the cerebral metabolic rate for oxygen. Brainstem blood flow was increased by a mean of 110, 145, 306, and 378% with 10 μ M, 100 μ M, 1 m M, and 10 m M concentrations, respectively. Except for the highest concentration, CBF response was dose dependent in each region of the brain with the following order of potency: brainstem > periventricular area > telencephalon, midbrain, total brain, and cerebellum. These data indicate that, in the newborn, adenosine is a potent vasodilator of cerebral vessels. If the newborn brain can synthesize appropriate concentrations of adenosine, this nucleoside may play a major role in regional CBF regulation during the neonatal period.

scholarly journals Ketogenic diet and metabolic regulation of brain microglia

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv8-iv9
Author(s):  
Adrian Benito ◽  
Nabil Hajji ◽  
Kevin O’Neill ◽  
Hector C Keun ◽  
Nelofer Syed
Keyword(s):  
Immune System ◽  
Ketogenic Diet ◽  
Brain Tumours ◽  
Metabolic Regulation ◽  
Ketone Bodies ◽  
Tumour Progression ◽  
Tumour Mass ◽  
Nutritional Interventions ◽  
New Knowledge ◽  
The Brain

Abstract Ketogenic diet (KD) has been proposed as a coadjuvant therapy in the treatment of brain tumours. Reduction of blood glucose and increase in ketone bodies concentration are amongst the most important changes induced by KD in patients. Preliminary data collected in our lab indicates that KD induces substantial changes in the immune system in mice bearing brain tumours. Microglia are brain-resident immune cells that account for around 30% of the tumour mass and play a major role in controlling tumour progression by adopting a protumour (M2 polarisation) or antitumour (M1 polarisation) phenotype. We are interested in understating the molecular and metabolic determinants of microglia polarisation and how these can be modulated by the metabolic microenvironment and KD. We report some initial findings that indicate microglia adapt to changes in the metabolic microenvironment and that nutrient availability can modulate microglia activation and polarisation. We believe that the study of microglia metabolism and nutritional interventions like KD can provide new knowledge about the regulation of the brain immune system and unveil novel routes for brain cancer treatment.

scholarly journals An fMRI Investigation into the Effects of Ketogenic Medium-Chain Triglycerides on Cognitive Function in Elderly Adults: A Pilot Study

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2134
Author(s):  
Yukihito Yomogida ◽  
Junko Matsuo ◽  
Ikki Ishida ◽  
Miho Ota ◽  
Kentaro Nakamura ◽  
...  
Keyword(s):  
Energy Source ◽  
Cognitive Function ◽  
Task Performance ◽  
Ketone Bodies ◽  
Elderly Subjects ◽  
Medium Chain Triglycerides ◽  
Medium Chain ◽  
Extra Energy ◽  
The Brain ◽  
Back Task

Evidence suggests that oral intake of medium-chain triglycerides (MCTs), which promote the production of ketone bodies, may improve cognitive functions in elderly people; however, the underlying brain mechanisms remain elusive. We tested the hypothesis that cognitive improvement accompanies physiological changes in the brain and reflects the use of ketone bodies as an extra energy source. To this end, by using functional magnetic resonance imaging, cerebral blood oxygenation level-dependent (BOLD) signals were measured while 20 healthy elderly subjects (14 females and 6 males; mean age: 65.7 ± 3.9 years) were engaged in executive function tasks (N-back and Go-Nogo) after ingesting a single MCT meal (Ketonformula®) or placebo meal in a randomized, double-blind placebo-controlled design (UMIN000031539). Morphological characteristics of the brain were also examined in relation to the effects of an MCT meal. The MCT meal improved N-back task performance, and this was prominent in subjects who had reduced grey matter volume in the dorsolateral prefrontal cortex (DLPFC), a region known to promote executive functions. When the participants were dichotomized into high/low level groups of global cognitive function at baseline, the high group showed improved N-back task performance, while the low group showed improved Go-Nogo task performance. This was accompanied by decreased BOLD signals in the DLPFC, indicative of the consumption of ketone bodies as an extra energy source.

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