To evaluate the possible early consequences of impaired glucose metabolism on the brain by assessing the relationship of diabetes, fasting blood glucose (FBG) levels, and insulin resistance with cognitive performance and brain integrity in healthy young and middle-aged adults.
The sample included dementia-free participants (mean age 40 ± 9 years; 53% women) of the Framingham Heart Study third-generation cohort with cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n = 2,126). In addition, brain MRI examination (n = 1,597) was used to determine white matter, gray matter, and white matter hyperintensity (WMH) volumes and fractional anisotropy measures. We used linear regression models to assess relationships between diabetes, FBG, and insulin resistance with cognition, lobar gray matter, and WMH volumes as well as voxel-based microstructural white matter integrity and gray matter density, adjusting for potential confounders. Mediating effect of brain lesions on the association of diabetes with cognitive performance was also tested.
Diabetes was associated with worse memory, visual perception, and attention performance; increased WMH; and decreased total cerebral brain and occipital lobar gray matter volumes. The link of diabetes with attention and memory was mediated through occipital and frontal atrophy, and the latter also through hippocampal atrophy. Both diabetes and increased FBG were associated with large areas of reductions in gray matter density and fractional anisotropy on voxel-based analyses.
We found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism.
© 2015 American Academy of Neurology.
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DIET, KETONES AND TRAUMATIC BRAIN INJURY
Technical but of great interest. We are successfully using the ketogenic diet alongside other multiple anti-inflammatory approaches. If you want to try this treatment modality for TBI or cognitive impairment (dementia), please contact the office.
Published in final edited form as:
Epilepsia. 2008 November ; 49(Suppl 8): 111–113.
DIET, KETONES AND NEUROTRAUMA Mayumi Prins, Ph.D.
UCLA David Geffen School of Medicine, Department of Neurosurgery
SUMMARY
The annual incidence of traumatic brain injury far exceeds the rates of any other disease in the United States, yet progress towards age-relevant therapies, attention to patients needs and research funding have all been minimal. Cerebral metabolism of glucose has been shown to be altered after head injury and increasing cerebral metabolism of alternative substrates (ketones) has been shown to be neuroprotective in several models of traumatic brain injury. This altered dietary approach may have tremendous therapeutic potential for both the pediatric and adult head injured populations.
Keywords
ketones; brain substrate; metabolism; injury; development
Traumatic brain injury (TBI) remains the most under-addressed pediatric health issue in the United States. Each year TBI affects 1.5 million people, almost half of whom are children and young adults. Each year 300,000 children survive TBI and are discharged with life-long disabilities. This silent epidemic is the number one cause of death and disability among children. While age-specific treatment options have yet to be established, improving cellular metabolism with dietary approaches may provide therapeutic options in the near future.
Traumatic brain injury is generated by mechanical forces acting on the brain causing rapid movement of the brain in the skull. These biomechanical forces cause immediate release of neurotransmitters and disruption of ionic equilibrium across membranes. This chaos initiates an immediate but transient elevation in cerebral glucose metabolism, followed by a prolonged period of glucose metabolic depression (Yoshino et al., 1991). The pattern of glucose metabolic changes is similar among postnatal day (PND)17 rats, but the duration of the metabolic depression is significantly truncated (Thomas et al., 2000). During this period of depressed glucose metabolism there is an increase in flux of glucose through the pentose phosphate pathway (Bartnik et al., 2005), decreased Mg++, free radical production, and activation of PARP (poly ADP ribose polymerase) via DNA damage (Hall, 1993). PARP- mediated DNA repair process can deplete cytosolic NAD+ (nicotinamide) pool and can decrease GAPDH activity (glyceraldehydes 3 phosphate dehydrogenase, a key enzyme in the glycolytic pathway). Disruption of cellular metabolism results in increased cell death and behavioral dysfunction.
Dietary supplements have been used to restore energetic and ionic deficiencies after TBI. Post-injury decreases in ATP have been treated with creatine supplementation after controlled cortical impact injury in the adult rodent (Sullivan et al., 2000). Administration of creatine 4 weeks prior to injury decreased contusion volume by 50%, improved ATP and mitochondrial bioenergetics. Similarly, Mg++, which is essential for glycolytic and oxidative enzyme function, decreases after TBI and supplementation with Mg++ after injury also improves histology, behavior and edema (McIntosh et al., 1988).
In contrast to dietary approaches to re-establish TBI-induced deficiencies in brain metabolites, diets have also been used to replace or redirect essential brain substrates. TBI- induced impairments of the glucose metabolic machinery may make glucose a less favorable energy substrate. In fact, hyperglycemia has been long associated with poor outcome after TBI. Early administration of glucose after severe TBI suppresses ketogenesis, increases insulin and increases lactic acid production (Robertson et al., 1991). TBI patients who were fasted or maintained on a ketogenic-like diet to minimize hyperglycemia showed significantly lower plasma glucose and lactate concentrations, elevated ß-hydroxybutyrate levels and better urinary nitrogen balance compared to standard fed patients (Ritter et al., 1996). Similar plasma substrate changes were observed with 24-hr starvation in the adult rodent after controlled cortical impact injury. The fasted animals showed significant cortical tissue preservation, improved cognitive outcome and improved mitochondria bioenergetics (Davis et al., 2008). The neuroprotection associated with acute starvation was determined to be associated with the ketosis and not hypoglycemia. These studies bring to question the current standards for patient management of plasma glucose levels after TBI and suggest that replacing or redirecting the brain’s primary fuel source with an alternative substrate may be beneficial.
Cerebral metabolism of ketone bodies (ß-hydroxybutyrate, acetone and acetoacetate) alters mitochondrial metabolism which improves metabolic efficiency, increases the ΔG’ of ATP hydrolysis, and decreases the production of free radicals (Veech, 2004). These metabolic properties of ketones are thought to contribute to their neuroprotective potential and have recently been applied to the juvenile brain post-injury.
While the adult brain is not static in its fuel options, the ability of the brain to increase reliance on alternative fuel metabolism appears to be age-dependent, even after weaning. This fact has been particularly important following TBI where rapid changes require early intervention. Administration of ketones during this period of glucose metabolic depression has resulted in age-related neuroprotection. Postnatal day (PND) 35 and PND45 rats placed on a ketogenic diet immediately after controlled cortical impact injury showed 58% and 39% reduction in cortical contusion volume at 7 days, respectively (Prins et al., 2005). PND35 rats were also shown to have improved motor and cognitive performance (Appelberg et al., 2007). PND65-75 and PND17 rats failed to show ketogenic neuroprotection after injury. The lack of neuroprotection among PND17 animals may be due to the fact that both glucose and ketones are essential substrates for brain development, unlike post-weaned age groups where ketones serve as an alternative substrate. In contrast to PND17, the cerebral uptake of ketones may be insufficient during the acute post-injury period among PND65-75 rats. Recent studies have shown an age-dependent increase of both monocarboxylate transporter (MCT)2 and MCT1 expression after TBI in the ipsilateral cortical microvasculature (Prins and Giza, 2006; Prins et al., 2007). The greater magnitude of MCT1 and 2 expression in the juvenile brain at 6 and 24 hrs post-injury may contribute to a greater and more rapid ketone uptake during the critical early changes after TBI.
The ketogenic diet is composed of various types of fatty acids (FA) which are broken down by the liver and increase plasma ketones. Unlike ketones, FAs are not readily transported
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into the brain (with a few exceptions). Dietary administration of omega-3 FA for 4 weeks prior to TBI improved cognitive performance and normalized markers of plasticity (Wu et al., 2004). However, not all FAs are created equal. In order to mimic the typical American fast-food diet, adult rodents were given a high-fat/high sucrose diet 4 weeks prior to fluid percussion injury. Injury alone resulted in impaired cognitive performance and decreased BDNF, synapsin I and CREB. Both the cognitive and molecular markers of plasticity were further worsened on the high fat/high sucrose diet (Wu et al., 2003).
This brief review summarizes the reported effects of dietary approaches, especially ketones, on neurotrauma. Whether ketosis is achieved by starvation or administration of a ketogenic diet, the common underlying conditions of low plasma glucose in the presence of an alternative substrate (ketones) have consistently shown neuroprotective effects after various types of brain injury. If TBI induces altered glucose processing then maintenance of “normoglycemia” may not be the optimal approach. As the evidence accumulates, the current TBI patient management guidelines of plasma glucose regulation may need to be revisited as will the establishment of age-specific guidelines.
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Here is a good summary on ketogenic diet in traumatic brain injury and other neuroinflammatory conditions. More citations to follow.
The concept of dietary therapy for epilepsy has played an important role in the approach to the treatment of seizures for centuries–particularly with the development and utilization of the classic ketogenic diet over the past 90 years. Recently, there has been developing interest in the utilization of diet in other medical disorders, including autism spectrum disorders, traumatic brain injury, degenerative neurologic disorders, and cancer. As the utilization of dietary therapy expands, there are several issues that need to be addressed and better characterized to better understand the role of diet in the treatment of epilepsy and other disease.
epilepsy; ketogenic diet; low glycemic index treatment
23666037
[PubMed – indexed for MEDLINE]
Maurice Preter, MD is a European and U.S. educated psychiatrist, psychotherapist, psychopharmacologist, neurologist, and medical-legal expert in private practice in Manhattan. He is also the principal of Fifth Avenue Concierge Medicine, PLLC, a medical concierge service and health advisory for select individuals and families.
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