The Neuroprotective Effects of Ketones in TBI

Neuroprotective Effects of Ketones in TBI

Bryan Barksdale MD/PhD studentPAH Winter Retreat 2016

Outline

● What is TBI? ● Epidemiology● Pathophysiology● Current Treatments and Focus● Ketogenic Diets and Ketones● TBI Studies using KD ● Other Fuel Sources● Other Nutritional and Lifestyle Considerations● Taking it to the Clinic and Potential Problems

What is TBI?

● Traumatic Brain Injury (TBI) is defined as an impact, penetration, or rapid movement of the brain within the skull that results in an altered mental state (Prins et al 2013)

● TBI is a very heterogenous disease (Kabadi and Faden 2014)

○ Every injury results from a unique set of circumstances (Meaney et al. 2014)

○ This leads to differences in severity and type of injury

○ Pre-injury conditions affect pathophysiology and outcome (UpToDate)

What is TBI?

● Generally TBI is classified by severity and injury type (UpToDate)

○ Mild (13-15), Moderate (9-12), and Severe (<8) by Glasgow Coma Scale

○ Concussion is often used synonymously with mild TBI (mTBI) but probably describes a subset of

milder brain injury

○ Diffuse or local, impact or nonimpact, closed or penetrating, blast related

What is TBI?

● Symptoms

○ mTBI is characterized by confusion and amnesia +/- preceding L.O.C.

○ Early: headache, dizziness, lack of awareness of surroundings, and nausea and vomiting

○ Late: mood and cognitive disturbances, sensitivity to light and noise, and sleep disturbances

(Post concussion syndrome)

○ Moderate and Severe TBI- persistent headache, focal neurologic symptoms, coma, problems

with speech and language, vision and other sensory perception, movement and balance

(Barkhoudarian et al. 2011)

What is TBI?

● Mild TBI usually has full recovery● Moderate and Severe TBI are associated with permanent neurologic and

functional impairments● Chronic disability due to TBI is common with a prevalence of 3.2-5.3 million● TBI survivors can suffer from cognitive, behavioral, emotional,

endocrinological, and physical deficits● Only 25% of survivors of severe TBI achieve long-term functional

independence

(UpToDate)

Epidemiology

● 1.74 million people sustain a TBI in the US every year

● The majority are of TBIs are mild (75-95%)

● Most prevalent cause of death for those under 45 and most common cause of long term disability

(CDC.GOV)

(UpToDate)

Epidemiology

● TBI caused by sports and military service are gaining attention more recently due to:○ TBI being considered the signature wound from Afghanistan and Iraq

conflicts ○ The link between sports related concussions and CTE

(Kabadi and Faden 2014, Hiebert et al. 2015)

Epidemiology

● The annual incidence of sports related concussions in the US is 1.6 to 3.8 million (Barkhoudarian et al. 2011)

● These numbers are likely underestimated as many cases go unreported (Meaney et al. 2014)

● The likelihood of an athlete sustaining a concussion is as high as 20% per season (UpToDate)

● There exists an opportunity for a second insult

Epidemiology

● From a survey of returning Iraq War vets, 5% reported injuries with loss of consciousness and 10% with altered consciousness (UpToDate)

● The severity of combat related TBI tends to be higher compared to civilian (Meaney et al. 2014)

● 67% of TBI injuries requiring hospitalization in US military operations in Iraq and Afghanistan were from explosions (Meaney et al. 2014)

Pathophysiology of TBI

● Primary injury consists of the mechanical damage that happens at the time of impact (or transfer of force)

● These forces tend to occur within 100 ms● Shearing, stretching or compaction of axons and disruption of cell membranes● Vascular injury which can cause intracerebral bleeding and hematoma

formation● Focal: Vascular injury, Contusions, Lacerations● Diffuse: Diffuse Axonal Injury (DAI)

(Mustafa and Al-Shboul 2013)

TBI Pathophysiology

● Mechanoporation and opening of K+ channels leads to K+ efflux and depolarization

● Release of excitatory amino acids, especially glutamate

● Activation of receptors, particularly NMDARs which allow Ca2+ influx as well as K+

efflux (feedback loop)● Spreading depression

(neurologic deficits)● Ca2+ is sequestered by

mitochondria which induces oxidative stress and causes mitochondrial dysfunction


TBI Pathophysiology

● Ca2+ also activates many enzymes that increase oxidative free radical production and impair cytoskeletal integrity

● Increased ATP demand to restore ionic homeostasis, period of hyperglycolysis

● Decreased ATP production due to defects in glycolysis and mitochondrial dysfunction

● Leads to energy crisis and if severe ultimately apoptosis


TBI Pathophysiology

● Hypometabolic state caused by:○ Decreased glucose

uptake○ Decreased glycolytic

processing (decreased hexokinase, GAPDH, and PDH activity)

○ Shunting to reparative pentose phosphate pathway

○ Decrease in ATP production due to damage of ETC complexes

○ Increase in oxidative damage

(Prins and Matsumoto 2014)

TBI Pathophysiology

● Initial hypermetabolic period followed by prolonged metabolic depression

● Prolonged increase in Ca2+

● Prolonged reduction in blood flow

● Metabolic recovery time correlates with severity of injury and age

● Moderate and severe TBI may take 2 weeks to several months

(MacFarlane and Glenn 2015)

Current Treatments and Pipeline

● There are very few treatments for TBI● The current focus is on:

○ Controlling CBF by reducing ICP ○ Preventing hypotension or hypoxia○ Managing temperature and blood glucose○ Preventing infection and seizures

● Surgical interventions exist for hematomas, penetrating injuries and depressed skull fracture

● Neuroprotection is a huge field of study but clinical translation has been poor (Algattas and Huang 2014, Kabadi and Faden 2014, Stocchetti et al 2015)

○ HBOT and Hypothermia- animal studies were positive but clinical trials are weak and mixed○ Other failures include EPO, Magnesium, Progesterone, Citicoline

Current Treatments and Pipeline

(Algattas and Huang 2014)

What Should We Target Instead?

● Multitargeted approach will likely translate better (Kabadi and Faden 2014)

● Consensus is that neuroinflammation, free radical formation and metabolic dysfunction are key determinants of outcome (Gajavelli et al. 2014)

● Mitochondria have been shown to be a key participant in TBI pathophysiology (Gajavelli et al. 2014, Yokobori et al. 2014, Hiebert et al. 2015)

● Even when hypoxia, hypotension, and low CBF are “corrected” there is still substantial damage from other mechanisms (Bouzat et al. 2013, Jalloh et al. 2015)

● Decreased cerebral metabolism is a consistent finding after TBI and associated with poor outcomes (Bouzat et al. 2013)

● Markers of mitochondrial dysfunction through microdialysis (lactate, pyruvate, and glucose) and MRS (NAA) correlate with severity and outcome (Gajavelli et al. 2014,

Yokobori et al. 2014)

What Should We Target Instead?

(Bouzat et al. 2013)

Ketogenic diets and Ketone bodies

● Ketones are byproducts of fat metabolism produced during times of fasting or starvation

● They are also produced when carbohydrates in the diet are severely restricted, these are called ketogenic diets (KD)

● There are 3 main ketone bodies Beta-Hydroxybutyrate, Acetoacetate, and Acetone.

● Ketone bodies enter the TCA cycle through conversion to Acetyl-CoA to produce ATP

● Ketones can supply significant amount of brain’s energy demand

(Gano et al. 2014)

Ketogenic diets and Ketone bodies

(Gano et al. 2014)

Ketogenic Diets

(Gano et al. 2014)

Established Mechanisms of KD in Neurologic Disease

● Shown to be neuroprotective in models of epilepsy and other neurologic disease

● Ketones provide an alternative energy substrate● Reverse mitochondrial dysfunction, stimulate mitochondrial biogenesis and

mitophagy● KD and ketone bodies have been shown to reduce oxidative stress● Decrease apoptosis● Anti-inflammatory● Increases CBF● Reduces seizure threshold and changes balance of neurotransmitters

(Maalouf et al. 2009, Gano et al. 2014)

Established Mechanisms of KD in Neurologic Disease

(Gano et al. 2014)

KD in TBI: Animal Studies

● These findings are from studies that have been done with multiple injury model types and ages of rat

● Behaviorally KDs increase motor function and cognitive function after TBI● KDs reduce lesion volume and edema● Decrease number of apoptotic cells● Decrease pro-apoptotic proteins such as BAX and Cytochrome C release● Increase levels of ATP, creatinine, phosphocreatinine and normalizes NAA and

lactate● Increase activity of ETC complex 2-3, bypass defects in complex 1

(White and Venkatesh 2011, Prins and Matsumoto 2014)


● Decrease markers of oxidative stress● Increase levels of endogenous antioxidants● Increase latency to seizure● Protect against a second insult● However one recent study showed that BHB did not prevent the BBB damage

after TBI (Orhan et al. 2016)



● However many of these findings are age dependent● The neuroprotective effects are not seen as robustly in adult animals ● TBI physiology itself changes with age, the metabolic changes last longer● KDs take longer to produce ketones in adults● Older animals take longer to produces MCTs which transport ketone into the

brain

(Prins and Matsumoto 2014, Prins and Matsumoto 2014b)

KD in TBI: Human Studies

● There is only one published study in humans● Ritter et al. placed 20 head injury patients on a carbohydrate free diet (KD) (Ritter

et al. 1996)

● Patients on the KD had stable blood sugar, lower blood lactate, and better nitrogen balance

● However clinical outcomes were not reported on● There is an ongoing clinical trial in pediatric TBI patients run by Matsumoto

○ ClinicalTrials.gov Identifier: NCT02174016○ Estimated Primary Completion Date: December 2016


Other Fuels: Lactate, Pyruvate, Glucose

● New data indicates that lactate, directly and indirectly, is the primary fuel after brain injury

● Lactate-animal and human studies have been positive, multiple pleiotropic effects similar to ketones

● Pyruvate- animal studies have been positive but safety is questionable, is also converted to lactate

● Glucose- post TBI hyperglycemia is beneficial, neutral or harmful depending on the study

● However no adverse effects with exogenous glucose in animal or human studies

(Prins et al 2013, Brooks and Martin 2015, Glenn et al 2015, Glenn et al 2015b)

Other Nutritional Aspects

● Adequate calories-recommendation is full feeding within 7 days, TBI leads to a catabolic state (UpToDate, Brooks and Martin 2015)

● Omega 3s- contribute to the fluidity of function of neural and synaptic membranes

● Have demonstrated benefit in animal studies of TBI● May reduce inflammation, increase neurotrophic factors, improve

mitochondrial function● Improved learning and cognition on animal models of TBI● No human trials, but 2 are currently recruiting for pediatric mTBI

(Pillsbury et al 2011, Prins and Matsumoto 2014)

Other Nutritional Aspects

● Acetyl-L-Carnitine-improved behavioral outcome and decreased lesion volume in animal model of TBI (Scafidi et al., 2010)

● Zinc-Patients with TBI are at higher risk for developing zinc deficiency. However zinc supplementation studies haven’t been positive

● Choline● Creatine● Vitamin D● Antioxidants-Vit C, Vit E, CoQ10● Phytochemicals-Resveratrol, Curcumin

(Pillsbury et al 2011)

Other Lifestyle Factors: Exercise and Fasting

● Preconditioning with exercise may provide protection against ischemic injury (Yokobori et al. 2013)

● Delayed exercise has been shown to improve outcomes in animal studies (Kabadi

and Faden 2014, Hiebert et al. 2015)

● Similarly intermittent fasting and caloric restriction are known to be neuroprotective in many models of neurologic disease including TBI (Maalouf et al

2009, Pani 2015)

Bench to Bedside: Taking This to the Clinic

● KD is already established for epilepsy so it would be easier to implement● Ketone salts are available and esters are in the pipeline● The problem is how and when to initiate it, hard to translate from animal data● Will it work in adults as well? can we improve it with fasting or using ketone

salts and esters● Combine with lactate? ● How much evidence do we need? Is what we already have actionable?● Pretreatment for athletes and military?


Potential Problems with KD

● In human trials high doses of ketone esters caused serious GI side effects, headache, and dizziness

● Ketone salt solutions are alkalizing and a large sodium load● Exogenous ketones may stimulate insulin release and inhibit hepatic

ketogenesis● KD have the potential for hypoglycemia, excessive acidosis, GERD,

nephrolithiasis, increased in uric acid and hypercholesterolemia● Prolonged use had been associated with growth retardations, obesity, nutrient

deficiency, decreased bone density, hepatic failure, and immune dysfunction● Reports of dilated cardiomyopathy on KD


Summary

● TBI is the number one cause of death and chronic disability in those under 45● There are few current treatment options and a failure to translate animal

research● Metabolic dysfunction is a key part of TBI pathophysiology currently not

addressed● Ketogenic diets and ketones have been shown to be neuroprotective because

they address metabolic dysfunction, and so much more● The animal data for KD in TBI is very promising but is age dependent● Human trials are desperately needed

Questions?

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UpToDate

Evans, RW. Concussion and mild traumatic brain injury. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2016.

Hemphill, JC., Phan, N., Traumatic brain injury: Epidemiology, classification, and pathophysiology. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2016.

Hemphill, JC., Phan, N.,Management of acute severe traumatic brain injury. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2016

Health & Medicine

The Neuroprotective Effects of Ketones in TBI