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Reversing Brain Damage in Former NFL Players: Implications for Traumatic Brain Injury and Substance Abuse Rehabilitation

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Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.
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Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 1 Volume 43 (1), March 2011
Journal of Psychoactive Drugs, 43 (1), (insert page range of article here), 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0279-1072 / 2159-9777 online
DOI: 10.1080/02791072.2011.566489
Reversing Brain Damage in
Former NFL Players: Implications
for Traumatic Brain Injury and
Substance Abuse Rehabilitation
Daniel G. Amen, M.D.*; Joseph C. Wu, M.D.**; Derek Taylor*** & Kristen Willeumier, Ph.D.****
Abstract—Brain injuries are common in professional American football players. Finding effective
rehabilitation strategies can have widespread implications not only for retired players but also for
patients with traumatic brain injury and substance abuse. An open label pragmatic clinical intervention
was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated
brain damage and cognitive impairment. The study included weight loss (if appropriate); sh oil (5.6
grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that
included nutrients to enhance blood ow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine
and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average
was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain
SPECT imaging. In the retest situation, corrected for practice effect, there were statistically signicant
increases in scores of attention, memory, reasoning, information processing speed and accuracy on the
Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the
prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study
demonstrates that cognitive and cerebral blood ow improvements are possible in this group with
multiple interventions.
Keywords—brain trauma, football, MicroCog, rehabilitation, SPECT
†Players were recruited with the help of the Los Angeles Chapter of
the Retired NFL Players Association, The Summit, and Dave Pears blog.
The authors wish to thank Anthony Davis, Marvin Smith, Reggie Berry,
Dave Pear, Robert Lee and all the retired players for their assistance. No
competing nancial interests exist for any of the authors.
*Assistant Clinical Professor, UC Irvine School of Medicine, Irvine, CA.
**Associate Professor, UC Irvine School of Medicine; Clinical Director,
Brain Imaging Center, UC, Irvine School of Medicine, Irvine, CA.
***Data Analysis, Amen Clinics, Inc., Newport Beach, CA.
****Research Director, Amen Clinics, Inc., Newport Beach, CA.
Please address correspondence and reprint requests to Daniel G.
Amen, M.D., Amen Clinics, Inc., 4019 Westerly Place Suite 100, Newport
Beach, CA 92660. Phone: 949-266-3717, fax: 949-266-3766, email:
Brain injuries are common in professional American
football players, and their incidence has been associated
with mild cognitive impairment, dementia and depression
(Guskiewicz et al. 2007, 2005). A study sponsored by the
National Football League (NFL) found that retired players
aged 30 to 49 receive a dementia-related diagnosis at a rate
of 1.9%, or 20 times the rate of age-matched populations,
while 6.1% of players over the age of 50 receive a dementia-
related diagnosis representing ve times the national average
of 1.2% (Weir, Jackson & Sonnega 2009). In a recent study
conducted on 100 active and retired NFL players the authors
found overall decreased cerebral perfusion and a higher in-
cidence of depression, obesity and memory and attentional
problems compared to the general population (Amen et al.
2011). In addition, brain injuries have also been found to
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 2 Volume 43 (1), March 2011
increase the risk of substance abuse (Olson-Madden et al.
2010; Graham & Caron 2008).
Brain injuries affect not only retired professional
football players, but also an estimated 1.7 million people
annually (CDC 2010) and many soldiers returning from Iraq
and Afghanistan. In addition, substance abusers also experi-
ence high levels of brain damage from the toxic effects of the
drugs or alcohol and the higher incidence of brain injuries
during intoxication (Gold et al. 2009).
Evaluating potential treatments to rehabilitate or reverse
brain damage is important in many clinical populations,
especially for patients with traumatic brain injury and sub-
stance abuse. Brain SPECT imaging is a standard, widely
available functional brain imaging tool that has been found to
help evaluate baseline brain function and the effect of treat-
ment interventions (Amen 2010). In this report we describe
our experience with 30 retired NFL players who took part
in a pragmatic open-label, clinical intervention to attempt
to reverse brain damage and cognitive dysfunction.
As part of a larger study we recruited 100 retired NFL
players, representing 27 teams and all positions. Each player
met our inclusion criteria of being on an active NFL roster
for a minimum of three years. We excluded any subjects
who could not cease taking psychoactive medications (recre-
ational or otherwise) for an appropriate washout period prior
to scanning. All subjects signed informed consent as part of
an IRB protocol. The study started in 2009 and concluded
in 2010.
Evaluation Procedures
Each participant was interviewed by a physician and
completed a detailed medical and psychiatric history.
Weight, height and waist size were obtained on all partici-
pants and body mass index (BMI) and waist-to-height ratios
were calculated. As part of the evaluation each participant
took the Microcog Assessment of Cognitive Functioning
(MACF; Powell et al. 2004), which contains nine subtests:
general cognitive functioning, general cognitive prociency,
information processing speed, information processing ac-
curacy, attention, reasoning, memory, spatial processing and
reaction time. The MACF scores were compared to its own
standardized sample (n= 810) chosen to be representative of
the U.S. population of adults between the ages of 18 and 89
in regards to education, gender, and ethnicity. The MACF
was chosen because the means from test to retest were stable
over time and showed little practice effect (Powell et al.
In addition, each subject underwent high-resolution
brain SPECT imaging to measure regional cerebral blood
ow (rCBF). Each subject received an age/weight-appropri-
ate dose of Tc99m HMPAO intravenously. Subjects were
injected in normal lighting while they performed a go, no-
go, continuous performance task. The radiopharmaceutical
was injected three minutes after starting the 15-minute test.
All subjects completed the task. Subjects were then scanned
30 minutes later using a high-resolution Picker Prism 3000
triple-headed gamma camera with fan beam collimators,
acquiring data in 128x128 matrices, yielding 120 images
per scan with each image separated by 3 degrees spanning
360 degrees.
SPECT data was processed and attenuation correction
performed using general linear (Chang) methods. All images
were reconstructed and resliced using an oblique reformat-
ting program, according to anterior-posterior commissure
line so nal images were similarly aligned for analysis.
All subjects were offered the opportunity to participate
in a pragmatic interventional phase. Pragmatic interventions
are ones that participants might experience in a “real-world”
clinical situation. The interventions included education on a
brain-healthy lifestyle, such as proper nutrition, regular ex-
ercise, limiting alcohol, eliminating drug abuse and cigarette
smoking, getting appropriate sleep, and having sleep apnea
assessed if symptoms were endorsed. As obesity has been as-
sociated with dementia and a smaller brain (Raji et al. 2010),
Before and After Percentile Scores on the Microcog Assessment of Cognitive Functioning in 30 NFL Players
MicroCog Before After Number of Players with
Domains Mean (Std. Dev) Mean (Std. Dev) p Value > 50% improvement
General Cognitive Functioning 31.8 (24.1) 43.4 (25.7) <0.000 14
General Cognitive Prociency 24.7 (20.1) 35.2 (23.5) <0.000 14
Processing Speed 33.1 (24.8) 39.3 (25.5) 0.026 12
Processing Accuracy 40.9 (28.7) 48.5 (29.1) 0.012 13
Attention 38.4 (26.2) 48.7 (27.6) 0.025 9
Reasoning 32.7 (25.7) 41.6 (28.0) 0.006 11
Memory 33.8 (27.4) 42.9 (28.4) 0.022 17
Spatial Processing 69.0 (21.8) 74.3 (13.2) 0.154 3
Reaction Time 70.2 (24.5) 74.67 (22.9) 0.669 6
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 3 Volume 43 (1), March 2011
we encouraged overweight or obese players to lose weight.
Forty-eight percent of players in the initial study were over-
weight or obese, even taking into account their large body
frames. Author KW ran an optional weight-loss group for
players. In addition, players were given 5.6 grams of sh oil
a day, containing 1720mg of EPA and 1160mg of DHA, as
omega-three fatty acid supplementation has shown benets
with memory, mood and cognition (Michael-Titus 2009;
Conklin et al. 2007) and a high-potency multiple vitamin,
which has been shown to enhance mental performance (Ken-
nedy et al. 2010). Participants in the interventional study also
received a brain enhancement supplement that contained
clinically effective dosages of nutrients to enhance blood
ow: ginkgo (Santos et al. 2003) and vinpocetine (Gulyás
et al. 2002); decrease cortisol: phosphatidylserine (Monte-
leone et al. 1990); enhance acetylcholine: acetyl-l-carnitine
(Jones, McDonald & Borum 2010) and huperzine A (Zhang,
Yan & Tang 2008); and enhance antioxidants: alpha-lipoic
acid (Arguelles et al. 2010) and n-acetyl-cysteine (Dodd et
al. 2008). The trial for each participant ranged from two to
12 months, with the average being six months, depending
on the participant’s ability to travel to the study location in
Southern California.
In the follow-up evaluation, participants underwent
a clinical interview, completed a questionnaire on their
progress, had a follow-up brain SPECT scan, and retook
the MACF.
SPECT Image Analysis
Differences in HMPAO uptake were analyzed using
SPM8 software (Wellcome Department of Cognitive Neu-
rology, London, UK) implemented on the Matlab platform
(MathWorks Inc., Sherborn, MA). Statistical parametric
maps (SPMs) are spatially extended statistical processes that
are constructed to test hypotheses about regionally specic
effects in neuroimaging data. Statistical parametric map-
ping combines the general linear model and the theory of
Gaussian random elds to make statistical inferences about
regional effects (Friston, Holmes & Worsley 1995). The
images were spatially normalized using a twelve parameter
afne transformation followed by nonlinear deformations
(Ashburner & Friston 1999) to minimizing the residual
sum of squares between each scan and a reference or tem-
plate image conforming to the standard space dened by
the Montreal Neurological Institute (MNI) template. The
original image matrix obtained at 128x128x29 with voxel
sizes of 2.16mm x 2.16mm x 6.48mm were transformed
and resliced to a 79x95x68 matrix with voxel sizes of 2mm
x 2mm x 2mm consistent with the MNI template. Images
were smoothed using an 8mm FWHM isotropic Gaussian
As a group, we compared participants’ original SPECT
scans with their follow-up scans using a paired t-test with
ANCOVA. Based on our prior study (Amen et al. 2011),
our hypothesis was that we would see increased rCBF in the
prefrontal cortex, anterior cingulate gyrus, temporal lobes,
parietal lobes, occipital lobes and cerebellum. SPM(z) score
differences for a-priori regions of interest (Table 2) were
computed using the WFU PickAtlas toolbox within the
SPM8 framework (Maldjian et al. 2003, Maldjian, Laurienti
& Burdette 2004).
In the retest situation, corrected for practice effect, there
were statistically signicant increases in MACF scores in
general cognitive functioning, general cognitive prociency,
attention, memory, reasoning, information processing speed
and accuracy (see Table 1). There were also increases in
spatial processing and reaction time, although these were not
statistically signicant. Many of the participants had robust
increases in performance. Table 1 also lists the number of
participants in each category who had greater than a 50%
increase in percentile scores.
The brain SPECT scans also showed signicant in-
creases in brain perfusion at p < 0.001, especially in the
prefrontal cortex, anterior cingulate gyrus, parietal lobes,
occipital lobes, and cerebellum (see Table 2 for specic areas
of signicant increases and Figure 1 for a visual represen-
tation of the areas of signicant increase). No signicant
Signicant Areas of Increased Perfusion After Treatment at p < 0.001
AAL Areas Cluster Size Location Z
Prefrontal Infer-Mid-Sup Lt 473 -24 62 16 4.69
Prefrontal Mid Sup Rt 2064 36 50 24 3.58
Inferior Orbital Lt 244 -2 52 -32 4.05
Anterior Cingulate Rt 79 12 40 24 3.68
Parietal/Angular Lt 77 -60 -54 48 4.49
Parietal/Precuneus Lt 205 -12 -56 74 4.32
Parietal/Precuneus Rt 188 20 -54 78 4.35
Occipital/Cuneus Lt 136 2 -102 18 4.30
Occipital/Cuneus Rt 197 26 -104 8 3.89
Cerebellum Crus Rt 104 48 -78 -22 4.01
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 4 Volume 43 (1), March 2011
decreases were seen. These ndings were consistent with our
hypothesis, except at this level we did not see increases in
temporal lobe perfusion. When the threshold was lowered to
p < 0.05 there were signicant increases in the left and right
fusiform gyrus and lateral temporal lobes. Symptomatically,
participants reported increases in memory (69%), attention
(53%), mood (38%), motivation (38%), and sleep (25%).
This clinical study targeted retired professional football
players who had experienced traumatic brain injuries as a
result of numerous impacts over extended periods of time.
Our goal was to design an interventional strategy that would
improve cognitive function by enhancing cerebral blood
ow, acetylcholine and antioxidant activity. We utilized a
standard brain imaging tool (SPECT) and a standard com-
puterized neuropsychological test (MACF) to determine if
improvement could be obtained. Our ndings on this unique
population are encouraging as we observed signicant im-
provements in general cognitive functioning, information
processing speed, attention and memory in close to half of
the participants. Plus, there were signicant increases in
regional cerebral blood ow seen on SPECT.
Areas of Increased Perfusion on SPECT with Treatment at p < 0.001 are Highlighted
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 5 Volume 43 (1), March 2011
The implications of this study directly apply to the larger
traumatic brain injury and substance abuse communities. We
were able to demonstrate improvement in brain function and
cognitive performance in retired players who sustained brain
injuries often decades previously, demonstrating brain plas-
ticity. This is an area where much more research is needed.
Because of the high incidence of traumatic brain injury and
the long-term damaging effects of substance abuse, focus-
ing on brain health and brain rehabilitation strategies in
addiction treatment programs could potentially signicantly
improve patient outcomes.
This clinical study is limited by its nonrandomized,
open-label, multifaceted design and the results must be
interpreted with caution. Our hope is to use this trial as a
starting point to more rigorously study the individual parts
of the treatment protocol and to extend the study to include
other types of brain damage, including blast injuries, single-
incident brain traumas, and substance abuse.
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... Amen et al. [34] Participants: Retired athletes with cognitive impairment and who experienced recurrent TBIs or SRCs during their playing career. Intervention: n-3FAs (1720 mg EPA and 1160 mg DHA), multivitamin and brain-enhancement supplement (containing antioxidants) with education for up to 1 year. ...
... The initial search identified 6164 articles using database searches. Following the title and abstract screening, 91 entire papers were retrieved and assessed for inclusion, with 9 being eligible for inclusion [34][35][36][37][38]40,48]. Walton et al. [41] was excluded in the final review stage because it was unclear whether the participants (ex-National Football League players with a history of SRC) had chronic symptomology. ...
... The participants had to make contact within 10 days of initial injury, and the intervention lasted 3 months. The majority of included studies were conducted after 2011 [34,35,37,38,40,41,48]. Of the ten studies, five were randomised-controlled trials (RCTs) [36][37][38]48]. ...
Full-text available
Mild traumatic brain injury (mTBI) represents a significant burden for individuals, economies, and healthcare systems worldwide. Recovery protocols focus on medication and physiotherapy-based interventions. Animal studies have shown that antioxidants, branched-chain amino acids and omega-3 fatty acids may improve neurophysiological outcomes after TBI. However, there appears to be a paucity of nutritional interventions in humans with chronic (≥1 month) symptomology post-mTBI. This systematic literature review aimed to consolidate evidence for nutrition and dietary-related interventions in humans with chronic mTBI. The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021277780) and conducted following the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three reviewers searched five databases (PubMed/MEDLINE, Web of Science, SPORTDiscus, CINAHL Complete and Cochrane), which yielded 6164 studies. Nine studies met the inclusion criteria. The main finding was the lack of interventions conducted to date, and a quality assessment of the included studies was found to be fair to good. Due to heterogeneity, a meta-analysis was not feasible. The six nutrition areas identified (omega-3 fatty acids, melatonin, Enzogenol® , MLC901, ketogenic diet and phytocannabinoids) were safe and well-tolerated. It was found that these nutritional interventions may improve cognitive failures, sleep disturbances, anxiety, physical disability, systolic blood pressure volume and sport concussion assessment tool scores following mTBI. Potential areas of improvement identified for future studies included blinding, reporting compliance, and controlling for confounders. In conclusion, further research of higher quality is needed to investigate the role of nutrition in recovery from mTBI to reduce the burden of chronic outcomes following mTBI.
... Of the 19 longitudinal studies, nine had 20 subjects or less. Four longitudinal studies had 100 subjects or more (64)(65)(66)(67). For example, Gowda et al. (66) prospectively performed CT and perfusion SPECT scans on 92 patients with acute TBI. ...
... Experts in the field are calling for greater collaboration between neurologists and nuclear medicine physicians to conduct the needed studies required to convince Neurology of the value of SPECT neuroimaging in the assessment of TBI (67,(108)(109)(110). Critics continue to claim that SPECT is not useful in the evaluation of TBI. ...
Full-text available
Brain perfusion single photon emission computed tomography (SPECT) scans were initially developed in 1970's. A key radiopharmaceutical, hexamethylpropyleneamine oxime (HMPAO), was originally approved in 1988, but was unstable. As a result, the quality of SPECT images varied greatly based on technique until 1993, when a method of stabilizing HMPAO was developed. In addition, most SPECT perfusion studies pre-1996 were performed on single-head gamma cameras. In 1996, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (TTASAAN) issued a report regarding the use of SPECT in the evaluation of neurological disorders. Although the TTASAAN report was published in January 1996, it was approved for publication in October 1994. Consequently, the reported brain SPECT studies relied upon to derive the conclusions of the TTASAAN report largely pre-date the introduction of stabilized HMPAO. While only 12% of the studies on traumatic brain injury (TBI) in the TTASAAN report utilized stable tracers and multi-head cameras, 69 subsequent studies with more than 23,000 subjects describe the utility of perfusion SPECT scans in the evaluation of TBI. Similarly, dementia SPECT imaging has improved. Modern SPECT utilizing multi-headed gamma cameras and quantitative analysis has a sensitivity of 86% and a specificity of 89% for the diagnosis of mild to moderate Alzheimer's disease—comparable to fluorodeoxyglucose positron emission tomography. Advances also have occurred in seizure neuroimaging. Lastly, developments in SPECT imaging of neurotoxicity and neuropsychiatric disorders have been striking. At the 25-year anniversary of the publication of the TTASAAN report, it is time to re-examine the utility of perfusion SPECT brain imaging. Herein, we review studies cited by the TTASAAN report vs. current brain SPECT imaging research literature for the major indications addressed in the report, as well as for emerging indications. In Part II, we elaborate technical aspects of SPECT neuroimaging and discuss scan interpretation for the clinician.
... In human studies, ALC has shown the ability to improve cognitive performance and slow decline in the early stages of neurodegenerative diseases (Spagnoli et al., 1991), as well as reduce neurodegenerative oxidative and nitrosative stress (Calabrese et al., 2003). Taken in conjunction with other nutritional supplements and lifestyle interventions, ALC has also demonstrated cognitive improvements and increased cerebral blood flow in retired American football players with a history of concussion (Amen et al., 2011). Furthermore, a human trial of L-carnitine on patient with severe TBI showed preservation of neurological function after just 1 week of daily administration (Mahmoodpoor et al., 2018). ...
Full-text available
Repetitive mild traumatic brain injuries (rmTBI) may contribute to the development of neurodegenerative diseases through secondary injury pathways. Acetyl-L-carnitine (ALC) shows neuroprotection through anti-inflammatory effects and via regulation of neuronal synaptic plasticity by counteracting post-trauma excitotoxicity. This study aimed to investigate mechanisms implicated in the etiology of neurodegeneration in rmTBI mice treated with ALC. Adult male C57BL/6J mice were allocated to sham, rmTBI or ALC + rmTBI groups. 15 rmTBIs were administered across 23 days using a modified weight drop model. Neurological testing and spatial learning and memory assessments via the Morris Water Maze (MWM) were undertaken at 48 h and 3 months. RT-PCR analysis of the cortex and hippocampus was undertaken for MAPT, GFAP, AIF1, GRIA, CCL11, TDP43, and TNF genes. Gene expression in the cortex showed elevated mRNA levels of MAPT, TNF, and GFAP in the rmTBI group that were reduced by ALC treatment. In the hippocampus, mRNA expression was elevated for GRIA1 in the rmTBI group but not the ALC + rmTBI treatment group. ALC treatment showed protective effects against the deficits displayed in neurological testing and MWM assessment observed in the rmTBI group. While brain structures display differential vulnerability to insult as evidenced by location specific postimpact disruption of key genes, this study shows correlative mRNA neurodegeneration and functional impairment that was ameliorated by ALC treatment in several key genes. ALC may mitigate damage inflicted in the various secondary neurodegenerative cascades and contribute to functional protection following rmTBI.
... Another aspect of biomarker utility is the demonstration of change. Perfusion SPECT scans have been utilized to demonstrate response to a number of novel treatments (15)(16)(17)(18). Best et al. revealed two additional novel treatments effective in complex, treatment-resistant cases of depression, dementia, and TBI. ...
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With an increasing number of neurodegenerative diseases and brain injuries, the focus of the research using synthetic and herbal medicines with an objective to treat the existing problems in neuroscience is ever-increasing. The availability of natural resources, knowledge about ancient herbs, and the mechanisms underlying neurodegenerative disorders and brain injuries is essential to developing herbal supplements with the potential to treat brain diseases and injuries. Despite the variety of synthetically manufactured drugs for brain health, the need for herbal and natural supplements is ever-rising due to the adverse long-term side effects of synthetic drugs. Ginkgo biloba — an Asian plant that is known to possess various neuroprotective properties — has been used as a medicine, even before 1505 AD. G. biloba extract EGB761 has been known to treat and manage impaired nervous system disorders. The current review discusses the neuroprotective properties of G. biloba and its repair mechanisms against subarachnoid hemorrhage, central nervous system (CNS) injuries like traumatic brain injury, ischemic brain injury, early brain injury, spinal cord injury, hypoxia, neuronal apoptosis, neurodegenerative diseases like Alzheimer’s, Parkinson’s, neuroplasticity, neurogenesis, synaptogenesis and its free radical scavenging activity, and neuroleptic properties for a nutritional approach to manage neurodegenerative disorders and CNS injuries.
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When mild traumatic brain injury (mTBI) occurs following an impact on the head or body, the brain is disrupted leading to a series of metabolic events that may alter the brain’s ability to function and repair itself. These changes may place increased nutritional demands on the body. Little is known on whether nutritional interventions are safe for patients to implement post mTBI and whether they may improve recovery outcomes. To address this knowledge gap, we conducted a systematic review to determine what nutritional interventions have been prescribed to humans diagnosed with mTBI during its acute period (<14 days) to support, facilitate, and result in measured recovery outcomes. Methods: Databases CINAHL, PubMed, SPORTDiscus,Web of Science, and the Cochrane Library were searched from inception until January 6, 2021; 4,848 studies were identified. After removing duplicates and applying the inclusion and exclusion criteria, this systematic review included 11 full papers. Results: Patients that consumed enough food to meet calorie and macronutrient (protein) needs specific to their injury severity and sex within 96 h post mTBI had a reduced length of stay in hospital. In addition, patients receiving nutrients and non-nutrient support within 24–96 h post mTBI had positive recovery outcomes. These interventions included omega-3 fatty acids (DHA and EPA), vitamin D, mineral magnesium oxide, amino acid derivative N-acetyl cysteine, hyperosmolar sodium lactate, and nootropic cerebrolysin demonstrated positive recovery outcomes, such as symptom resolution, improved cognitive function, and replenished nutrient deficiencies (vitamin D) for patients post mTBI. Conclusion: Our findings suggest that nutrition plays a positive role during acute mTBI recovery. Following mTBI, patient needs are unique, and this review presents the potential for certain nutritional therapies to support the brain in recovery, specifically omega-3 fatty acids. However, due to the heterogenicity nature of the studies available at present, it is not possible to make definitive recommendations. Systematic review registration: The systematic review conducted following the PRISMA guidelines protocol was registered (CRD42021226819), on Prospero. KEYWORDS: brain injury - traumatic, mild traumatic brain injury (mTBI), concussion, omega 3 (n-3) polyunsaturated fatty acids, vitamin, supplementation, nutrition
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Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
Traumatic brain injury and the susceptibility to secondary injury pose a public health problem with a substantial financial burden on the society. Current researches suggest that consumption of certain diets or their associated physiologically active constituents may be linked to disease risk reduction. This chapter reviews some of the extensively explored dietary supplements like eicosapentaenoic acid, docosahexaenoic acid, creatine, vitamins, zinc, magnesium, and their clinical interventions for the treatment of TBI and recovery from the tissue damage. On the brighter side, there appear to be no adverse effects to any of these dietary supplements, when used appropriately. The major challenges of the future are performing well-designed clinical studies in patients to confirm anticipated effects, to define the optimal doses, to compare single vs multiple dietary components, and to assess possible side effects.
Sports deserve a special place in human life to impart healthy and refreshing wellbeing. However, sports activities, especially contact sports, renders athlete vulnerable to brain injuries. Athletes participating in a contact sport like boxing, rugby, American football, wrestling, and basketball are exposed to traumatic brain injuries (TBI) or concussions. The acute and chronic nature of these heterogeneous injuries provides a spectrum of dysfunctions that alters the neuronal, musculoskeletal, and behavioral responses of an athlete. Many sports-related brain injuries go unreported, but these head impacts trigger neurometabolic disruptions that contribute to long-term neuronal impairment. The pathophysiology of post-concussion and its underlying mechanisms are undergoing intense research. It also shed light on chronic disorders like Parkinson's disease, Alzheimer's disease, and dementia. In this review, we examined post-concussion neurobehavioral changes, tools for early detection of signs, and their impact on the athlete. Further, we discussed the role of nutritional supplements in ameliorating neuropsychiatric diseases in athletes.
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OBJECTIVE Cerebral concussion is common in collision sports such as football, yet the chronic neurological effects of recurrent concussion are not well understood. The purpose of our study was to investigate the association between previous head injury and the likelihood of developing mild cognitive impairment (MCI) and Alzheimer's disease in a unique group of retired professional football players with previous head injury exposure. METHODS A general health questionnaire was completed by 2552 retired professional football players with an average age of 53.8 (±13.4) years and an average professional football playing career of 6.6 (± 3.6) years. A second questionnaire focusing on memory and issues related to MCI was then completed by a subset of 758 retired professional football players (≥50 yr of age). Results on MCI were then cross-tabulated with results from the original health questionnaire for this subset of older retirees. RESULTS Of the former players, 61% sustained at least one concussion during their professional football career, and 24% sustained three or more concussions. Statistical analysis of the data identified an association between recurrent concussion and clinically diagnosed MCI (χ² = 7.82, df = 2, P = 0.02) and self-reported significant memory impairments (χ² = 19.75, df = 2, P = 0.001). Retired players with three or more reported concussions had a fivefold prevalence of MCI diagnosis and a threefold prevalence of reported significant memory problems compared with retirees without a history of concussion. Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population CONCLUSION Our findings suggest that the onset of dementia-related syndromes may be initiated by repetitive cerebral concussions in professional football players.
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The authors recruited 100 active and former National Football League players, representing 27 teams and all positions. Players underwent a clinical history, brain SPECT imaging, qEEG, and multiple neuropsychological measures, including MicroCog. Relative to a healthy-comparison group, players showed global decreased perfusion, especially in the prefrontal, temporal, parietal, and occipital lobes, and cerebellar regions. Quantitative EEG findings were consistent, showing elevated slow waves in the frontal and temporal regions. Significant decreases from normal values were found in most neuropsychological tests. This is the first large-scale brain-imaging study to demonstrate significant differences consistent with a chronic brain trauma pattern in professional football players.
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Brain SPECT imaging is a nuclear medicine study that uses isotopes bound to neurospecific pharmaceuticals to evaluate regional cerebral blood flow (rCBF) and indirectly metabolic activity. With current available technology and knowledge SPECT has the potential to add important clinical information to benefit patient care in many different areas of a substance abuse practice. This article explores the clinical controversies and limitations of brain SPECT, plus seven ways it has the potential to be immediately useful in clinical substance abuse practice, including: adding valuable information to the prevention, evaluation, and treatment of substance abusers; helping clinicians ask better questions; helping them in making more complete diagnoses and preventing mistakes; evaluating underlying brain system pathology in individual patients; decreasing stigma and increasing compliance; visualizing effectiveness via follow-up evaluations; and encouraging the exploration of innovative and alternative treatments.
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A significant proportion of the general population report supplementing their diet with one or more vitamins or minerals, with common reasons for doing so being to combat stress and fatigue and to improve mental functioning. Few studies have assessed the relationship between supplementation with vitamins/minerals and psychological functioning in healthy cohorts of non-elderly adults. The present randomised, placebo-controlled, double-blind, parallel groups trial assessed the cognitive and mood effects of a high-dose B-complex vitamin and mineral supplement (Berocca(R)) in 215 males aged 30 to 55 years, who were in full-time employment. Participants attended the laboratory prior to and on the last day of a 33-day treatment period where they completed the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and General Health Questionnaire (GHQ-12). Cognitive performance and task-related modulation of mood/fatigue were assessed with the 60 min cognitive demand battery. On the final day, participants also completed the Stroop task for 40 min whilst engaged in inclined treadmill walking and subsequent executive function was assessed. Vitamin/mineral supplementation led to significant improvements in ratings on the PSS, GHQ-12 and the 'vigour' subscale of the POMS. The vitamin/mineral group also performed better on the Serial 3s subtractions task and rated themselves as less 'mentally tired' both pre- and post-completion of the cognitive demand battery. Healthy members of the general population may benefit from augmented levels of vitamins/minerals via direct dietary supplementation. Specifically, supplementation led to improved ratings of stress, mental health and vigour and improved cognitive performance during intense mental processing.
There is substantial evidence that omega-3 polyunsaturated fatty acids (PUFAs) have therapeutic potential in neurology and psychiatry. Spinal cord injury (SCI) and traumatic brain injury (TBI) have dramatic consequences, and no neuroprotective or neuroregenerative treatment is available. The pathogenetic mechanisms involved in SCI and TBI include excitotoxicity associated with increased glutamate, oxidative stress and neuroinflammation. Studies have shown that omega-3 PUFAs can induce significant neuroprotection in SCI. In rat hemisection and compression SCI, long-chain omega-3 PUFAs such as docosahexaenoic acid, administered within the first hour after injury, can reduce neuronal and glial cell death, limit oxidative stress and the inflammatory cascade triggered by the primary injury, and improve neurological function. Emerging observations in TBI support a similar neuroprotective potential. Omega-3 PUFAs also have neurotrophic properties. These findings support the idea that treatment with omega-3 PUFAs could represent a promising therapeutic approach in the management of neurotrauma, which would be easy to translate to the clinic, considering the well-documented safety and tolerability of these compounds in other indications.
Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data. The importance of this framework is twofold: (i) Conceptual and mathematical simplicity, in that the same small number of operational equations is used irrespective of the complexity of the experiment or nature of the statistical model and (ii) the generality of the framework provides for great latitude in experimental design and analysis.
One of the biochemical pathways affected by aging in all organisms is protein synthesis. Previous reports from our laboratory have indicated that the elongation step is specially affected by aging as a consequence of alterations in elongation factor-2 (eEF-2). In the present work, we studied in vitro the effectiveness of several individual nutritional antioxidants in protecting the levels of hepatic eEF-2 subjected to oxidative stress induced by cumene hydroperoxide. The in vitro system employed consisted of rat liver homogenates treated with cumene hydroperoxide. The antioxidants used in this study were lipoic acid, coenzyme Q10, tethrahydrofolic acid, and N-tert-butyl-alpha-phenylnitrone. The results indicate that the antioxidants have different capacities to prevent eEF-2 loss, folic acid being the most effective. A comparison between the antioxidants used and their potential pro-oxidant activity is also discussed, on the basis of the oxidative stress parameters measured.
Explore the incidence of traumatic brain injury (TBI) in veterans seeking outpatient substance abuse treatment and the association between TBI and psychiatric diagnoses. The Ohio State University TBI identification method (OSU TBI-ID) was administered to veterans with positive TBI-4 screens; substance-related and psychiatric diagnoses were extracted from the medical record. : Over an 18-month period, 247 veterans completed the TBI-4. Of the 136 who screened positive, 70 were administered the OSU TBI-ID. On the basis of the TBI-4, 55% (95% CI: 49%-61%) of veterans screened positive for a history of TBI. The OSU TBI-ID was used to confirm screening results. Those who completed the OSU TBI-ID sustained an average of 3.4 lifetime TBIs. For each additional TBI sustained, after initial injury, there was an estimated 9% increase in the number of psychiatric diagnoses documented (99% CI: 1%-17%). For each additional documented psychiatric diagnosis, there was an estimated increase of 11% in the number of injuries sustained (99% CI: 1%-22%). Also, 54% (38/70) had a positive history of TBI prior to adulthood. These results emphasize the need for TBI screening in this vulnerable population, as well as the importance of increasing brain injury awareness among those abusing substances and their care providers. These findings also highlight the need for specialized services for those with TBI and co-occurring substance misuse aimed at decreased future TBIs or negative psychiatric outcomes or both. Further study is needed to clarify best practices.
l-carnitine is present in mammalian cells as free carnitine and acylcarnitines. The acylcarnitine profile has been shown to be useful in identifying inborn errors of metabolism and to be altered under different metabolic conditions. While carnitine's most widely known function is its involvement in beta-oxidation of fatty acids, it may also have other roles in metabolism. The importance of acylcarnitines in tissues with high rates of beta-oxidation such as heart and muscle is intuitive. However, acylcarnitine and carnitine supplementation have resulted in beneficial effects in the treatment of various neurological diseases, even though fat is not the major fuel for brain. Recent data indicate new, multifactorial roles for acylcarnitines in neuroprotection. Brain acylcarnitines can function in synthesizing lipids, altering and stabilizing membrane composition, modulating genes and proteins, improving mitochondrial function, increasing antioxidant activity, and enhancing cholinergic neurotransmission. Currently a relatively small subset of acylcarnitines is usually investigated. More research is needed on the use of acylcarnitines in the treatment of neurological diseases using a list of acylcarnitines encompassing a wide range of these molecules. In summary, carnitine is not merely a cofactor in beta-oxidation, but rather it has many known and yet to be discovered functions in physiology.
Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.