Novel Therapies for Cognition, Concussion, Dementia, Demyelination, Neurodegeneration, Stroke, TBI, SCI, & Neural Functions
Neuroprotective and nootropic agents in the treatment of nervous system injuries, conditions, & disorders.
"Consciousness dashes and ambles around the labyrinthine tracks of the mind, returning again and again, however briefly, to the senses." --Annie Dillard.
Concussion and traumatic brain injury (TBI) events can be life-altering events for patients. TBI mechanisms are complex and multifactorial, which is why we take the utmost care in assessing these injuries. TBI often involves not just direct biomechanical neural damage, but also significant vascular, hormonal, and immune changes that have long-term effects. This includes notable effects on cerebral vascular flow and activation of microglia. Normally microglia are neuroprotective, cleaning out debris that may contribute to neurodegenerative diseases or damage from ischemic stroke, but in the case of TBI it appears they can become overactivated and exacerbate neuroinflammation (with upregulated TNFa, C3, NK-kB, CD68, etc), and vascular changes can result in headaches, neurovascular flow changes, and blood-brain barrier disruption. Some evidence suggests that nutrition and diet can be protective of neural function, especially with the MIND diet focused on anti-inflammatory, antioxidant, and leafy green foods (1). With more severe injury, synapse disruption, axonal injury, excitotoxicity, and cell death also become major effectors. In animal models, inhibition of certain tyrosine-kinase receptors has shown good recovery (VEGF/MET) but this has not yet been applied to human trials. I suspect that in mild TBI, VEGF activation may be beneficial (having shown improved neurolymphatic flow and perfusion for greater learning and memory), but in moderate to severe TBI it may be far more therapeutic to block VEGF/MET to prevent neuroglial overactivation, gliosis, and chemokine secretion, and we hope to conduct further research on these conditions.
For now, neurological and cognitive assessments as well as imaging studies can be useful (such as brain MRI with vascular flow, functional MRI, PET scan, and/or NeuroQuant imaging). Hormone testing is helpful-- especially for pituitary functions that affect stress hormones, sex hormones, fluid balance, and prolactin release ("post-traumatic stalk syndrome")-- and additional labs can further help identify the extent and severity of neural injury as well as the potential for progression to cognitive impairment or dementia (including tests such as phosphorylated tau protein, neuron-specific enolase, 14-3-3 protein, neurofilament light-chain, amyloid 42/40 ratio, GFAP, ApoE4, etc.). Evidence suggests that people who test positive for glial inflammation (aka astrocyte reactivity) as well as plaque formations are the most predisposed to progress toward symptoms of cognitive decline (2). The most recent research has demonstrated a detailed progression of biomarkers and mechanisms necessary for understanding Parkinson's and Alzheimer's disease development, and "elevated neuroinflammatory responses have been implicated in neurodegenerative diseases, such as PD and Alzheimer’s disease." Because mesenchymal stem cells (MSCs) have been shown to produce anti-inflammatory effects in neural tissue, "these findings have led to increased interest in MSCs as a potential cell source candidate owing to their immunomodulatory effect [and] MSCs have demonstrated the capability to differentiate into astrocyte-like cells that secrete neurotrophic factors and ameliorate the motor deficits in a rodent model of PD." (3a) (3b) Patients' own MSCs can safely be harvested and prepared for many specific applications with substantial evidence of good safety and effectiveness, and we continue to investigate their unique benefits in the treatment of ischemic stroke and neural tissue repair (3c).
In addition to the above tests, there are also many types of neuroprotective therapies that can be helpful in brain injury and cognition after a concussion, including certain types of neuroprotective infusions and nootropic medications, as well as many types of nerve blocks, ganglion blocks, and trigger point injections can also substantially relieve many symptoms and regulate neurovascular control. Anti-epileptic medications are generally avoided except in the context of post-traumatic seizures, but some headache and anti-depressant medications can sometimes be helpful. Many types of neuroprotective agents, neurocognitive agents, peptides, and antioxidant infusions can also help neurocognitive recovery, while some modulators of BDNF and VEGF remain experimental, and stem cell therapies continue to be researched and optimized for neuroprotection and brain recovery. Many post-traumatic brain injuries present with significant neurovascular flow changes, which is why our approach of transcranial ultrasound imaging of cerebral vessels can help directly visualize and measure perfusion and flow problems non-invasively in many cerebrovascular brain disorders (4a) including traumatic brain injury, stroke, vasospasm, micro-emboli, atherosclerosis, headaches, Alzheimers disease, dementia, and others. This technology can also be used to temporarily open blood-brain-barrier (along with microbubble techniques) to deliver neuroprotective agents and other medications directly to brain tissue (4b) (4c) (4d) (4e) (4f) (4g) (4h).
We are also offering stem cell therapies for neural injuries and conditions, which have recently been shown to be useful for traumatic spine injury, traumatic brain injury, stroke, concussion, dementia, and even neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS (5) (6) (7) (8) (9) (10) (11) (12a) (12b) (12c). Stem cells and exosomes may protect neuron function by many mechanisms including releasing neurotrophic growth factors, regulating glial cell activity, enhancing BDNF activity, shutting off neuroinflammatory signals, controling cell turnover and cell death, downregulating formation of plaque, gliosis, and scar, and upregulating microRNA expression signals for neural repair (13) (14) (15) (16) (17) (18). Stem cell options vary considerably for what targets and delivery route should be used (intravascular, intrathecal, epidural, intranasal (olfactory/sphenopalatine ganglion), intraventricular, etc.), but we are on the cutting edge to optimize these therapies and publish significant research on this work in the future! (18a) (18b) (18c) (18d) (18e) (18f) (18g)
Much research has recently been published in some of the most prestigious academic journals showing extraordinary new strides in understanding the molecular mechanisms of neural function, stem cells, peptides, hormones, and other important signaling mechanisms, all of which can be modulated in beneficial ways. These can include Sirtuin, mTOR, AMPK, WNT, HDAC, GH, Telomerase, and many other signaling pathways that modify DNA methylation patterns and transcriptional activity involved in the biological processes of injury and regeneration, thereby driving epigenetic, transcriptomic, and metabolomic changes in many types of cells and tissues. Fortunately, we now provide numerous scientifically-backed therapies available directly in our clinic, and we provide individualized care with an integrative functional medicine approach to your recovery.
More advanced regenerative therapies have also been discovered and are now being implemented clinically. The 2009 Nobel Prize winning discovery of telomeres and telomerases was first made in the ancient, long-lived Bristlecone Pines, then found to also be at work to a lesser degree in human cells. The discovery of the mTOR enzyme also uncovered a fascinating mechanism of metabolic controls in the cell, where mTOR acts as a major regulator of cell metabolism and is heavily involved in stem cell differentiation, acting as a sort of integrated metabolic switch and fuel sensor of oxygen, amino acids, and energy supply. When mTOR is inhibited under hypoxic or low-calorie conditions (as happens in endurance exercise), it promotes stem cell mainenance and regenerative capabilities. Dr. McMurtrey published a summary of his own stem cell research work describing the complexity of these signaling pathways in the academic journal Stem Cells & Development. Evidence suggests that the above-listed phytomolecules, flavonoids, anti-oxidant-rich, fiber-rich, vegetable-focused diets, along with exercise, can both enhance telomere length and inhibit mTOR to promote stem cell maintenance and the cellular regenerative capabilities of more youthful cells both in laboratory culture and in the human body (19) .
Cellular Regenerative Potential: Ground-breaking research has shown that NAD+, NR, or NMN can renew stem cell profiles, increase the regenerative capacity of cells, and induce more youthful epigenetic landscapes in our DNA via a class of signaling molecules known as "sirtuin modulators" (SIRT1) and "calorie restriction mimetics" that activate or inhibit certain sirtuin gene functions, and in numerous studies they have shown measurable anti-aging effects at the cellular and organ levels all the way up to measurable gains in muscle repair strength and physical and mental performance capacity (20) (21) (22) (23) (24) (25) (2) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40). Agents like Sirolimus, NAD+, and related co-factors optimize cellular metabolism and prime cells to better adapt to metabolic demands and regenerate via these Sirtuin-1 (SIRT1) pathways. SIRT1 is also known as the "longevity gene" because of its role in reducing the risk of diabetes, obesity, metabolic syndrome, atherosclerosis, kidney disease, liver disease, neurodegeneration, and cancer. Activation of Sirtuin has been shown to suppress reactive astrocytes and can thus be used to help treat many forms of neurological disorders like traumatic brain injury and inflammatory neurodegenerative diseases like multiple sclerosis (41). There may also be a role for its use in rapid muscle repair as well as several muscle wasting diseases and mitochondrial disorders (42) (43) (44). Many other pathways are also involved in these effects, like mTOR and AMPK signaling pathways that increase the capacity of cells to renew, proliferate, and differentiate. We provide sirtuin modulators like NAD+ therapy and other medications that provide a unique anti-aging effect that can be injected or infused intravenously in the clinic for best absorption by cells, providing optimal dosing and bypassing digestive tract and absorption limitations. We also provide prescriptions for other types of anti-aging medications like metformin semaglutide, tirzepatide, and others (see below). Interestingly, other variants of this class of molecules like niacin or vitamin B3 do not appear to exhibit such extent of anti-aging or neuroprotective effects.
Cognitive Recovery, Improvement, Neuroprotection, & Mental
Acuity:
We provide many potential options for treating and combating brain and
spinal cord injuries, concussion effects, cognitive decline,
demyelination, multiple sclerosis, Alzheimer's disease, Parkinson's
disease, and other forms of neurodegeneration and dementia, including
prescriptions for neuroprotective agents, peptides, nootropic
peptides, antioxidants, medication infusions, NAD+, ALA, GSH,
methylene blue, ergoloid mesylates, ALA, and many others-- see our
peptides (like BPC-157, Semax, TB-500,
Epithalon, P021, NVG-291, BIIB080, or others) and
IV infusion pages for additional details
on many additional therapies. We can also order many types of brain
imaging studies to specifically quantify neuron damage and many
diagnostic lab tests to help establish a proper detailed diagnosis in
complex cases, and do transcranial doppler ultrasound imaging of
brain and cerebrovascular flow as well as ultrasonic blood-brain
barrier opening directly in the clinic.
Methylene blue (MeBl) was first noted as a potential therapy for
dementia when it was dropped on an Alzheimer's tissue sample and
found to help dissolve fibrillary tangles and amyloid plaques
associated with the disease. Interestingly, in addition to the
potential cognitive benefits and protective effects against
Alzheimer's disease
(45)
(46)
(47)
(48)
(49), methylene blue appears to have more general neuroprotective
memory-enhancing properties and is being studied as a therapeutic
agent for improving brain function after concussion and traumatic
brain injury
(50)
(51)
(52)
(53). MeBl is also being studied for its anti-aging and anti-cancer
properties
(54)
(55)
as well as for its therapeutic effects on peripheral neuropathy and
nerve pain
(56)
(57)
(58)
(59)
(60)
Interestingly, MeBl has also been shown to enhance fibroblast
rejuvenation and collagen production in skin, similar to GHK-Cu
peptide, giving a more youthful appearance and texture
(61)
(62)
(63).
In addition to MeBl therapy, evidence shows that some types of
dementia are associated with certain deficiencies and may be stopped
and even reversed by infusions of agents such as glutathione and
methyl-B12 injections
(64)
(65)
(66). As we age, B12 levels tend to decline, and low B12 levels and
high homocysteine levels have been linked with dementia onset as
well as several inflammatory diseases, but B12 injections restore
B12 to healthy levels and reduce homocysteine (making it also
beneficial for cardiovascular disease)-- see the
infusions page for more info. Although
cholesterol is essential for certain cell functions, there may be a
role for atorvastatin in preventing some dementias (especially in
patients with certain metabolic syndromes or with ApoE4 mutations),
with possible reduction of β-amyloid production, reduction of
vascular inflammation, protection of endothelial cell function and
reduction of brain ischemia
(67). Most importantly, numerous other neuroprotective and neurotrophic growth factors like BDNF-analogs and LM11A-31 are currently being studied for their cognitive and therapeutic benefits, especially their ability to preserve and promote neural networks and neuron health, particularly in the setting of neurodegenerative diseases like Alzheimer's disease, FrontoTemporal Dementia (FTD), Parkinson's Disease (PD), and Lewy-Body Disease, as well as ischemic or traumatic neural injury
(68a)
(68b)
(68c)
(68d). Thus therapeutic approaches differ based on the underlying mechanisms of amyloidopathies, tauopathies, synucleinopathies, vasculopathies (e.g. cerebrovascular disease, microvascular disease, vascular dementia, or ischemic injury), autonomic failure, multiple system atrophy, demyelinating diseases (e.g. multiple sclerosis), and so on.
We also offer many therapies for traumatic brain injury,
concussion, nerve injury, cognition, dementia, neurodegeneration,
neuroinflammation, migraines, and post-operative neural tissue
healing. Several studies have suggested that brain injuries have
many complex interacting mechanisms, often involving autonomic
dysregulation and changes in vascular flow dynamics in addition to
possible neural and axonal damage. We can provide counseling on many
different therapies and medications specific to your particular
injury and condition. Evidence suggests that stellate ganglion
blocks may be helpful for many types of concussion, brain injury,
autonomic dysregulation, and PTSD symptoms
(see the pain treatments page). Also, in 2015 researchers discovered that the brain has its own
lymphatic system and that lymph flow can influence neurodegenerative
and neuroinflammatory disease processes
(69), which the National Institutes of Health described as one of the
'most promising medical discoveries with potential for enhancing
human health' in 2018. The brain must clear out the metabolic
byproducts and wastes from each day through the lymph system and
into the venous drainage, much like flushing a toilet, and this
process requires both sleep and lying down, which maximizes both
lymphatic and venous outflow. When this process is inhibited it can
result in accumulated proteins, toxins, and metabolic byproducts in
the brain that may lead to dementia. We have developed vascular doppler
blood-brain barrier ultrasound analysis, personalized
IV infusions, therapeutic
nerve blocks, nutrition strategies, spinal interventions, peptide therapies, specialized lab analysis, stem cell therapies, regenerative interventions, prolotherapy, hydrodissection of nerve entrapments, hormone optimization for the syndrome of cognitive impairment, cognitive decline, brain fog, headaches and/or neck pain, plus there are also additional therapies under investigation like certain peptides (possibly including BPC-157,
Semax, TB-500, Epithalon, P021, NVG-291, BIIB080, or others) and Sirtuin
modulators listed above, as well as
shockwave therapy,
myofascial release, and image-guided
nerve releases and procedures that can relieve pain, release spasms,
and increase lymphatic flow.
Hormone Optimization & Hormone Replacement Therapy: Traumatic injury to the brain can often result in hormonal imbalances and pituitary dysfunctions that give rise to long-term detrimental effects, particularly with altered blood supply or mechanical shearing effects on hormone-regulating neural pathways in the hypothalamus and pituitary gland. We are able to test for hormonal imbalances and pituitary dysfunctions after concussion, stroke, trauma, or other central nervous system injuries. Interestingly, new research is also being conducted using specific neuroactive hormones and peptides to treat many conditions that affect neural function in the brain, spinal cord, and peripheral nerves. For example, it was recently found that that replacement of growth hormone could improve cerebral metabolism, knowledge, memory, and behavior in mild cognitive impairement (70), and that replacement of a natural signaling peptide called Gonadotropin-Releasing Hormone (GnRH) could significantly improve learning and cognition in Down's syndrome patients (71). In addition, as we age, normal levels of hormone can drop precipitously, but using safe and established protocols that replicate natural physiology, these processes can be reversed and youthful vigor restored in healthy and targeted ways. One approach to anti-aging medicine is to restore declining levels of endocrine hormones to more normal youthful levels, including thyroid, growth hormone, or sex hormones. For example, when prescribed and used appropriately, testosterone and other hormones can be very safe and effective in improving physical function, lean body mass, bone density, vitality, longevity, energy, mood, and sexual function, while also reducing adiposity, cholesterol, insulin resistance, and when used properly evidence shows such interventions do not generally increase the risk of prostate cancer (72) (73) (74). Furthermore, numerous studies have shown neuroprotective and neuroregenerative effects of bio-identical testosterone in addition to accelerated healing from musculoskeletal injuries (75) (76) (77) (78) (79) (80) (81) (82) (83). There can be some small risks with some types of hormone replacements, but with proper modern optimization protocols that can augment your own natural hormone production, these risks are generally avoidable, rare, or temporary, meaning any risks can easily be minimized by tailoring protocols to your specific personal needs and physiology.
See more information at our peptides page and more information on anti-inflammatory, anti-oxidant, anti-cancer, and immunomodulatory agents on our infusions page.
Altogether, the above therapeutic agents show fascinating effects on the internal workings of cells, ultimately steering their functions and fates. These different cell fates can be thought of as a landscape or manifold where cell functions navigate through different topologies and over time they naturally come to rest at steady-states at certain depressions in the landscape. Researchers are vigorously studying cell pathways involved in these different states and have made several interesting and surprising discoveries. For example, by focusing on just three different modes of aging in yeast cells, researchers found that the complex interactions among multiple complex pathways could be modelled mathematically, providing a better understanding of these landscape patterns in aging and allowing them to drive certain gene expression patterns that could optimize cell lifespan (84). We strive to lead the way in keeping up to date with all the latest research and clinical applications in regenerative therapies for numerous types of neurological disorders.
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ASOI © 2021 All Rights Reserved*Disclaimer: We seek to always provide the highest-quality evidence-based care to our patients customized for their specific conditions, injuries, and diagnoses, which may include FDA-approved therapies as well as additional investigational, alternative, or regenerative therapies. We always discuss potential risks and benefits of all these options. The information presented here is for informational use and cites the ongoing cutting-edge research and medical advancements on these relevant topics. There are many treatments, interventions, and protocols routinely practiced in medicine and surgery which the FDA has not studied nor formally approved yet which have demonstrated overwhelming evidence of efficacy and clinical benefit, while many standard treatments and common surgeries can actually have high rates of failure and complication. The FDA does not regulate the practice of medicine but rather regulates medical marketing of devices and drugs. The FDA does not conduct clinical trials or attempt to discover new treatments, but rather requires companies or other entities to fund marketing approvals. Breakthrough technologies typically require years to decades of research work to optimize the technology and collect enough data to prove efficacy and superiority, which in some cases can optionally be submitted to the FDA if there is sufficient financial backing to market a specific product or drug. Thus the FDA has not yet studied, evaluated, or formally approved many regenerative therapies currently practiced by many of the top physicians and surgeons in the United States and around the world. Some therapies, products, or interventions may still be considered investigational or "off-label" even with substantial evidence of efficacy, and many different applications of regenerative therapies continue to be researched by our institute and other top institutions around the world. The rapid evolution and advancement of medicine demands that physicians continually update their knowledge and practice techniques to adapt to future improvements and advancing technologies. These statements have not been evaluated by the FDA, and the treatments and products presented here are for informational purposes and not guaranteed to diagnose, treat, cure, or prevent any specific disease or condition. All injuries and conditions should be formally evaluated by a knowledgeable medical professional whereby standard treatments and additional therapeutic interventions may be considered with the diagnosis and treatment plan.