Long time readers of the Moss Nutrition Report may remember that I became quite interested in the late 90s and early 2000s in mood and behavioral disorders such as attention deficit hyperactivity disorder (ADHD), burn-out, and the anti-social behavior that happened at Columbine High School and many other locations, as we have seen all too often since. At that time my focus was research on stress endocrinology (cortisol, etc.), toxicology, and diet. However, as compelling as all this research was, I had a lingering feeling that there was much more to these neurologic disorders than just diet, toxicology, and psychological stress. Not just anything, though. It was something big that underlies not only the behavioral disorders mentioned above that I was addressing but virtually all chronic behavioral and neurodegenerative disorders.
Of course, many felt that what I was missing was acknowledgement of traditional biobehavioral issues such as parental and social relationships and attitudinal issues about life in general that are addressed through counseling and medication. While I certainly agree that traditional approaches offered by psychologists and psychiatrists have great value, I still felt something was missing.
Could this something big that I was missing in terms of chronic neurologic dysfunction be related to neurotransmitter activity, particularly in relation to key neurotransmitters such as serotonin, dopamine, GABA, glutamate, etc.? Interestingly, the idea of manipulating neurotransmitters to address mood, behavioral, and neurodegenerative disorders is nothing new. For, treating disorders such as depression and anxiety by modulating neurotransmitters with drugs such as benzodiazepines, monoamine oxidase inhibitors, and tricyclines had occurred since the 1950s. Then, as we all know, modulation of serotonin using selective serotonin reuptake inhibitors (SSRIs) gained great popularity in the 1980s and has remained popular since that time. Unfortunately, though, all these drugs often demonstrated inconsistent efficacy and sometimes significant side effects.
During the late 90s and early 2000s many in the alternative medicine community took note of the successes and failures of pharmacologic approaches to modulate neurotransmitters in patients suffering from mood, behavior, and neurodegenerative disorders and theorized that supplementation of certain natural substances could demonstrate at least equal results seen with the pharmaceutical approaches with greatly reduced side effects. Furthermore, it was postulated that efficacy with natural substances could be enhanced even more if recommended based on individualized measurements of either neurotransmitters or neurotransmitter metabolites in the urine. All these years later, has this approach delivered all that was promised? Just about everyone with whom I spoke agreed that this approach yielded fewer side effects than the pharmaceutical approach. Unfortunately, efficacy feedback has been very conflicted. On one hand, some of you felt outcomes were impressive. However, other equally compelling feedback I have received suggests that efficacy of this approach has been frustratingly unpredictable.
Despite all this unpredictability and uncertainty, though, in the early 2000s I still was of the belief that mood, behavior, and neurodegenerative disorders could be reliably and predictably be addressed purely by modulating neurotransmitters with natural substances. However, I was also of the opinion that more predictable efficacy could only be obtained if we could understand why imbalances in neurotransmitters occurred with these conditions. What was causing the neurotransmitters to be imbalanced in the first place? For, if we could not answer this question, even if good symptomatic results were obtained with natural substances, we would be condemning patients to a lifetime of use since causes were not being addressed and symptoms would, therefore, inevitably return with discontinuation of supplementation.
To address this concern about “why,” about 10 years ago I started an intensive self-education program on neurotransmitters and their metabolism through seminars and reading many studies and texts on the subject. Unfortunately, the more I learned, the more confused and frustrated I became. Yes, I did learn much about the biochemistry and physiology of neurotransmitters. I also encountered many books, research papers, supplement companies and “experts,” all advocating a myriad of “state-of-the-art” functional lab tests and panacea-like treatment approaches employing pharmaceutical and/or natural approaches. However, my question of “why” was rarely addressed and when it was I usually received one of the following, somewhat dismissive, replies:
1. The answer is diet, food allergies, toxins, and exercise.
My reply: Over the years I have met many people with neurologic disorders who optimally exercise, eat excellent diets, and carry toxic loads consistent with a large portion of the general population. In my mind there had to be more to “why” than just diet, exercise, and toxic load.
2. The answer relates to somewhat complicated neurochemistry and neurophysiology that I alone have discovered.
My reply: While I am certainly far from an expert on neurochemistry and neurophysiology, it has been my experience that true experts can provide explanations that do not require an advanced Ph.D. to understand. Furthermore, it has been my experience that true experts can provide explanations for which credible documentation can be found from other experts who publish in reputable journals. Finally, it seems to me that the most universally respected experts, one of whom I will discuss shortly, generally report that truth can most often be found through simplicity, not complexity.
Not getting the answers I was seeking as to “why,” I hypothesized that a highly regarded textbook on neuropsychiatry might give me the answers as to why neurotransmitters are imbalanced with neurologic disorders. Therefore, I consulted the text Neuropsychiatry edited by Fogel et al (1). Unfortunately, while the text profusely described the many complex disturbances in neurotransmitter and neurotransmitter receptor activity seen with various neurologic disorders and provided great detail on the impact of pharmaceuticals on symptoms and neurotransmitters and their respective receptors, I was disappointed to find that virtually nothing was stated as to what led to the neurotransmitter and receptor site imbalances.
In the end, none of these sources with all their lab tests and expertise could not answer my central question that I felt must be answered to reduce unpredictability, disappointment, and needless expense when the recommended “panaceas” did not work and avoid a lifetime of dependence when they did. Why were the neurotransmitters imbalanced in the first place??? All my years in health care and alternative medicine had led me to the conclusion that, for virtually every chronic illness, unless causes are also addressed, from a long term standpoint pharmaceutical and/or supplemental approaches will yield highly unpredictable results. Why should neurologic disorders be any different?
Having reached what appeared to be a dead-end in pursuit of the answers to my question of “why,” I largely gave up my search and put the whole subject in the back-burner of my mind. Then, quite unexpectedly, at a symposium I was attending about 6-7 years ago, I finally had an extended conversion with one of those true experts I alluded to above who many of you probably know, Richard Lord, Ph.D. For those of you who do not know Dr. Lord, for many years he was the director of the Department of Science and Education at Metametrix Clinical Laboratory. In addition, he was the co-author of the universally recognized standard text on functional medicine diagnosis “Laboratory Evaluations for Integrative and Functional Medicine, Revised 2nd Edition” (2). I had known Dr. Lord for many years previously and was familiar with his work and research, particularly in the area of clinical application of organic acids testing. Because of this, our conversation at that meeting 6-7 years ago focused on organic acids. While much of the conversation was somewhat routine, one topic that related to a specific portion of the organic acids profile caused Dr. Lord to demonstrate excitement and enthusiasm I had rarely seen in a top expert and researcher. While I must admit that I did not understand much of what Dr. Lord was telling me, it was clear from his passion that the organic acid neurotransmitter metabolites involved with what is known as the “kynurenine pathway” were a “Rosetta stone” of sorts in terms of understanding neurologic disorders. It was also clear that I was finally getting my answer to the question “why.” As I mentioned, during that conversation my comprehension was limited. However, what I did understand is that the key neurotransmitter involved in neurologic disorders, serotonin, is a metabolite of the essential amino acid tryptophan. Furthermore, with many neurologic disorders tryptophan is diverted away from the production of serotonin to another set of metabolites collectively called “kynurenine” metabolites. Finally, as I mentioned above, Dr. Lord, being a true expert, was able to make his key points on the kynurenine pathway easy to understand. In addition, as is also found with true experts, I discovered after our conversation that it was easy to find profuse research documentation to support everything Dr. Lord had told me and so much more.
What you are about to read in this series is the result of my years of reading and study that was inspired by that conversation with Dr. Lord. As an overview of what you will see, what exactly have I learned?
Similar to what many others have stated as noted above, virtually every chronic and neurodegenerative, mood and behavior disorder involves neurotransmitter imbalances of various types.
However, as first suggested to me by Dr. Lord, from a causational standpoint, the reason these imbalances occur is not unique for every disorder. Rather, “why” they occur is fairly uniform and straight forward:
- Chronic inflammation and the other side of the chronic inflammation “coin,” insulin resistance.
- Cumulative environmental stressors that elicit what I have discussed many times before, an allostatic response and the resultant “allostatic load.”
Much of what you will read is research on the impact of chronic inflammation and its specific impact on diverting tryptophan metabolism away from the production of serotonin and towards production of metabolites that can be neurotoxic and neuroinflammatory when produced in excess by a chronic inflammation/insulin resistance-induced hyperfunctioning kynurenine pathway. However, in this first installment of this series I will focus almost exclusively on research that discusses the impact of chronic inflammation on neurologic function. Eventually I will be presenting elaborate discussions on the various facets of all the disturbances of tryptophan metabolism that are seen with up regulation of the kynurenine pathway. For now, if you would like to read a brief overview of kynurenine metabolism, please see the October and November 2015 product newsletters where I discuss research relating to our new product, Niadoxene Select.
INFLAMMATION AND CNS DYSFUNCTION – AN OVERVIEW
As most of you know, there has been a revolution in health care in general, and functional medicine in particular, over the last 10-20 years that has flown directly in the face of traditional medical thinking that all illnesses are distinct and totally unique entities that require different diagnostic and therapeutic approaches. What is this revolution? It is the concept that there exists a foundational metabolic imbalance, largely created by accumulated environmental stresses, that greatly contributes to or causes from an outright standpoint all somatic illnesses ranging from diabetes to cancer to cardiovascular diseases. What is this metabolic imbalance? It is the two-sided “coin” of chronic inflammation and insulin resistance. Interestingly, because of long term medical traditions in this country that tend to separate “mind” from “body,” we have been slow to accept the idea that this framework of somatic illness could equally apply to ailments of the brain and central nervous system. Evidence of this can be seen almost every day with news reports that feature “experts” who lament that both the clinical and research communities have absolutely no idea what causes illnesses such as Alzheimer’s disease and more research is needed. As you will see from the research papers I am about to review in this series, it is clear that statements like “we have no idea” are more reflections of personal ignorance rather than a general lack of information. For, while chronic inflammation and insulin resistance may not be the whole story with mood, behavior, and neurodegenerative diseases, they certainly are such a big part of the story that claims of “we have no idea” are actually gross misrepresentations of reality.
Powerful evidence of this hypothesis can readily be seen in the paper “Immune aging, dysmetabolism, and inflammation in neurological diseases” by Deleidi et al (3). The authors begin their paper by pointing out what I have discussed in previous newsletters that, as we age, chronic inflammation tends to increase. This age related increase in chronic inflammation has been termed “inflammaging”:
“One of the most recognized effects of aging is the dysregulation of the immune system as a result of defects in both initiation and resolution of immune responses (immunosenescence) and chronic low-grade inflammation (inflammaging). This chronic subclinical condition has been linked to an increased incidence of metabolic syndrome, atherosclerosis, cancer, and neurodegenerative diseases.”
The next quote makes an extremely important point about a key cell type in the central nervous system that is greatly affected by this age related alteration in immune function and inflammation, contributing to the same changes in the nervous system that are seen with somatic diseases such as atherosclerosis and cancer. This cell type is the “microglia”:
“Similarly, recent work suggests that microglia, the innate immune cells of the brain, undergo a process of senescence that may in turn contribute to the development of neurological diseases in elderly people.”
The next quote from Deleidi et al (3) provides more detail on the impact of inflammaging:
“As we age, the immune system undergoes a process of senescence characterized by a progressive decline in immune function associated with an increased frequency of infections and chronic diseases. Aging affects both the adaptive and the innate immune system.”
“Immunosenescence is accompanied by a low-grade chronic proinflammatory environment in multiple tissues characterized by increased production of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), acute phase proteins, reactive oxygen species (ROS), and autoantibodies. This proinflammatory environment has been defined as ‘inflammaging.'”
The next few quotes point out an extremely important contributor to chronic inflammation that I feel is still not fully appreciated by both the allopathic and alternative medicine communities, chronic infection:
“Chronic infections promote immunosenescence and inflammaging; cytomegalovirus (CMV) promotes age-like immune changes and CMV reactivation has been associated with increased levels of IL-6 and TNF and premature mortality.”
“Other chronic infectious diseases such as HCV and HIV may also have a role in immunosenescence.”
Could parasites fall into this category? Absolutely!!
“Parasites such as Toxoplasma gondii (T. gondii) also contribute to immune dysregulation. Chronic infection with T. gondii is characterized by the presence of intraneuronal cysts that are controlled by the immune system. Growing evidence shows a link between chronic infection and CD8 T-cell dysfunction that in turn may promote the psychiatric disturbances often observed in these patients.”
What else might contribute to immunosenescence? Deleidi et al (3) point out:
Genetic predisposition leading to an increased tendency toward uncontrolled inflammatory responses can also accelerate immunosenescence and inflammaging.”
“Hormonal changes such as the decreased production of estrogen or androgen also influence the secretion of cytokines. Finally, alteration of mitochondrial function and metabolic changes in adipose tissue contribute to immunosenescence and inflammaging.”
Thus, as I hope you can see, immunosenescence and inflammaging are classic examples of a tenet of functional medicine suggesting that chronic illness is a manifestation of genetic propensity combined with increased environmental stress load plus the impact of the allostatic response to these stressors (“hormonal changes” and “alteration of mitochondrial function and metabolic changes in adipose tissue”) that has been collectively termed “allostatic load.”
More on microglial dysfunction and chronic illness
As noted by Deleidi et al (3), an understanding of microglial activity during chronic illness is vital to understanding how chronic systemic inflammation can lead to neurologic dysfunction and degeneration:
“Senescent and hyperactive microglia have been detected in the aged and diseased brain. Microglia are the innate immune cells of the central nervous system (CNS) and are involved in several physiological and pathological brain functions. They play essential roles in brain development and actively support neural circuitries and plasticity either through the removal of synaptic elements or the secretion of neurotransmitters and neurotrophic factors.”
Before continuing, please note again that microglia play a vital role in secretion of neurotransmitters. Of course, activated microglia do not represent a neural suicide sequence. They do serve an important role:
“During infections, brain injury or neurodegenerative diseases, resting microglia transform into an active state and release immune molecules including cytokines, ROS, and growth factors. Activated microglia exert beneficial functions such as the phagocytic clearance of pathogens and cellular debris.”
Nevertheless, increased microglial activity has been directly linked with neurodegeneration:
“Animal studies show increased microglial expression of MHC class II antigens and CD68 as well as decreased arborization and abnormal cytoplasmic structures. Interestingly, these morphological changes precede the appearance of tau morphology in Alzheimer’s disease (AD) patients suggesting that a loss of microglial function contributes to the onset of the disease.”
The following quotes specifically discuss how microglia provide a major link between systemic and brain inflammation:
“…peripheral immunosenescence and inflammaging can modulate microglial phenotype and reactivity and drive low-grade brain inflammation. This hypothesis is supported by the observation that systemic low-grade inflammation is accompanied by an increase of cytokines in the brain and an imbalance between pro- and anti-inflammatory molecules.
Systemic inflammation promotes the activation of brain immune cells in humans as well as in non-human primates and can prime neurons and immune cells in the brain increasing the risk of developing neurological disorders.”
With the above in mind, the authors state:
“In summary, the aging of the peripheral immune system can promote or exacerbate microglial senescence and drive neuroinflammation. The individual genetic background as well as infections and environmental exposures over a lifetime could further exacerbate the dysregulation of immune responses, increasing the risk of neurological disorders.”
The relationship between obesity and neuroinflammation
To fully understand the relationship between obesity and neuroinflammation, it is first important to note the inflammatory potential of adipose tissue:
“Both hypertrophic fat cells and immune cells infiltrate the adipose tissue and secrete inflammatory molecules that can promote systemic low-grade inflammation. Adipocytes secrete more than 600 bioactive molecules, which are collectively termed adipokines and include proinflammatory mediators such as TNF-α, monocyte chemoattractant protein (MCP)-1, and IL-6, as well as anti-inflammatory molecules. A link between obesity and inflammation has been initially hypothesized based on the observation of increased levels of IL-6 and C-reactive protein (CRP) in obese animals and humans. Interestingly, concentrations of these cytokines decrease after weight loss. Circulating adipokines have immune as well as neuronal functions and can influence brain inflammation.”
With the above in mind, as you might expect, excess adipose tissue, because of its impact on low-grade inflammation, affects not only classic somatic diseases but those involving neurodegeneration:
“Thus, excess adiposity drives low-grade systemic inflammation that increases the risk of developing insulin resistance, type 2 diabetes, cardiovascular disease, stroke, cancer, and neurodegeneration.”
Deleidi et al (3) conclude their discussion on adipose tissue and neurologic dysfunction with the following statement:
“In summary, fat accumulation and changes in fat redistribution with age lead to the dysregulation of adipokine secretion and metabolic changes linked to systemic and local inflammatory responses that, in turn, contribute to accelerated aging as well as cardiovascular and neurological disorders.”
Inflammation and mood and behavior disorders
The next several sections of the Deleidi et al (3) paper are devoted to information on the specific relationship between inflammation and various mood, behavioral, and neurodegenerative disorders. In this section neuropsychiatric (mood and behavioral) disorders are addressed. The first quote below from this section that I would like to present discusses the grossly under-appreciated relationship between neuropsychiatric disorders and infection and inflammation that might occur during late pregnancy and early childhood:
“…it is well established that infections and inflammation during the perinatal period increase the risk of developing neurological and neuropsychiatric diseases in childhood. Infectious diseases can cause direct neuronal damage; in other circumstances, such as after LCMV infection or chronic T. gondii infection, neuronal dysfunction may also be linked to immune reactions.”
As we all know, incidence of neuropsychiatric disorders in young children appears to be on the rise and has generated much media attention and a large variety of theories on causation. Therefore, it continues to surprise me that infection and/or significant inflammation during late pregnancy and early childhood have received such little attention, especially in relationship to the many dietary and lifestyle issues that are well known to promote chronic inflammation and increase susceptibility to infection. In particular, as suggested above, it appears that obesity would be a significant risk factor for chronic inflammation and suboptimal neurologic function during the perinatal period. Therefore, it is my hope that we can educate more women during pre-pregnancy counseling about the need to have a goal of weight optimization before conception.
Next, the authors discuss specifics of the neuropsychiatric impact of viral infections. As I have mentioned previously, one of the most important impacts is alteration of tryptophan metabolism via up regulation of the kynurenine pathway:
“It is…well established that viruses can alter neurotransmission and activate the kynurenine pathway causing chronic fatigue, cognitive impairment and mood disorders. In particular, the alteration of the kynurenine pathway is linked to an increased risk for neurological and neuropsychiatric disorders.”
In addition, viruses can contribute to neuropsychiatric disorders by up regulating excitatory activity:
“It has also been hypothesized that viruses such as LCMV alter inhibitory circuits causing unbalanced excitatory neurotransmission and neuronal death via excitotoxicity (‘Virus induced disinhibition and excitotoxicity’).”
The next quote points out some other neuropsychiatric ailments that can be affected by altered immune and inflammatory activity:
“Several immune changes are associated with neuropsychiatric disorders; increased levels of inflammatory mediators have been reported with schizophrenia, depression and autism spectrum disorders.”
In addition, as you might expect, alterations in microglial activity are found with these disorders:
“Neuropsychiatric disorders are also characterized by the activation of the brain innate immune system and increased density of activated microglia has been found in brains of schizophrenic and autism spectrum disorders (ASD) patients.”
The next quote provides an overview of the lifestyle related pro-inflammatory factors that promote neuropsychiatric disorders:
“Aging, metabolic changes, obesity, and chronic stress modulate the communication between the immune system and the brain and may promote neuropsychiatric diseases. Neuropsychiatric disorders are indeed common in people with metabolic dysfunctions. In these patients, inflammation is one major determinant of depressive symptoms. Obesity is also a contributing factor; in obese women adiposity is associated with increased concentrations of inflammatory markers (IL-6, CRP, and adipokines) that correlate with depression and anxiety.”
The next quote addresses an interesting question. With the knowledge that inflammation can contribute to neuropsychiatric disorders, could the reverse be true? Could neuropsychiatric disorders promote the formation of inflammatory mediators? Deleidi et al state (3):
“The brain, in turn, is able to regulate the immune system via neurotransmitter signals. As a consequence, psychological stress and depression are often associated with impaired immune function and increased risk of acute respiratory infections.”
Inflammation and Alzheimer’s Disease
Next, Deleidi et al (3) discuss several neurodegenerative disorders, starting with Alzheimer’s disease (AD). The first quote on this subject describes key neurologic findings with AD:
“AD is the most common form of dementia in the elderly affecting more than 35 million people worldwide. In AD, the progressive neuronal loss in the medial temporal lobe and many other brain regions causes cognitive decline. The pathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles and gliosis consisting of activated microglia and astrocytes surrounding β-amyloid plaques.”
Before continuing, please note again in the above quote the existence of “activated microglia.” The next quote provides more detail on the significance of this finding:
“Neuroinflammation and microglial activation have been proposed as key players in the pathogenesis of the disease. Inflammation is an early event in the amyloid pathology and precedes plaque deposition in experimental models of AD. Amyloid deposition leads to microglial activation and the production of proinflammatory mediators that contribute to disease pathogenesis.”
Of course, as I have mentioned about other proinflammatory responses, activation of microglia is not a suicide sequence. The body is doing it for a purpose:
“However, microglia also play a beneficial role in restricting senile plaque formation by clearing Aβ deposits and secreting neuroprotective factors.”
Therefore, as with so many other body responses that make up the allostatic response to environmental stressors, the issue is not that they occur at all but that they occur in excess for an excessive amount of time.
Inflammation and amyotrophic lateral sclerosis
As any of you who have made an attempt to assist patients suffering from this horrible affliction know all too well, our efforts to even understand the illness, let alone improve quality of life or offer some type of permanent resolution, have been frustratingly futile. Therefore, I welcome any information on ALS, especially information that will give us some idea of underlying mechanisms and contributing causations. For me, the following quote is truly a breath of fresh air in that it suggests that there is a possible mechanism that is similar to that seen with all other neurodegenerative diseases – chronic inflammation and microglial dysfunction. However, as you will see, with ALS the issue concerning microglial function is not so much a matter of up regulation in activity but a shift in phenotype from the M2 neuroprotective phenotype to the pro-inflammatory and neurodestructive M1 phenotype. Deleidi et al (3) state the following about ALS:
“The etiology of ALS remains largely unknown. Most cases are sporadic, whereas approximately 5-10% of the cases are caused by an autosomal dominant mutation. The pathological hallmarks of ALS are the presence of cytoplasmic ubiquitinated protein inclusions in degenerating motor neurons and intense inflammatory reactions characterized by microglial/astroglial activation and infiltration of peripheral T cells. Thus, both innate and adaptive immune responses are involved in the pathogenesis of ALS. Experimental and clinical evidence supports the hypothesis that microglia activation occurs at early stages of the disease. In experimental ALS, the microglial phenotype changes with disease progression, with a shift from the M2 phenotype in the early disease phase to M1 phenotype at later stages, suggesting that the decreased function of neuroprotective microglia correlates with disease progression.”
With the above in mind, please note the following quote that points out, in its early stages, inflammation during ALS may be neuroprotective:
“These data suggest that inflammation plays a neuroprotective role during the initial stages, whereas immune dysfunction correlates with the progression of the disease at later stages. With regard to ALS, it is still unclear whether immunosenescence, inflammaging, and dysmetabolism affect disease risk. ALS is associated with metabolic alterations, including weight loss, hypermetabolism, and hyperlipidemia, and dyslipidemia has been described as a neuroprotective factor.”
Unfortunately, the above quotes still suggest that there is more that we do not know about ALS pathogenesis and treatment than what we do know. Nevertheless, I feel this information on inflammation and alterations in microglial metabolism at least gives us a logical starting point for a disease where, in the past, we have most often had no idea at all where to begin.
Inflammation and Parkinson’s Disease
Along with Alzheimer’s disease, Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases seen throughout the world. In addition, along with the other chronic neurodegenerative diseases, much is unknown both about causation and clinical management. As with all the other ailments discussed so far in this monograph, I feel that understanding the link between inflammation and PD could both increase our knowledge about causation and open up new vistas for assisting so many patients suffering from the symptoms of PD. To introduce the subject, Deleidi et al (3) state the following:
“PD is the second most common neurodegenerative disorder affecting over 4 million people worldwide. In PD, the interaction between aging, individual genetic vulnerability, and environmental factors leads to the death of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta and other vulnerable neuronal populations.”
Concerning the connection between PD and inflammation, the authors state the following:
“Even though inflammation has been associated with the pathogenesis of PD, it is still under debate whether this is a cause or consequence to neuronal death. Several lines of evidence support a role for both the innate and the adaptive immune system in disease pathogenesis. These include the increased levels of proinflammatory cytokines observed in PD patients and the association of the disease risk with certain HLA variants.”
In addition, there seems to be a link between PD and diabetes:
“It has been suggested that common dysregulated pathways converging on mitochondrial dysfunction, endoplasmic reticulum stress, and inflammation as well as glucose and lipid metabolism, link diabetes and PD.”
There may also be an under-appreciated but important link between caloric intake and PD:
“It has been proposed that energy intake influences the vulnerability of neurons during aging by modulating the production of neurotrophic factors and inflammation.”
Is there a specific white blood cell type that is more involved with PD? Deleidi et al (3) state:
“It has been shown that peripheral monocytes from PD patients have a proinflammatory phenotype and impaired phagocytic function compared to controls.”
Is there a link between infection and PD? As you might expect based on what has been stated so far, the answer is yes:
“Viral infections and inflammatory reactions are a possible environmental trigger for PD. A viral etiology for PD is based on epidemiological studies showing a high incidence of severe progressive parkinsonism has also been described in people developing encephalopathy after the 1918-1919 influenza outbreak. In addition, parkinsonism has also been described in patients infected with other viruses such as Japanese encephalitis virus, Epstein-Barr virus, Coxsackie, St. Louis, West Nile and HIV viruses. Even though viral parkinsonism is extremely rare, an emerging hypothesis is that viral infections cause inflammatory reactions that prime vulnerable neurons to degenerate in response to other cellular insults over time.”
Finally, as with all ailments, genetic propensity can play a role in PD development:
“Finally, as many PD-linked genetic mutations play a role in the regulation of the immune system, it is likely that genetic vulnerability predisposes to the development of midbrain DA neurodegeneration via inflammatory mechanisms.”
However, the connection between PD and genetic vulnerability may not be direct. It is also possible that genetic vulnerability increased risk of infections and inflammation which, in turn, leads to increased odds of PD development:
“Nevertheless, emerging evidence suggest that the interplay between aging and genetic vulnerability results in increased susceptibility to infections or abnormal inflammatory reactions that overtime predispose to PD.”
Inflammation and multiple sclerosis
Contrary to the other neurodegenerative ailments mentioned so far in this monograph, it is well known that multiple sclerosis (MS) is primarily an inflammatory disorder. Deleidi et al (3) note:
“Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS in which the interaction between environmental exposures and genetic predisposition leads to persistent inflammation, oligodendrocyte death, and loss of the myelin sheath. Even though the sequence of events that initiate the disease remains largely unknown, MS is generally believed to be an immune-mediated disorder that occurs in genetically susceptible people.”
Furthermore, the metabolic imbalances and environmental stressors underlying MS are fundamentally the same as with the other neurodegenerative diseases discussed:
“Diverse disease processes, including autoimmunity, viral infections, and metabolic changes may lead to the formation of inflammatory demyelinated plaques.”
In turn, as with all the other neurologic ailments discussed, environmental factors and genetic propensity contribute to the main underlying causational factor emphasized in this paper, immunosenescence:
“It has been hypothesized that both genetic and environmental factors such as viral infections accelerate immunosenescence in these patients and contribute to disease pathogenesis.”
The first quote I would like to present from this section of the paper is intriguing in that it points out that many of the medications used with the mood disorders mentioned in this paper with a fair degree of success have under-appreciated anti-inflammatory properties:
“With respect to neuropsychiatric disorders, it is noteworthy that many antipsychotics and antidepressants decrease the levels of pro-inflammatory cytokines and inhibit immune-inflammatory pathways in humans and experimental models of inflammation.”
Specific interventions – Reduced caloric intake
Recall the involvement of the NLRP3 inflammasome that was mentioned above. Reduced caloric intake can have a beneficial ketogenic effect by leading to increased production of the ketone body β-hydroxybutyrate:
“The NLRP3 inflammasome is another potential therapeutic target. The NLRP3 inflammasome is an immune sensor that could link systemic and brain-related inflammation. Interestingly, Youm et al. showed that caloric restriction in animal models reduces chronic inflammation with a mechanism involving inhibition of NLRP3 inflammasome and reduced levels of IL-1β and IL-18 in human monocytes by the ketone metabolite β-hydroxybutyrate. Thus, dietary or pharmacological approaches should be exploited to treat NLRP3-mediated inflammatory diseases.”
Specific interventions – nutritional supplements
As you might expect based on all that has been stated so far, there is every reason to expect that the anti-inflammatory supplements we typically use would be of assistance with mood and neurodegenerative disorders:
“Nutritional supplements such as natural anti-inflammatory molecules can dampen the inflammatory environment and promote healthy aging. For example, omega-3 essential fatty acids decrease the levels of IL-1, IL-6, TNF, and CRP and improve cognitive dysfunction in aged mice.”
Deleidi et al (3) also point out supplements that enhance mitochondrial function could be of assistance.
Final thoughts expressed by Deleidi et al (3)
“In summary, the interplay between aging, genetic predisposition, and environmental exposures initiate systemic and local metabolic changes as well as inflammatory reactions that predispose to neuropsychiatric and neurodegenerative disorders. We would further argue that targeting age-associated inflammation, especially in selected patients with high immune risk profiles, can be an advantageous strategy to prevent or delay the onset of these diseases.”
In part II of this series I will review still more compelling papers that make an increasingly strong case that chronic inflammation and insulin resistance are truly the common denominators for virtually all mood and neurodegenerative disorders, which, for me, opens up whole new vistas of possibilities in terms of assisting afflicted patients.
Moss Nutrition Report #266 – 12/01/2015 – PDF Version
- Fogel BS et al, ed. Neuropsychiatry. Baltimore: Williams & Wilkins; 1996.
- Lord RS & Bralley JA, ed. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2012.
- Deleidi M et al. Immune aging, dysmetabolism, and inflammation in neurological diseases. Frontiers in Neuroscience. 2015;9.