Complexity Theory and Alzheimer's disease: A Call to Action

The brain of a healthy person is constantly changing. Neurons and glial cells constantly die and get replaced with new cells. More than 30,000 proteins constantly misfold and get degraded, they are cleared from the brain. Constant mini injuries to the brain are accommodated without change in capacity. Where memories are constantly re-imaged and prioritized. Where cognitive functions are shifted from one area of the brain to another. All of these events define the daily functioning of our brain. The question that needs to be asked is why does this ongoing maintenance stops or becomes overwhelmed?

The emerging conclusion—that Alzheimer’s disease is a syndrome—derives from a century of anomalies in research. The National Institute on Aging’s and Alzheimer’s Association  (NIA/AA) new guidelines, based on the Amyloid Cascade hypothesis (Jack et al, 2011) are incomplete. Emerging evidence is elaborating a more complex process. More than one cause, or type of causes, may result in similar or different outcomes. The initial injury might or might not progress.  The neurological disease might or might not affect cognition. The chorus of scientists voicing this approach to Alzheimer’s disease is unremitting. These valid criticisms remain shunned from NIA/AA new research agenda.

So far, after a century of confusion in studying Alzheimer’s disease, it is time to stop repeating the same mistakes in the hope of coming up with new results. We need a new methodology that might provide different results.  This new approach comes from Complexity Theory. Complexity Theory is an open theory—many variables, some known others still unknown influence the outcome. The utility of broadening the theory is to allow for a more inclusive approach that allows diverse literature to be included rather than to remain ignored. A simplified view of the brain states that by looking at individual components you can understand the whole machine--as with the Amyloid Cascade hypothesis (Hardy & Higgins, 1992). Such a mechanistic approach—that harks back to the 14th century—is too limited to explain a behavioral disease such as Alzheimer’s disease.

Such models are useful in generating hypotheses but limited in furthering our understanding of how the brain functions.  Especially because of non-linear effects, a large change might result in a small effect and a small change a large effect. We cannot predict what the effect will be. In strokes for example—where a blockage in the blood vessels destroys an area/s of the brain—we might find a large stroke resulting in little diminished capacity or a small stroke with debilitating results. We cannot predict the outcome with certainty even if we know the area of the trauma. Each stroke is unique, as is Alzheimer’s disease.

Within this theory, systems or units exist, seemingly independent from each other that nevertheless rely on each other, communicating directly within a hierarchy of networks. We know these networks exist because of the presence of hormones, neurotransmitters and cytokines mediated in the body by hundreds of different types of lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases (Mohamed et al, 2005; Clarke & Sperandio, 2005).  Additionally, the system changes and evolves.

A Complexity Theory would address these variances and how the body maintains these systems in balance—a balance that is unique for each individual. This homoeostasis is based on an internal set of regulators, defined by both past experiences and unique adaptive responses to new stimuli from the environment. The theory would also need to refrain from separating our beliefs, expectations, and behavior from the wider social, political, and cultural systems in which we exist. These units interact within the whole system in (as yet) unknown ways (Doidge, 2015; Merzenich, 2013). In such an open system, both established and new external forces can, and do, impinge on its internal activity. The best example of this is psychosomatic illness where although the disease is caused by the psychology of the person—psychogenic—the physical effects are real (Shorter, 2008).

Because Complexity Theory utilizes input from a variety of disciplines, it is necessarily transdisciplinary (Albrecht et al., 1998). It may help address the philosophical complexity exposed by postmodernist philosophy (Cilliers, 1998; Henrickson & McKelvey, 2002). Complexity theory addresses situations where linear cause and effect do not apply. Examples of such complex theories have been applied to biology, management, computer science, psychology, and other fields. In medicine, Complexity Theory has been applied to immunology (eg. Efroni, Harelb & Cohenb, 2005). Brown & Moon (2002) note that the new public health has “advocated a multi-causal approach that saw infectious and chronic, degenerative disorders as being the result of a complex interaction between biophysical, social or psychological factors.” (pp. 362–363.

The theory’s “complexity” is because it is composed of many parts (sub-units) that interconnect in known and unknown ways (Sussman, 1999) and intricate ways (Moses, 2006), where cause and effect are subtle and change over time (Senge, 2014).

In Alzheimer’s disease research, Complexity Theory might explain why many causes may exist although the disease is expressed uniformly. It might also be that depending on where you are in your lifespan, the disease expresses itself differently, evolving across time (Coveney & Highfield, 1995). Complexity Theory attempt to reconcile the unpredictability of different systems—in this case, areas of the brain interact together in ways as yet unknown—with a sense of underlying order and structure (Levy, 2000). Complexity Theory can be the foundation for understanding all types of Alzheimer’s disease. It can easily be adapted to anomalies in research in a way that makes the theory predict outcomes. At the same time, the theory must be able to explain existing anomalies.

How does a theory of Alzheimer’s disease deal with such confounders? Under Complexity Theory these processes are inclusive, and can be mediated and moderated by other variables. For example, Alzheimer’s disease can be mediated by protecting against injuries (e.g. head injuries, toxicity, radiation). It might also be mediated by maintaining a healthy lifestyle (and the effect this has on supplying the brain with oxygen—cerebral perfusion), or eating a healthy balanced and varied diet that provides all the nutrients and bacterial flora that we require at older ages (Bredesen, 2014). While a century of work has looked at how plasticity, neurogenesis and capacity can delay or protect against Alzheimer’s disease. All these factors—injury, penumbra, perfusion, plasticity—become important processes and sub-units in discussing the etiology of the disease under a Complexity Theory.

But perhaps we are not the first to request this: ”….demonstrate to us in an impressive way how difficult it is to define disease solely with respect to their clinical features, especially in the case of those mental disorders which are caused by an organic disease process. (Alzheimer, 1912, p)  Fox, Freeborough & Rossor (1996) conclude by saying that “…no clear cut distinction exists between senile Alzheimer’s disease and normal aging as far as the clinical and anatomo-pathological elements are concerned” (p. 146). If this is true then we are back to square one with Alzheimer’s disease. It is a disease of old age.

Reference.

Garrett MD (2015). Politics of Anguish: How Alzheimer’s disease become the malady of the 21st century. http://www.amazon.com/Politics-Anguish-Alzheimers-disease-century/dp/1518892930

© USA Copyrighted 2016 Mario D. Garrett

Piaget's Missing Cognitive Stage: Socioemotional Selectivity in Older Adulthood

The Swiss psychologist Jean Piaget is a most prolific renaissance man, publishing in biology, psychology, morality, language and philosophy. His lasting legacy has however been his identification and definition of stages in children’s thinking. Each stage is marked by shifts in our understanding of the world, as though our brain clicks into a different qualitative mode of processing information. We cannot learn a specific concept if our mind has not yet developed the capacity to understand it. A theory "so simple only a genius could have thought of it" according to Albert Einstein. The same concept applies to animals, in that their brain is “intelligent’ enough to represent the world they live in to enable them to survive and prosper. The same constrains exist among humans as they develop. Piaget termed this as Genetic Epistemology; how we learn about our environment.

The stages include sensorimotor (up to age 2) preoperational (2-7) operational stage (7-11) formal operational (11+). These stages move us from learning about the environment by touching and moving objects through it, to the development of language where we begin to apply symbolism and acquiring the concept of an ideal world. From this stage we start making rational judgments about concrete or observable phenomena using language to manipulate symbols. At the last stage we develop hypothetical and deductive reasoning. Increasingly more complex processes are incrementally added to the previous stages established in earlier stages of our development.

The model that we build in our mind is similar to how scientists organize the world in terms of classes of objects or schemas.  Improving upon existing schemas through a process of logical assimilations or by changing the schema through accommodation this process aims for equilibrium--what Piaget terms “equilibration.”  The beauty of this type of thinking is that intelligence is a reflection of an active process. Our brain is forming a model of the outside world that helps us understand and predict the world. And there are specific developmental stages in how we do this.

But Piaget stopped at young adulthood and he stopped at the cognitive. In a world of “hypercognitive snobbery”—where cognition is prized above other equally valuable aspects of being identified in 2006 by Stephen Post p.223—we assume that thinking is the ultimate, but cognition is not comprehensive enough to explain our world. We also have an emotional component in living, perhaps more important, but surely as important.

As with the current thinking at the turn of the 20th century, “old age” was seen as a decline from a peak of early adulthood. Piaget, following this prejudice, did not think that much happens after attaining formal operational stage. But he was wrong.

There is, at least, another stage of reasoning that we can also identify.  The late Fredda Blanchard-Field with the Georgia Institute of technology promoted a stage of emotional development for older adults. What has developed into the socioemotional selectivity theory, this theory argues that we become more intelligent and mature about how we feel, where we select to remember positive experiences above negative ones. Pruning our social circles of friends or acquaintances and learning to let go of loss and disappointments are the external expression of this stage in thinking. But there is more. Our brain is wired so that the older we get the more that we focus and remember positive events while forgetting negative ones.

Psychologists Laura Carstensen—director of the Stanford Center on Longevity—and Charles Mather—with the University of California Santa Cruz—reported on neural mechanism that might be responsible for this selection of positive emotions. They identified cases where the amygdala—a small almond sized structure deep within the two sides of the brain—seems to be activated differently by younger versus older adults. Younger adults activate this structure more for negative images while older adults had higher activation for positive images.

But this did not explain why older adults remembered positive experiences better. It took a New Zealand psychologist Donna Addis and her colleagues to identify a possible mechanism. They asked young and older adults to view a series of photographs with positive and negative themes while recording their brain activity (fMRI). They found that in older adult brains, two regions that are linked to the processing of emotional content were strongly connected to regions that are linked to memory formation. Suggesting that older adults remember the good times well because the brain regions that process positive emotions also process memory.

Older adults experience an increase in positive thoughts and feelings, along with a decrease in negative emotions like anger and frustration. Living longer makes you remember positive emotions better because we are engineered that way—Genetic Epistemology. Like Piaget’s stages of cognitive development, this socioemotional stage involves a qualitative difference in how we process our environment.  Reclaiming older adulthood as a unique stage in our development—rather than seeing older age simply as a decline—dictates that we assign this socioemotional selectivity stage on equal basis with the other stages of development. We cannot learn a specific concept if our mind has not yet developed the capacity to understand it. We need to mature to learn how to interpret emotional reality.

References.

Isaacowitz, DM & Blanchard-Fields, F. (2012). Linking Process and Outcome in the Study of Emotion and Aging. Perspectives on Psychological Science, 7(1), 3-17

Piaget, J. (1970). Genetic Epistemology. New York: Norton.

Piaget, J. (1977). Gruber, H.E.; Voneche, J.J. eds. The essential Piaget. New York: Basic Books.

Piaget, J. (1983). Piaget's theory. In P. Mussen (ed). Handbook of Child Psychology. 4th edition. Vol. 1. New York: Wiley.

Post, SG. (2006). Respectare: Moral respect for the lives of the deeply forgetful. In J. C. Hughes, S. J. Louw, & S. R. Sabat (Eds.), Dementia: Mind, meaning, and the person (pp. 223–234). Oxford: Oxford University Press.

© USA Copyrighted 2016 Mario D. Garrett

The Fallacy of the Epidemiological Transition

​History dictates that with a changing population structure there is a parallel mirror process affecting health. The theory behind population change is called the demographic transition, while the historical change in mortality is called the epidemiological transition [1].   Epidemiological transition piggybacks on an established mathematical theory that argues that populations go through a cycle of high death and high birth rate, followed by declining death rate and declining birth rate.  Finally reaching a stage characterized by very low birth rate and low but fluctuating death rate.  The epidemiological transition posits that throughout this cycle mortality changes from infectious diseases to chronic disease. Finally reaching a stage of delayed chronic diseases. Unlike the distinct definitions of fertility and death rate that determine the demographic transition, the cut-off between an infectious disease and a chronic disease has become blurred.

In the United States, according to the Centers for Disease Control and Prevention (USA-CDC) more than seventy percent of all deaths are due to chronic diseases [2] .  Chronic diseases are characterized by Alzheimer’s disease, heart disease, diabetes and cancer. Since the causes of chronic disease was argued to be a combination of genetic, environmental, or lifestyle factors, public health was relegated as unimportant in dealing with chronic diseases. Public health is something that concerns only developing countries, until this year.

When an accountant managed water quality in Flint, Michigan, we very quickly saw a public health disaster enfold. Resulting in tainted water that marred the lives of a countless number of children for the rest of their lives. We created a chronic problem from a public health disaster.  So perhaps we need to revisit the epidemiological transition, since infectious diseases might also contribute to chronic diseases.  Especially since we are finding that chronic disease may apparently be infectious after all. If we can show that chronic diseases are infectious then the epidemiological transition becomes irrelevant.

An increasing number of chronic diseases are coming under scrutiny as possibly caused by infections. There are multiple examples to support the view that chronic diseases are in fact infectious diseases with a delayed expression. However, the search for bacterial, viruses, or environmental toxicity causes is difficult. Primary difficulty lies in detecting and replicating the causative agents in the laboratory. In most cases there are lags between the infection and the expression of the disease. Sometimes by the time the symptoms of the chronic disease appear, the causative agent is no longer present. But there are already strong signs that the three main chronic diseases have elements of infections: Alzheimer’s disease, cancer and heart disease.

Alzheimer’s disease

The initial infection that starts Alzheimer’s disease is unknown. As a chronic disease most of the research focuses on genetic mechanisms. But there is growing evidence that other, more relevant mechanisms exist, especially if we look at Alzheimer’s disease as a public health concern. These mechanism are: viral (HIV/AIDS, herpes simplex virus type I, Varicella zoster virus, cytomegalovirus, Epstein-Barr virus), bacteria (syphilis and Lyme-disease/borrelia), parasites (toxoplasmosis, cryptococcosis and neurocysticercosis), behavior (Alcohol, cigarette smoking, recreational drugs, concussion/mild/severe brain trauma) environmental elements (possibly aluminum), infections (possibly prions such as in Cretchfeldt-Jakobs disease), vascular causes (stroke, multiple-infarct dementia hydrocephalus, and injury or brain tumors, and emotional trauma. There are numerous studies that correlate all of these factors with Alzheimer’s disease, but surprisingly none of these factors appear in the federal “guidelines” for Alzheimer’s disease. [3]

As an example of the likely bacterium connection to Alzheimer’s is Lyme disease. Alois Alzheimer—who identified the disease in 1907—was primarily interested in syphilis. For centuries, other than just old age, syphilis was the main and only known cause of dementia. Although neurosyphilis is rare today, another bacterium gaining interest is Lyme disease. Lyme dementia has become a greater concern because it is the most common vector-borne disease in the northern hemisphere. Since there is no cure the expectation is that more patients will develop Lyme dementia in the near future [4].

Cancer

Other example where an infectious or an environmental substance contributes to chronic diseases is cancer. Viral causes of cancer are common enough that we call viruses that can cause cancer an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein-Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias).

Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma. Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma.)

The human papillomavirus, for instance, causes more than 90 percent of cervical cancer cases and is one of the most common cancers in the world especially in Asia. With childhood immunization programs, including the hepatitis B vaccine, this cancer will become less prevalent. Hepatitis C virus causes cirrhosis, end-stage liver disease, and liver cancer. Human herpesvirus 8 causes Kaposi’s sarcoma, a malignant complication of AIDS. Helicobacter pylori, a spiral-shaped bacterium, is the agent of peptic ulcers and gastric cancer and has an important  story of resistance, although not biologically but politically.

In 2005, two Australians, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology for their pioneering work identifying the bacterium Helicobacter pylori as the cause of peptic ulcer disease. Overnight peptic ulcer disease was no longer a chronic disease but an infectious disease that can be cured by a short regimen of a pair of antibiotics. But despite evidence, it took more than ten years to persuade the scientific community. At the end, it took the primary author, Barry Marshall to infect himself with the bacteria to prove his point to a disbelieving scientific community. The long held view that peptic ulcer disease was a chronic disease wrestled against any competing views that it might be infectious.

Heart Disease

The relationship between heart disease and bacteria/virus is still sparse and interpretation of results is limited by potential biases. A large number of studies have reported on associations of human coronary heart disease and certain persistent bacterial and viral infections. One concluded that the relationship of heart disease with H pylori is weak, while for C pneumoniae, the evidence of association is stronger but still uncertain  [5].  Endocarditis is a disease characterized by inflammation or infection of the inner surface of the heart usually caused by a bacterial infection from the mouth that enters the heart.

And there are already evidence for the efficacy of an approach that looks at chronic disease as caused by infections. At the 2016 annual meeting of the American Association for the Advancement of Science, Stanley Riddell with Seattle's Fred Hutchinson Cancer Research Center, announced how T-cell therapy can help the human immune system fight off cancer cells the way it would attack foreign bacteria or a virus. This finding joins the arsenal of some vaccines to prevent cancer.

Such associations have been difficult to expose because the path from exposure of an infection to the expression of the chronic disease is usually not linear. There are other mediating or/and moderating factors. For example, the role of infection mediated through chronic inflammation is then associated with a variety of chronic diseases such as multiple sclerosis, rheumatoid arthritis, lupus, and other autoimmune diseases. But the pharmaceutical industry, despite their advantage at being able to “cure” chronic disease has been reticent in accepting the full force of this implication. It is not a clever economic strategy to cure diseases, only to manage them.

What we need is a broader approach to look at cancer, heart disease and Alzheimer’s disease more as a public health concern. Looking at chronic disease as a long-term assault from an external agent, whether this agent is a bacterium, virus or some toxic element. By re-addressing our priorities in research, perhaps this is the way out of this research cul-de-sac we find ourselves in. It is such radical thinking that is needed to hopefully start finding cures that have evaded us so far.

References

[1]   Omran, A.R (2005. First published 1971), "The epidemiological transition: A theory of the epidemiology of population change" The Milbank Quarterly 83 (4): 731–57, doi:10.1111/j.1468-0009.2005.00398.x

[2]  Centers for Disease Control and Prevention. Death and Mortality. NCHS FastStats Web site. http://www.cdc.gov/nchs/fastats/deaths.htm. Accessed December 20, 2013.

[3] Garrett MD, Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.

[4] Blanc F,Philippi N,Cretin B,Kleitz C,Berly L,Jung B,de Seze J. Lyme Neuroborreliosis and Dementia. Journal of Alzheimer’s Disease 2014; 41(4):1087-1093.

[5] Danesh, J., Collins, R., & Peto, R. (1997). Chronic infections and coronary heart disease: is there a link?. The lancet, 350(9075), 430-436.

© USA Copyrighted 2016 Mario D. Garrett