DISORDERS OF REGULATION: TOWARDS A MODEL OF SYSTEMIC BASED

INDIVIDUALIZED TREATMENT FOR AUTOIMMUNE DISEASE,

NEURODEGENRATIVE DISORDERS, AND CANCER

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DISORDERS OF REGULATION: A SYSTEMS APPROACH

The brain and the body work as a cohesive system. However, most theoretical

understandings of disease processes do not take a systems-based approach to understanding the

way that complex behavior emerges from these physical structures. Applying systems thinking to

the problem diseases could yield novel models for disorders and treatment approaches. This

paper will outline a theoretical basis for a class of disorders identified here as disorders of

regulation, apply a systems-based approach to the modeling of these diseases and delineate some

principals that could be used to create viable treatments.

Some systems are capable of complex behavior that lasts for long periods of time. Some

systems are not and degenerate into a form of repetitive order (Shank et al., 1999). An example

of the latter in the brain is the kindling effects of grand mal seizure activity (Shousea & Ryan,

1984). In the kindling of a seizure the brain begins to synchronize its firing until an entire

hemisphere fires at once. During a seizure the brain system becomes highly structured and

organized, and the ability to produce complex human behavior is diminished. It is only within a

coherent range of systemic functioning that complex behavior can emerge and be maintained. In

other words, if the disruptions in the functioning of a system of the body or brain leads to a

reduction of complex behavior or a disruption in the functional balance between systems, it can

lead to disease and, in some cases, death.

A complex system has points in its state space in which it is highly vulnerable to

disintegrating into one of the aforementioned patterns of loss of systemic complexity (Prigogine

& Holte, 1993). The balanced oscillation between systems forms a coherent pattern of

relationship. If that coherent pattern of relationships is disrupted in minor ways, the system will

display small perturbations in functioning until it can right itself (Shank et al., 1999). If that

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system exceeds its regulatory capacity at a key point for long enough or with sufficient intensity,

the entire system adapts, forming a new functional relationship between systems. The behavior

of many disease processes appears to be created and maintained by disruptions in the functional

relationship between systems.

At times it is the body’s own processes that are involved in the genesis and maintenance

of these syndromes (D. Kerr, personal communication, August 08, 2008). Some disorders that

appear to be effected by this type of disease process are autoimmune disorders, many types of

cancers, and neurodegenerative disorders. The causes for each of these disorders are highly

varied, as will be the treatments postulated; however, these disorders follow a similar pathway of

disruptions in the functioning of systems. This similar pathway can be a guide for the creation of

appropriate and effective clinical interventions.

Evidence that Dysregulation Leads to Pathology

There are many data points supporting the postulation that dysregulation leads to

pathological functioning in the body, brain and mind. Multiple studies have shown that over-

secretion of cortisol in both Cushing’s syndrome and depression leads to reduction in the cellular

density and dendritic connection in the hippocampus (Bourdeau et al., 2002; Bremner, Narayan,

Anderson, Staib, Miller, and Charney, 2000; Starkman and Schteingart, 1981; Dorn, Burgess,

Friedman, Dubbert, Gold, and Chrousos, 1997). Cortisol dysregulation in many leads to loss of

sleep. Loss of sleep in turn can lead to a reduction of neurogenesis in the hippocampus (Guzman-

Marin et al., 2005). Overproduction of insulin leads to symptoms including mood swings, weight

gain, hypoglycemia, increased facial hair in women, hair loss, bloating, and high blood pressure

(Norman, 2010). Underproduction of dopamine can lead to movement disorders, dementia,

alterations in working memory and symptoms of psychosis. Overproduction of Telomerase has

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been associated with development of cancerous tumors (Harley and Villeponteau, 2002).

Overproduction of glutamate can lead to cell death; elevated levels of glutamate are found in

dementia, Alzheimer’s type (Choi, 2004; Ulas et al., 1994).

Telomerase: A Regulator of Cellular Life Span

Cells in the body are created, maintained for some time and then die. Different regions of

the body and brain require different rhythms of cellular lifespans. In the span of one week most

pancreatic cells are replaced by other cells; over of the span of several years all the cells in the

body are replaced by other cells. This rhythm of cell loss and replacement requires a consistent

cycle of cell death, cell birth and cell maintenance. If these key functions begin to occur either

too frequently or too rarely, pathology can develop (Lowe & Lin, 2000). This exemplifies the

nature of disorders of regulation. They are disorders where the balance between the functional

demands of a system is disrupted to the point that other systems relying on that system and the

body as a whole no longer function effectively.

Telomerase is one of the key regulators of cellular life span (Gorbunova, Seluanov, &

Pereira-Smith, 2002).Telomeres are short, compacted segments of DNA forming a cap at the end

of the chromosomes (Gorbunova, Seluanov, & Pereira-Smith, 2002). As the cell goes through

each cycle of mitosis the telomere is shortened (Blasco, 2005). These segments of the

chromosomal DNA (telomeres) function as regulators for cell division. As they shorten past a

threshold point the cell can no longer divide and produce other cells (Blasco, 2005). Many

tissues require more cell divisions than the original telomere length allows. In order to maintain

physical health and systemic regulation, an enzyme called telomerase is produced (Gorbunova,

Seluanov, & Pereira-Smith, 2002). This enzyme stimulates the rebuilding the telomere end cap

of the chromosomes. The end cap is rebuilt thus extending the ability of cells to divide and

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replace cells at the end of their life span (Blasco, 2005).

Dysregulation of telomerase.

A hallmark of disorders of regulation is that there are many possible events that can cue

any single disruption in the functioning of a system. These disruptions lead to major systemic

functions occurring in dysynchronous manner. The dyssynchronous functioning of one system

can lead to large-scale dysfunctions in other systems. Dyssynchronous systemic functioning can

lead to what appears as symptoms of disease. There are multiple events and classes of events that

can lead to dysregulation of telomerase production, as there are multiple ways that telomerase

production can be altered (Epel et al., 2004). Some of these include genetic differences (e.g.,

disruptions in the Ras and Raf genes), autonomic stress, lifestyle choices, mental health and

chemical toxins, to name a few (Lua, Fua, and Mattson, 2001; von Zglinicki, 2002; Epel et al.,

2004). The effects of these events can act in isolation or in some cases synergistically to alter the

functioning of telomerase, if an individual has a genetic predeterminent for dysregulation of

telomerase that may or may not be sufficient to create major disruption in the tissues of the body.

If, however, that genetic determinent occurs along with other factors there could be a catalyzing

event leading to large scale disruptions in tissues and thus disease processes. In one study of a

telomerase deficient mouse, there were not global increases in symptoms of aging (Chang,

2004). However, the mice displayed reduced ability to repair injuries or recover from illnesses, a

shortened lifespan, and increased incidence of cancerous tumors (Serrano & Blasco, 2001). Thus

leaving them vulnerable to multiple disease processes.

Lifestyle and telomerase production.

A recent study implied that lifestyle changes such as alterations of diet, exercise, and

stress levels have a significant association with re-regulation in telomerase activity (Ornish et al.,

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2008). The study notes that causation cannot be inferred and that a more comprehensive

randomized study is warranted from these results (Ornish et al., 2008).

Comprehensive lifestyle changes significantly increase

telomerase activity and consequently telomere maintenance

capacity in human immune-system cells. Given this finding and the

pilot nature of this study, we report these increases in telomerase

activity as a significant association rather than inferring causation.

(Ornish et al., 2008)

Stress and telomerase.

Telomerase has an interaction effect with the autonomic stress response (Choia, Faucea,

& Effros, 2007; Epel et al. 2004). High levels of autonomic stress and cortisol have been

associated with down-regulation of telomerase and shorter telomeres (Choia, Faucea, & Effros,

2007; Epel et al., 2004). Allostatic load is the term coined by Bruce McEwen to describe amount

of energy needed to return a system to homeostasis. Long-term exposure to stress hormones due

to prolonged stressors or a very large stress response leads to a higher allostatic load (McEwen,

2002). Telomerase production is one of the systems affected by overproduction of stress

hormones (Choia, Faucea, & Effros, 2007). Several studies have noted that changes in telomere

length occurred in response psychological stress and mood disorders. T lymphocytes exposed to

high levels of cortisol have displayed a significant reduction of telomerase activity during both

primary and secondary stimulation of cells (Choia, Faucea, & Effros, 2007; Epel et al., 2004).

Dysregulation of telomerase: neurodegenerative disorders.

The pattern of disorders of regulation, starting as a disruption in one system and leading

to another, can be seen in the effects of prolonged autonomic stress response (Epel et al., 2004;

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McEwen, 2002). It is likely that cortisol levels produce a heightened risk environment that sets

the stage for other factors to catalyze into either a cancer or neurodegenerative disorder (R.

Sapolsky, personal communication, 2001). Recent studies have shown that TERT is present in

pre-differentiated neuronal blast cells but it precipitously drops off in adult neurons. Deficits of

TERT present in the cellular context have been shown to be predictive of the development of

neurodegenerative disorders. The presence of TERT is protective against the cell death due to

apoptotic factors and the onset of apoptotic cascade (Bermudez, Erasso, Johnson, Alfonso,

Lowell, & Kruk, 2006; Lua, Fua, & Mattson, 2001).

We found that expression of hTERT, the catalytic component of

telomerase, was sufficient and specific to reduce caspase-mediated

cellular apoptosis. Further, hTERT expression reduced activation

of caspases 3, 8, and 9, reduced expression of pro-apoptotic

mitochondrial proteins t-BID, BAD, and BAX and increased

expression of the anti-apoptotic mitochondrial protein, Bcl-2. The

ability of telomerase to suppress caspase-mediated apoptosis was

p-jnk dependent since abrogation of jnk expression with jip

abolished resistance to apoptosis. (Bermudez, Erasso, Johnson,

Alfonso, Lowell, & Kruk, 2006).

Increased cell death is a key aspect of multiple neurodegenerative disorders (Okouchi,

Ekshyyan, Maracine, & Yee, 2007). Down-regulation of telomerase is present in individuals with

Alzheimer’s dementia (AD), Parkinson’s dementia, Amyotrophic lateral sclerosis and Fronto-

temporal dementia, to name a few. In AD shortened telomere length was noted in T-

lymphocytes. This reduced telomere length correlated with scores on MMSE: “the

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proinflammatory cytokine TNFα (a clinical marker of disease status), with the proportion of

CD8+ T cells lacking expression of the CD28 costimulatory molecule, and with apoptosis.

(Panossian et. al, 2003).” Another study finds similarly, “Thus, a simple count of chromosome

ends for the ‘presence/ absence’ of fluorescence (marking telomerase) may provide a valid

biomarker of dementia status” in individuals who meet the criteria for AD (Jenkins, 2008).

Alterations in the “SOD1 gene [and] deletions of the telomeric copy of the SMN gene”

were noted in individuals with motor neuron disease (Orrell & Figlewicz, 2001). An

upregulation of telomerase has been shown to be neuroprotective and to reduce the chance of an

apoptotic cascade (Mattson, 2000). There are many factors that increase or reduce the risk of

apoptosis (Mattson, 2000). Some recent studies have indicated that telomerase is important to

responses to insults to the brain as well as neural development (Mattson, 2000; Lua, Fua, and

Mattson, 2001). The regulation of apoptosis is a key role of the immune system (Feig & Peter,

2007). The disruption in immune functioning due to reduced telomere length is a key example of

how a disruption in one system’s functioning can lead to the disruptions in another (Rudolph,

Chang, Han-Woong, Blasco, Gottlieb, Greider, and DePinho, 1999). The under-regulation of

telomerase increases susceptibility to apoptosis and correlates with dementia ratings and

increased inflammation, possibly linking alterations in immune functioning and

neurodegenerative disorders (Lua, Fua, and Mattson, 2001).

Life in the balance: The effects of telomerase an oxidative stress on cellular senescence.

Oxidative stress has been shown to reduce the length of telomeres and is not repaired as

easily as damage to other areas of the DNA (von Zglinicki, 2002). Oxidative stress has been

shown to play a key role for enchained cellular senescence and antioxidants have been shown to

decelerate cellular senescence (von Zglinicki, 2002; Naka, Akira, Ikeda, & Motoyama, 2003).

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There is an interaction between regulation of oxidative stress and the regulation of replicative

processes (von Zglinicki, 2002). One study has found that increased anti-oxidant protection plays

a key role in the ability of embryonic stem cells to remain pluripotent even after multiple mitotic

cycles (von Zglinicki, 2002; Naka, Akira, Ikeda, & Motoyama, 2003). This also points to the

interrelationships between systems. Upregulation of telomerase can reduce the effects of

oxidative stress and stop a cell from entering senescence, even in an oxidative upregulated

context (von Zglinicki, 2002; Naka, Akira, Ikeda, & Motoyama, 2003). Upregulation of

telomerase can also play a key role leading to immortalization of cells and the onset of a

cancerous replication cycle. One could easily imagine that a balance is established between

oxidative stress and telomerase that, if exceeded in either direction, could cause significant

disruptions to a single tissue/system or at a more global, body-wide level.

Systemic stress.

Systemic stress is a term this author uses to describe when the change to any one system

in the body enters into a state that exceeds its normal range of ability to return to a baseline of

functioning thus requiring increased energy or adaptations in other systems in order to return to

baseline. An excellent example of how certain types of systemic stress can be virtually

irreversible is the way cells can enter into stress-induced senescence. Senescence is the lack of

ability for a cell to continue to reproduce through mitosis. When cells are “exposed to sublethal

(systemic) stress” they will often enter what is known as stress-induced cellular senescence

(SIPS) (Naka, Akira, Ikeda, & Motoyama, 2003). Like with most disorders of regulation SIPS

can be triggered by multiple means: exposure to UV light, radiation, oxidative stress and other

external insults that damage the length of the telomere. These cells display key markers of

cellular senescence, such as flattening of the cell body, β-galactosidase activity, and a rapid

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reduction in telomere length. Overproduction of reactive oxygen can induce cellular senescence

(Naka, Akira, Ikeda, & Motoyama, 2003). The cellular senescence brought on by oxidative stress

cannot be reversed with an upregulation of telomerase. Similar findings exist for damage due to

other factors such as radiation. This indicates that global DNA damage also can induce

premature cellular senescence (Naka, Akira, Ikeda, & Motoyama, 2003). The oncogenes Ras and

Raf also trigger what appears to be stress-induced cellular senescence, resulting in a permanent

arrest to the cycle of mitotic replication. This is known as ontogenetic stress-induced senescence

(Naka, Akira, Ikeda, & Motoyama, 2003).

Global and local effects.

Adding to the complexity are the possible effects of global systems that set the tone of

multiple systems or in some cases the entire body. When there is a global disruption it can lead

to many symptoms that appear unrelated and disconnected from a single cause. Some of these

global systems could include diurnal patterns of endocrine and neurotransmitter production,

sleep cycles, autonomic stress reactivity and so on. As stated above, disorders of regulation is

that any single system’s functioning can be affected by many different events. These events can

be localized to a system or an area of tissue, such as the shortening of telomeres when oxidative

stress is upregulated in a specific region, and these events can also be global, such as with broad

scale damage to the DNA structure from radiation that leads to a cell entering senescence early

and losing the ability to replicate (von Zglinicki, 2002; Naka, Akira, Ikeda, & Motoyama, 2003).

To exemplify this overproduction of insulin effects the entire body including mood swings,

weight gain, hypoglycemia, increased facial hair in women, hair loss, bloating, and high blood

pressure (Norman, 2010).

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Complexity small changes big results.

As small differences happen in the replication process they can lead to large-scale

alterations in system functions (Briggs & Peat, 1989). This type of difficulty has a particular

sensitivity to initial conditions. Cellular senescence highlights this type of change. Multiple

replications of cells and the process of cell reproduction are ripe for dysregulation that mirrors

the dysregulations that are possible in the population growth equation.

Second Impact Syndrome

When individuals have a head injury there are profound alterations in the internal

working and chemical dynamics of the brain (Yoshinoa, Hovda, Kawamata, Katayama, &

Beckera, 1991). These shifts in metabolic and chemical functioning are intended to protect the

brain and allow it to heal after a concussive injury (Giza & Hovda, 2001). Medicine, even the

body’s own medicine in sufficient dosages, can cause damage. If certain aspects of the brain’s

functioning exceed its regulatory capacity, there can be a major loss of brain tissue and

functioning from what seems like insignificant insults to the brain (Giza & Hovda, 2001). This

process of an initial dysregulation of brain metabolism leading to vulnerable states from which

even a minor insult (e.g., small impact to the skull) leads to significant brain damage is an apt

example of the process of systemic dysregulation leading to a disease process.

The functional dysregulation model of disorders of regulation would hold that as a

system exceeds its regulatory capacity in one area, the entire system begins to adapt. It also holds

that there are key areas, times or states of vulnerability from which exceeding the regulatory

capacity would lead to fundamental alterations in the systemic function. These alterations occur

more frequently in two situations: 1. When the body’s defensive strategies put the system into

systemic stress (high allostatic load on the system) or 2. The dysregulation of one system

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precludes the effective functioning of another, thus leading to that system no longer functioning

as a regulatory boundary for the dysregulated system and the non-functioning system no longer

being able to perform its vital function, leading to more systemic adaptations and so on. In

McEwen’s (2002) theory of allostatic load alterations in stress response, either in intensity or

duration, the context leads to systemic adaptation. In this model I would extend the idea of

allostatic load to any significant functional adaptation of a systemic relationship due to the

inability to return to a functional baseline of oscillatory patterns between systems.“It is during

the post-injury period, when cellular metabolism is stretched to its limits, that the cell (and the

brain) is most vulnerable to further insults (Giza & Hovda, 2001).”

Multiple Causes – Multiple Systems

There are multiple systems in the body. Each system has multiple contextual events that

maintain its functioning. Disruption to a system can come from any surrounding system. Some

systems have global reach and can affect the entire organism at once. This adds a significant

layer of complexity in understanding the antecedents of symptoms. To put this in more concrete

terms, a neuron will die under many conditions (Trump, Berezesky, Chang, & Phelps, 1997).

Some of these include increased metabolism, excessive glutamate production, apoptosis inducing

factors, genetic abnormalities, epigenetic mutations, exceeding its number of mitotic cycles,

oxidative stress, being attacked by t-cells and so on. To quote John Muir, "When we try to pick

out anything by itself, we find it hitched to everything else in the Universe.” In the case of these

disorders, this is true. However, the goal is to identify the corner being tugged on and stop the

tug. The aforementioned list contains some of the systems affecting a neuron’s life. There are

countless other systems.

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Implications for treatment

The difficulty in addressing the symptoms of disorders of dysregulation stems from: a.

there being multiple possible causes for a single outcome, b. second order effects where the

primary cause is not the main cause for presenting symptoms, c. the symptoms are created by

adaptations in the functioning of the body’s own processes, d. there can often be additive effects,

and e. small disruptions can become larger over many iterations, such as through mitosis, across

a life span, thus making effect and causal events not apparently contiguous in time.

In this model creating a treatment is much more precise and therefore labor intensive than

in traditional treatments. The goal of treatment is not amelioration of symptoms but the re-

establishment of a coherent relationship between systems. This requires: a. identifying the areas

of dysregulation, b. identifying the main functions and regulators of these areas, c. in some cases

differentiating primary, secondary and tertiary symptoms, and d. interventions aimed at re-

establishing the body’s natural ability to return to a coherent allostatic range.

Current Treatments Using Systems Approaches to Treat Disorders of Regulation

There are many current treatments that utilize this type of reasoning to reestablish a

homeostatic pattern or to help a dysregulated system find a new stable pattern of systemic

oscillation. Some of these are: defibrillation as a treatment for certain classes of myocardial

infarction, deep brain electric stimulation for movement based Parkinsonian symptoms, motor

neuron atrophy due to encephalitis infection, cognitive behavioral therapy for depression, saline

trigger point injections for pain, and mindfulness-based stress reduction. Exploring existing

treatments and appling systems thinking to understanding patterns of dysregulation explanatory

model of how a treatment works to re-establish a coherent pattern of functioning could illuminate

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this further.

Neural Adapted Sinibus Virus (NSV)

Neuroadapted Sindbis virus (NSV) in humans is a moderate lung infection; in mice it

leads to a severe sickness that if it infects the brains of animals will cause paralysis, a stripping

of dendritic connections, global excitotoxic nerve death and eventually the death of the animal.

One of the key findings of the study of this infection is that the viral infection is not the direct

cause of these terrible effects (D. Kerr, personal communication, 2008). The animal will become

quite sick but it is not the infection of the cells that leads to the cell death. The virus it self leads

to the death of only around 20% of the neurons while at the end of three weeks the animal

displays 95% neuron loss. Douglas Kerr (2008) and his research group found that it is

dysregulation of autoregulatory functions of the microglial and a metabolic protective defensive

strategy in the neurons that leads to the catastrophic loss of cells.

It is a dysregulation of the re-uptake of glutamate and an increased neuron signaling of

stress through the secretion of nNOS that leads paralysis and death. What the researchers did not

know at first was that this upregulation of nNOS and the dendritic sloughing was a protective

strategy that is vital for a cell near metabolic overload. The secretion of nNOS signals to the

neuron it is in danger of excytotoxicity and evokes a protective strategy which is to reduce input.

If the dendrites coming into the neuron continue to signal it to fire, it will enter a metabolic crisis

and die; thus, dropping the dendritic connections protects the neuron against over-excitation,

attempting to be a shutoff switch if the neuron in colloquial speech, “overheats”.

However, because this virus leads to global upregulating of nNOS (rather then local

upregulation more normative for axotomy injuries) and the sloughing of dendritic connections in

the entire motor cortex the system is primed another form of paralysis and of cell death induced

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by isolation from other cells (D. Kerr, personal communication, 2008). Indeed when the

researchers down regulated nNOS and TNFa-alpha, what they found was that the dendrites

remained connected but the cells died due excytotoxitcity. The sloughing of dendrites is

protective function that if it happens on local level likely can be protective. If upregulation of

nNOS happens on a global level it exceed the brains capacity to regrow connections after the

need for the initial protective response has passed. Researchers working in systemic manor were

able to halt this process by providing other forms of protective interventions for the time when

the cells were in a vulnerable state.

From the systems perspective there are five key factors in this process. The first is that

there were alterations in the current system state due to a viral infection leading to priming

effects for a catastrophic cell loss. The second is that researchers identified the system areas

where the system entered a state space vulnerable to produce the results noted (e.g. finding

events that could cause dendritic sloughing). The third is that there were synergistic interactions

between multiple systems defensive responses that lead to disruptions in the ability of the state

space to return to homeostatic range after an allostatic protective response. Fourth is that the

team identified several systems and their defensive actions. In other words they identified the

key protective functions that are leading to the neuron entering into an allostatic response. Fifth

the team found ways to hold the system stable while time dependant defensive strategies could

complete and reduced the signaling for other defensive strategies that lead to the synergistic

catastrophic destabilizations of the spinal motor neuron functioning. Due to these contextually

relevant interventions during the critical period the normal and typically quite stable functioning

of the motor neuron system was allowed to reassert itself through re-establishing the regulatory

boundaries already present in the system (D. Kerr, personal communication, 2008).

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Applying a systemic approach to understanding the formation of symptoms of Alzheimer’s

Dementia: Role of Systemic Dysregulation in Alzheimer’s Dementia

AD, or Dementia of the Alzheimer’s type, has multiple precipitating events that lead to

the development of this condition (Attix & Welsh-Bohmer, 2006). The multiple precipitating

events are often additive, leading to a synergistic risk for the neurodegenerative disorder. The

traditional theory of AD is that there are disruptions of gene expressions that can lead to

development of AD (Bullido et al., 1998). Some recent theories hold that the disruption of gene

expression needs catalyzing events to make the transition from genotype to phenotype (Bullido

et al., 1998). Little consideration is given to epigenetic alterations in both gene expression and

gene patterns (Becker, 2004; Wang, Oelze, & Schumacher, 2008). Theorists have indicated that

many instances of AD are not accounted for by the current theories of the pathophysiology of

AD (Becker, 2003). The central tenet of the thesis presented here is that while the genetic theory

is accurate, there is another relevant story about the role of systemic regulation and interactions

between brain, body and environment that could have implications for understanding and

treating neurodegenerative disorders (Wang, Oelze, & Schumacher, 2008).

The systems dysregulation paradigm starts out with the premise that there are many roads

to neurodegeneration and there are multiple events and classes of events that can synergistically

lead to the same type of dysregulation and similar patterns of dysfunction. To exemplify this,

disruptions in cortisol secretion can be brought about through: a. tumors in HPA axis, b.

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depression, c. PTSD, and d. disruption in early attachment (Young, Abelsona, & Camerona,

2003; Yehuda, Teicherbc, Trestmana, Levengooda, & Sievera, 1996; Penza, Heim, & Nemeroff,

2003; Dorn, Burgess, Friedman, Dubbert, Gold, and Chrousos, 1997). Dysregulation of cortisol

has been associated with hippocampus shrinkage, loss of sleep patterns, disruption to the

dopamine system, disruptions in concentration, toxic cell death and anhadonia (R. Sapolsky,

personal communication, 2001). This is only one system. It is an important system for

autoregulation but not by any means the only.

From the systemic dysregulation paradigm, in order to for the genotype of AD to become

the phenotype of AD, there would need to be disruptions in the ability to form memories,

maintain hippocampus volume, rate of cell death, mitosis and maintain previously encoded

memories. These dysregulations could occur in multiple levels of the system. The interplay

between life events, environmental toxins, volitional behaviors and chemical contexts and the

functional relationship between anatomical structures are a few of the factors that could add to

disruptions in memory retention and formation. From a systems perspective this is not a surprise

because there are often several key areas of vulnerability in a system that lead to increased risk

for these patterns’ systemic dysregulation, not simply one.

Systemic Disruptions Present in Individuals with AD

In the paths leading to Alzheimer’s there are some major themes that emerge. These are:

a. changes in stress response, environmental stressors and systemic stress, b. changes in

subsystem functioning, c. functional shifts between systems, d. alterations in the metaplastic

environment, and e. changes in cellular senescence (Attix & Welsh, Bohmer; Chen, Kagan,

Hirakura, & Xie, 2000; Sorg et al., 2007; Peskind, Wilkinson, Petrie, Schellenberg, & Raskind,

2001). Mapping some of these key changes could illuminate possible places in the system where

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one might create interventions to re-establish the neurobiological system’s functional capacity to

maintain itself and auto-regulate.

Alterations in Stress Response

Abnormal stress response has been noted in many individuals with AD (Popp et al.,

2009). High levels of CORT have been shown to be associated with loss of hippocampal tissue

in depression, PTSD, Cushing’s syndrome and AD (Young, Abelsona, & Camerona, 2003;

Yehuda, Teicherbc, Trestmana, Levengooda, & Sievera, 1996; Penza1, Heim, & Nemeroff,

2003; Dorn, Burgess, Friedman, Dubbert, Gold, & Chrousos, 1997). In one study of the effects

of reducing CORT levels in individuals with Cushing’s syndrome, it has been noted that the

hippocampal tissue regenerated significantly (Starkman, Giordani, Gebarskic, Berent, Schork, &

Schteingart, 1999). Upregulation of CORT is associated with anhadonia, psychomotor

retardation, poor memory encoding, lack of ability to concentrate, loss of interest in sexuality,

increased anxiety and aggression. PTSD is a risk factor for the development of AD. In both AD

and PTSD there is a decrease in heart rate variability (HRV) in AD a direct relationship was

noted between HRV and symptom severity (Zulli et al., 2005; Cohen et. al., 1998, Zulli et al.,

2005).

Alterations in CORT levels also lead to disruptions in the dopamine system,

norepinephrine system, the serotonin systems and the acytocholine system (Oswald et al., 2005;

Pacaka et al., 2002; Idoyaga-Vargas, Abulafia, & Calandria, 2001; Geracioti, et Al., 2001; Pacak,

Palkovits, Kopin, & Goldstein, 1995; Meshorer, & Soreq, 2008; Kirkwood, Rozas, Kirkwood,

Perez, & Bear, 1999). CORT also plays a role in the regulation of dopamine and dopamine loss

could lead to increased LTD and reduced LTP (Calabresi et al., 2000). Cortisol may end up

being a large system that, if dysregulated, can lead to many systemic changes (R. Sapolsky,

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personal communication, 2001). Alterations in stress response due to life stress in younger

animals have been noted to create large-scale changes in multiple systems. “Compared to

controls, traumatized animals showed an increase in Ca2+ homeostatic proteins, dysregulated

signaling pathways and energy metabolism enzymes, cytoskeleton protein changes, a decrease in

neuroplasticity regulators…, and an increase in apoptotic initiator proteins (Uys, Hatting, Stein,

& Daniels, 2008).” CORT production decreases telomerase production throughout the body

(Choia, Faucea, & Effros, 2007; Epel et al., 2004). Telomerase down-regulation has been

implicated in AD and other neurodegenerative disorders (Mattson, 2000).

There are multiple determinants for the systemic functioning of CORT; genetics, diet,

environmental factors, and epigenetic factors. Some environmental factors are number of adverse

childhood events, PTSD, disruptions in infant child bonding, exercise, and social support (Shea,

Walsh, MacMillan, & Steinera, 2004). Genetics has been implicated in the creation of the

autonomic set point for CORT production and changes in set point were catalyzed in a gene by

environmental interaction (Adamafio, 2009; Wüst, Federenkoa, Hellhammera, & Kirschbaumb,

2000; Kirschbaum, Wust, Faig, & Hellhammer, 1992). Even short-term disruptions in parent-

child bonding or mild increases in parental aggression lead to significant life time alterations in

CORT response (Van Oersa, Kloetb, & Levinea, 1998). Number of adverse childhood

experiences correlates with increased depression, anxiety and self-destructive behaviors (Felitti,

Anda, Nordenberg, Williamson, Spitz, & Edwards, 1998).

Neuroplastic Dysregulation

The brain is a learning context. Each time we move, think or plan we are sculpting the

brain. In order for the brain to maintain optimal functioning it needs to balance its rate of change.

If it changes too quickly the brain becomes an unstable environment. If it does not change

20

quickly enough it will have difficulty learning to map experiences. There are currently seven

main processes that describe how the brain maintains its internal architecture at an optimal level

of flexibility: long-term potentiation, long-term depression, activity dependent changes,

metaplasticity, neurogenesis, kindling and salience effects (Burrell & Sahley, 2004; Eriksson et.

al., 1998; Ichise et. al., 2000; Kalivas, & O'Brien, 2008; Malenka, & Nicolla, 1999; Minabe &

Emori, 1992; Mueller, Pollock, Lieblich, Epp, Galea, & Mistlberger, 2007; Nitsche et. al., 2006;

Wickliffe & Bear, 1996). These are the learning-based regulators identified to date. Along with

these regulators there are also metabolic and structural regulators of plasticity. One of these is the

Mglur (Matabtropic glutamate receptors) that, when stimulated, reduce the number of AmpR

receptors attempting to control and regulate the level of excitatory potential possible. If the level

of excitatory potential is exceeded, then the neuron can die due to excytotoxicity (Choi, 1992).

Individuals with AD have multiple alterations in the rate of neuroplasticity (Arendt,

2003; Kimmo, Krystyna, Tomoaki, Daniel, & Stanley, 1999; Flood, & Coleman, 1990; Shankar

et. al., 1990). They also have been noted to display a decline in cell density in the hippocampus

that spreads over the course of the disease to other brain areas. One of the key areas of

dysregulation is in the actocholine systems which is a global regulator of the rate of plasticity

(McKay, Placzek, & Dani, 2007; Whitehouse, Martino, Antuono, Lowenstein, Coyle, Price, &

Kellar, 1986). Most current AD meications are acytocholinergic. Another effect on plasticity is

Abeta (often expressed in individuals with AD) in one study found to be a clear down-regulator

of LTP, possibly effecting neuronal pattern stability (Chen, Kagan, Hirakura, & Xie, 2000). In a

2010 study in a Prelisin 1 knock out mouse (a mouse model of some of the processes in AD)

there was noted an upregulation of LTD. These mice show an upregulation of LTP (early phase

LTP, late is phase similar to controls) early in life that drops off as they age. This produces a

21

high rate of quick changes that do not get stabilized into fully encoded neuronal patterns. This

upregulation thus leaves the brain vulnerable to destabilizing the patterns of connectivity and

catastrophic LTD. Another study found that chronic exposure to adrenergic stimulation (common

in those with AD) upregulated the LTD mediated by Alpha1AR (McElligott, & Winder, 2008;

Davis et. al., 1996; Popp et. al., 2009).

Endocannabinoids are another regulator of the rate of plasticity (Kyriakatos & Manira,

2007; Pazos, Núñez, Benito, & Tolón, 2004). They function as agents facilitating the increase of

excitatory synaptic plasticity, LTD and LTP (Pazos, Núñez, Benito, & Tolón, 2004). The

endogenous canibinoids are regulated by a calcium dependent mechanism. The mechanism

works like a switch priming cells to release eCBs but only coupled with a transient rise in Ca2+.

Another group of researchers found “the existence of profound changes in the location and

density of several elements of (the endocanibanoid) system in Alzheimer's disease tissue

samples, indicating that a non-neuronal endocannabinoid system is up-regulated in activated

glia” (Pazos, Núñez, Benito, & Tolón, 2004).

Multiple studies have shown changes in Serotonin in individuals with AD (Mintzera, et.

Al, 1997). Sertatonin has been noted to “regulate cell proliferation, migration and maturation in a

variety of cell types, including lung, kidney, endothelial cells, mast cells, neurons and astrocytes”

(Azmitia1, 2001). Alterations in the dopamine system (increasing D2/D3 receptors) have been

noted in individuals with AD (Reeves, Brown, Howard, & Grasby, 2009). Dopamine is a key

mediator of LTP and LTD firing for both salient (both positive and negative) and positive salient

events (O. Hikosaka, personal communication, May 7, 2009). If there is an action potential

previously associated with a dopamine response, that fires without dopamine modulation there is

a stimulation LTD. The acytocholine system and the dopamine system work in conjunction,

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modulating the rate of plastic change. Upregulation or down regulation of dopamine could have

profound effects on rates of neuroplastic change (Shen, Flajolet, Greengard, & Surmeier, 2008).

Another class of neuroplastic regulation is the activity dependent class of regulation.

Activity has been shown to prime patterns of cellular connectivity for LTP (Antonov, Antonova,

Kandel, & Hawkins, 2003). Previous firing of a pattern of neurons also primes the neurons for

firing. This is could easily form a positive feedback loop of learning. LTD is upregulated by

excitatory activity that does not produce a full action potential (Stanton, 1995). If multiple cells

send positive signals for action potential to a cell and that cell does not fire, this increases the

likelihood of LTD (Calabresi, Maj, Pisani, Mercuri, & Bernardi, 1992).

The ratio of signal to noise is another activity-dependent regulator of plasticity (M. Bear,

personal communication, June 16, 2003). The brain as a learning context would more likely be

served by encoding accurate patterns than irrelevant patterns. The mind is capable of tracking

irrelevant patterns if this system is co-opted by other regulators; among these is salience effects

and another is signal noise. If the pattern recognized by the brain is highly noisy (e.g., not a

strong predictable relationship) this would likely indicate that it is not a pattern. For phylogenic

reasons the brain would have been unlikely to evolve if it tracked too many irrelevant patterns.

Increased signal noise is a better predictor of LTD than long-term disuse of the synapse. In a

study conducted by Marc Bear (2003) Cats who have an eye disrupted chemically so that no

signal is getting to the brain, have less LTD in the visual cortex than a cat who wears a single eye

patch. In the cat with the patched eye, the increased noise of the eye seeing the blackness alters

the patterns of the visual cortex more with more loss in connections then the cat with the nerve

signal chemically blocked. In other words higher signal noise ratio lead to more LTD (M. Bear,

personal communication, June 16, 2003). This fact has profound implications for the loss of

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memory in AD: Earlier memories whose pattern is both more encoded and least likely to be

triggered by current context would be the most undisturbed by this process. It is possible that the

memory is evoked and the heightened plastic context, in conjunction with the increased noise-to

signal-ratio due to the flattening of salience indicators, leads to a destabilization of the cellular

pattern that marks the memory of the event. This destabilization in turn leads to a loss of

connectivity and eventually to cell tissue death.

In older adults there are several key possibilities increasing signal to noise and thus the

likelihood of a catastrophic loss of connectivity and apoptic cascade. These are: a. poor sensory

information due to changes in physical sensors (ear drum, hairs in the ear, hardening of the

cornea, slower reaction times, reduced sense of smell); b. inaccurate reading of the sensory

information by brain systems (changes in ear structure have not changed how the brain receives

the information from the ear); and c. internal events (stress, anxiety, pain, fear, other affect,

worry, thoughts creating internal distraction and increased signal noise) (Mahncke, Bronstone, &

Merzenich, 2006). This last class (internal events) is significant in older adults and has not been

discussed thoroughly as an impact on brain health in aging. Another final note on the activity

dependent regulators of plasticity is that in older adults, particularly in Western cultures, there

are alterations in lifestyle that can reduce the amount and quality of environmental stimulation. It

is interesting to note that increases in mobility, social stimulation and environmental novelty

have been noted to reduce symptoms of AD and be protective factors against developing AD

(Nithianantharajah & Hannan, 2006).

Major Types of Neuroplastic Change and Their Implication for Systemic Dysregulation

Regulation of Metaplasticity: Upregulation of long-term potential could in certain system

states lead to forming many patterns that are weakly associated, as in the blooming and pruning

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cycles early in life. This cycle leads to the formation of many new but not entirely accurate

patterns of neuronal associations. Later these patterns are not supported by external events. In

essence, an upregulation of metaplasticity, increasing LTP past a certain point, could lead to an

upregulation of LTD due to increased signal–to-noise ratio, thus leading to receptor loss,

destabilization of balance between functional areas, axonal connections and eventually cell

death.

Down-regulation of LTP, telomerase activity and neurogenesis could lead to an inability

to replace cells and rebuild damaged synapses. This leads to a slow but steady attrition of

memory and abilities that eventually reaches a crisis point when the relationship between

external events has such dramatic increased noise that it precipitates a rapid rate of LTD.

A metaplastic decreased LTD could lead to many patterns being encoded and competing

for attention there by disrupting retrieval and overloading pattern recognition with relevant

possibilities. It is also possible that this leads to a single external event triggering in a context

irrelevant manor many patterns of neuronal relationships disrupting the synchronous patterns of

firing.

Regulation of Neurogenesis: Neurogenesis is the forming of new neurons in the brain.

Until recently it was believed that neurogenesis stopped as an individual reached adulthood. An

under-regulation of neurogenesis could lead to lack of replacement for damaged cells, reduced

memory formation and overtime destabilization of current patterns of neuronal connectivity.

Regulation of Salience Effects: If dopamine cells fire in conjunction with a pattern of

neuronal firming, this marks the pattern or an aspect of the pattern as highly salient for the

continued functioning of the organism. This increases the possibility of LTP forming a new

neuronal pattern. If a pattern fires without a dopamine signal. the pattern is more likely to

25

destabilize and enter the LTD cycle. To be precise it is currently thought that dopamine fires at

both salient (both positive and negatively relevant events) and positive events.

Acytocholine Cells: These cells increase the sustained attention on the external event and

thereby the accurate encoding of a neuronal map of that pattern (Himmelheber, Sarter, & Bruno,

2000). Increases of ACh lead to a metaplastic increase in the rate of neuroplasticity

(Jerusalinsky, Kornisiuk, & Izquierdo, 1997). Upregulation in ACh could lead to destabilized

patterns of relationship due to the formation of neural circuits that are only loosely reflected in

the external context. An under-regulation of ACh could lead to a lack of ability to form new

memories and reduced activity-dependent maintenance of current patterns of neuronal firing.

This dysregulation would likely not produce a boom and bust cycle but rather produce a slow

degradation of memory and memory formation with an exponential increase in loss toward later

parts of the disease process.

Brain Derived Neurotropic Factors (BDNF) Regulation: BDNF is a protein responsible

for the growth and maintenance of nerve cells. As well as its action in the brain, it also plays a

role in motor neurons, kidneys, prostate and is often present in saliva (Binderm & Scharfman,

2004; Huber, Hempstead, & Donovan, 1996; Pflug, Dionne, Kaplan, Lynch & Djakiew, 1995;

Mandel, Ozdener, & Utermohlen, 2009). BDNF supports the health of existing cells, the growth

of new cells and the building of new synapses. It is found in areas related to higher order

learning, memory, and problem solving (e.g., hippocampus and cortex) (Hall, Thomas & Everitt,

2000). BDNF knock out mice have been shown to die at birth or have major neurological

difficulties, including sensory neuron loss (balance, hearing, and taste) and breathing problems

(Ernfors, Kucera, Lee, Loring, & Jaenisch, 1995). BDNF is implicated in multiple disease

processes including AD, depression, psychotic spectrum disorders, obsessive compulsive

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disorder, dementia, anorexia, and bulimia. Under certain conditions it can increase cell death

instead of protect against it (secretion of p75NTR in the absence of Track A, B or C can lead to

cell death). BDNF plays a large role in neurogenesis (Bekinschtein et. al., 2008). It has a reward

salience effect in the ventral tegemental area. BDNF has been shown to be increased by exercise,

restricted calories, treatments for depression and intellectual stimulation (Gómez-Pinilla, Ying,

Roy, Molteni, & Edgerton, 2002). BDNF is implicated in the reversal of hippocampal damage

that occurs subsequent to depression treatment. Cortisol has been shown to reduce overall brain

levels of BDNF (Smith, Makino, Kvetnansky, & Post, 1995). Under or overregulation of BDNF

could have catastrophic effects on brain health. If BDNF were down-regulated in a high cortisol

context elevated it could be catastrophic.

Amygdala and Bed Nucleus: The amygdala is a well known area of the brain that acts like

a smoke detector for threats, stimulating the brain and body into a fight, flight or freeze defensive

response. The AMY plays a large role in two aspects of neuroplasticity: it controls cortisol

secretion and thus affects the metabolic ways a neuron can live or die, and it regulates salience

effects for threat. Hyper-sensitive, easily triggered stress response or high number of triggering

events coded by the AMY could lead to profound cell damage due to being in a metabolic

endangered state such that minor insults could kill them. The bed nucleus is connected to the

same areas of the brain as the AMY. It mediates long-term anxiety. Thus it is highly implicated

in worry or psychological stress and may be responsible for the slow attrition of neurons seen in

individuals who are low in a dominance hierarchy or have poor emotional regulation skills.

Upregulation of these areas could lead to increased excitoxic cell death and Under-regulation of

these areas could lead to reduced salience effects and negative consequences on multiple systems

(Sopolsky, 2005).

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Activity Dependent - Previous Firing of Cells: Recent previous firing predisposes the area

to fire again under similar conditions (Antonov, Antonova, Kandel, & Hawkins, 2003). The cells

are thus primed to highlight certain relationships in external contexts by firing more easily in the

internal context. In a highly upregulated context of firing there is a loss of differentiation

between firing patterns. If firing becomes indiscriminant and not related to situational events it

could increased LTP, the encoding of inaccurate patterns of events and subsequently a

catastrophic destabilization of neural context. Under-regulation of firing rate could lead to

increased LTD due to inability for one part of a pattern of firing to trigger an action potential in

related systems.

Switching Neurological Sets: Another key aspect of the brain physiology that could

enhance the development of AD is the reduction of the ability to switch between functional

systems. Recent studies have found that there are major neurological organizational systems for

broad classes of types of life tasks (Taylor, Seminowicz, & Davis, 2009). Purely cognitive tasks

require different neurological demands than physical tasks or emotional learning tasks. A study

of individuals with early AD has found that there is a reduction of the ability to shift between

these larger scale functional systems. The insula, which often plays a gating function between

cognitive and emotional systems, no longer activates freely in those in early stage AD. A key

impact could be that mental states and memories that require the ability to shift between

functional systems could be difficult to access. This could lead a destabilization of neuronal

memory constellations and learned helplessness in accessing memories.

Attention and Signal Noise: Working memory has a limited amount of space for

processing information. Pain, psychological stress, and internal sensations could all co-opt

significant portions of working memory. This could lead to a feedback loop of increased focus

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on the pain or stressor, causing more pain and stress, and so on. If the pain and stress are

occupying significant amounts of working memory space, concentration goes down, the

metabolic effects of stress go up, and the ability to attend to and learn from the environment goes

down. This could lead to lack of neurogenesis, loss of nerve cells and reduced dendritic density

through increased signal noise ratio.

Metabolic Effects

Apoptotic Regulatory Factors

Multiple alterations in indicators of apoptosis are seen in individuals with AD. Amiloid B

protein, thought to be a major factor in the formation of AD, has been shown to be neurotoxic

(Cotman & Anderson, 1995). Alterations in reactive oxygen have been noted in individuals with

AD. Reactive oxygen is a major chemical used by the immune system to induce apoptosis in the

body. T-lymphocytes, the cells responsible for this immune function, are down-regulated in

aging but upregulated in individuals with AD. This study finds “elevation of [Ca2+]i appears to

be a prerequisite for apoptosis, which is suggested to be involved in the neuronal death occurring

in AD. An increased [Ca2+]i in AD is consistent with processes leading to neurodegeneration in

AD” (Sulgera, Dumais-Hubera, Zerfassa, Henna & Aldenhoffb, 1998). Alterations in caspase-8

have been noted, “[a] role for caspase-8 and the receptor-mediated apoptotic pathway as a

mechanism leading to the activation of caspase-3 within neurons of the AD brain” (Rohna,

Headb, Nessea, Cotmanb and Cribbs, 2001). Alterations in the mitochondrial-produced AIF

(apoptic inducing factor) have been noted in individuals with AD.

Apoptic Catastrophe

There are multiple major paths that can lead to a catastrophic apoptic cascade in the

subsystems of the brain. One path leads to apoptic cascade through a metabolic upregulation in

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cellular energy production (Choi, 2004). The second is through destabilization of cellular

connectivity through alterations in the homeostatic range of neuroplastic change. In this process

there are transformations in the brain’s potential to learn. This dysregulation could lead to

destabilization of a functional system or brain-wide, leading to loss of synapses, reduction of

neurogenesis and cell death. The third is through dysregulation in the process of cellular

reproduction, transcription, translation and the life cycle of a cell. The fourth is systemic

dysregulation of major homeostatic processes. In this process the destabilization of the

neurological environment is established by lack of vital chemicals, disruptions in autoregulatory

process (i.e., blood sugar, sleeping, metabolism, oxygenation, excretion, illness). The fifth is

dysregulation of the relationships between major psychoneurological functional areas, including

dysregulation of switching between functional systems, dissociation between functional areas in

a system, over-coupling between functional systems and increased irrelevant cueing for a

psychobiological functional area. The path to apoptic cascade includes multiple types of causal

events, including predispositions, synergistic events and non-linear dynamics.

There is an interplay in the brain between genetic determinants and contextual events that

sculpt its development (Thompson et. al., 2001; Caspi & Moffitt, 2006). The context of learning

is created by an algorithmic pattern of associative events that allows for the mapping of the

external realities, internal aptitudes and behavioral patterns in the biological relationship between

cells. This process is likely in part mapped genetically and determined by a self-organizing

process defined by the biological possibilities interacting with external events. Of note children

who face trauma, are raised under high stress or experience disruptions in parenting and have

differently organized cortical and sub-cortical areas (Schore, 2001).

Life-span Dependent Psychoneurochemical Changes

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In older adults there is often a confluence of difficulties that could increase the likelihood

of apoptic cascade due to either metabolic factors or learning-based factors. As adults age there

is an change in the production of GABA (one of the brain’s main inhibitory neurotransmitters)

and a decrease of the regulatory inhibition of gabanergic neurons by adenosine triphosphate

(ATP) (Marczynski, 1998). The increase of inhibitory neurotransmitters could increase the

likelihood of raising the resting state of the brain to a point well below the threshold for action

potential creating significant difficulty for the encoding of a new patterns.

Reduction in sleep and sleep disturbances are common among elders (Huanga, Liua,

Wangb, van Somerenc, Xub, & Zhou, 2000). Lack of sleep in younger adults has been associated

with precipitous drop-offs in neurogenesis and thus a slower ability to replace cells when they

die (Mueller, Pollock, Lieblich, Epp, Galae, & Mistlberger, 2008). REM sleep is the time of the

most major daily increase in acytocholine, a chemical involved in the regulation of attention,

encoding memory and the rate of plasticity. REM sleep is significantly reduced as modern

Westerners age (Ehlersa & Kupfe, 1989).

Another key time period of susceptibility for women is when entering menopause

(Solertea, Fioravantia, Racchib, Trabucchic, Zanettib, & Govonid, 1999). Reduction in estrogen

has been associated with the increased chance of development of neurodegenerative disorders

and low levels of estrogen replacement were found to be a mild protective factor against AD in

initial research (Vegetoa, Benedusia, & Maggi, 2008; Solertea et. al., 1999).

Another key time of vulnerability is in infancy. During this time even seemingly minor

increases in stress can lead to marked changes patterns of stress reactivity and regulation apoptic

factors in the hippocampus throughout a lifetime (Liu et. al., 1997; Anand & Scalzo, 2000;

Weaver, Grant, & Meaney, 2002). Other likely times of disruptions are in times of rapid

31

neurological development, such as myolenation of the frontal lobe in late teens or major life

transitions.

Often older adults live in an impoverished learning context due to several reasons: a.

significant over-learning about relevant environmental events and thus a lack of novelty, b. lack

of novel environmental cues and reduction of mobility, c. diminished perceptual strength due to

changes in sensory input, d. poor exercise, and e. poor social support due to ageism in Western

societies. An impoverished learning context has been associated with loss of synaptic density and

cell loss in neural structures (Sandeman & Sandeman, 2000; Turnera & Greenough, 1985; van

Praag, Shubert, Zhao, & Gage, 2005). Assessing the individual for disruptions that happen at key

points of developmental transition could lead to effective interventions.

Systems Based Approach: Implications for the modeling of brain aging and treatment of AD

As we have seen before there are multiple ways that any system can become unstable.

Alzheimer’s disorder has many different antecedent events (Attix & Welsh, Bohmer; Chen,

Kagan, Hirakura, & Xie, 2000; Sorg et. al., 2007; Peskind, Wilkinson, Petrie, Schellenberg, &

Raskind, 2001). As one prominent researcher notes pithily, when you have seen one case of

Alzheimer’s, you have seen one case of Alzheimer’s (Whitehouse & George, 2008). In the

systems approach it is assumed that there are many possible ways that the brain and body could

produce what looks like Alzheimer’s disorder. Each of these ways of creating symptoms called

Alzheimer’s Dementia will have a specific conglomeration of factors. The role of this section

will be to outline how to use this approach in identifying key dysfunctions in the brain system

and to provide means to reregulate these processes.

The first step in this process would be to identify on a case-by-case basis which major

systems are dysregulated. This would require identifying possible disruptions that could lead to

32

the symptoms at hand. Some key areas of systemic disruptions we have identified are

dysregulation of CORT, disruptions to oscillation between parasympathetic and sympathetic

nervous system functioning, disruptions in plasticity, dysregulation of cellular senescence, and

dysregulation of dopamine or acytocholine systems. These factors could be exacerbated by

natural aging effects on the neural systemic contexts. Events such as changes in GABA

production and the phase transition from pre-menopausal to post-menopausal neurochemistry

could create synergistic effects with the above systems. These disruptions could be identified by

multiple types of tests such as diurnal cortisol tests, measuring for overall telomerase production,

assessing glutamate production, and assessing if GABA is presented in age-appropriate levels.

These and other findings could be assigned a statistical range of likely contribution to the disease

process (identified through studies and the existing literature), the additive effects, synergistic

effects and catalyzation points for phase change in the brain could be also be quantified. A good

multivariate analysis could assess the impacts, interactions and synergies and find threshold

levels for phase changes in the brain.

The second step would be to assess if there are global or local effects of the

dysregulation. This could be vital information for how to assess which systems are more likely to

be vulnerable and which systems are main drivers for the dysregulation.

The third step is to identify typically occurring protective defensive responses in these

systems and the steps and stages of return to systemic coherence after an insult. Of particular

interest are areas vulnerable to feedback loops. Often when a given system is taxed or is injured

it will enter an allostatic response as it attempts to mitigate the damage as it occurs and repair

damage that is existing. The ability of the tissue to instigate this pattern and then return to

baseline once the threat is gone are both vital to the health of the organism. As Dr. Kurr noted in

33

his work with the neural adapted sinibus virus, sometimes these defensive responses can

themselves trigger other protective responses and enter into a deadly feedback loop.

The fourth step is to identify what resources the system needs to meet the demands of

completing the protective response. Sapolsky, in a 2001 talk on Alzheimer’s disorder and over-

activation of cortisol, describes that cells, when stimulated by cortisol, can enter into an energy

crisis. The demands for energy in the hippocampal tissue exceed the tissue’s ability to meet those

demands. The dendritic connections are sloughed off and many protective measures are taken to

avoid the metabolic crisis that occurs if the cell is over-stimulated. Sapolsky (2001) goes onto to

state that if the cells are given an easy to digest form of glucose, thus providing enough energy to

complete the defensive measures and meet the demands of the cell, the crisis is averted and the

cells will not die.

The fifth step is to identify the secondary, tertiary, etc., systemic effects and note if any of

these effects will not re-regulate once the regulatory boundary is re-established for the system of

primary dysregulation (e.g., hippocampal tissue loss will be stopped and reversed through

reregulation of CORT; on the other hand, in another system the reregulation of telomerase will

not lead to reduction of stress-induced premature cellular senescence). The effects of a primary

dysregulation on other systems could be that situational stress leading to increased CORT

production is leading to: a. increasing the rate of cellular senescence; b. reduced cognitive

functioning that synergistically compounds these effects through enhancing poor eating habits, c.

increased anhadonia through disruption in the dopamine systems, leading to lack of motivation

and impoverished social environments; and d. increased aggression disrupting the ability the

primary social support system to provide regulation for stress reactivity.

34

The sixth step would be to identify means to work with the system to re-establish a

functional regulatory range. A key assessment in this is to identify when to use “global” or top

down interventions vs. when to use focused bottom up interventions. Bottom up interventions

address the regulation of the whole system by changing a single system, function, protein or

chemical. Top down interventions change the regulation in subsystems by re-regulating the

entire context of the body (e.g. increasing sleep and re-establishing sleep architecture can change

metabolism, neurogenesis, BDNF levels and work functioning etc.). In the case in which

dysregulation of CORT is the major driver for dysregulation building in the ability for the

nervous system to smoothly down-regulate through establishment of a parasympathetic braking

of the sympathetic system could be vital. This could be accomplished through multiple means.

Increased sleep and re-establishing healthy sleep architecture could lead to down-regulation of

the stress system. Increase in number and duration of pleasurable events could increase the

parasympathetic tone. Social engagement also increases parasympathetic tone. Many stress

reduction techniques found in CBT, MBSR and other protocols could reduce the stress response

(Koszyckia, Bengera, Shlika, & Bradwejna, 2007; Praissman, 2008). This could then leave the

system more able to form new memories and regrow the hippocampal tissue.

The seventh step is to assess the functioning of affected systems post re-regulation of the

primary dysregulated system. Any systems that do not re-establish their functional range may

need to have a process that addresses their functional dysregulation. Assessing in this case for

dysregulation and factors reducing the system’s ability to return to functional range will likely

allow the clinician to help this system return to functional capacity. It may in fact turn out that

the stress reactivity set in motion alterations that have made a stable phase shift. Finding means

to hold the regulatory boundaries for that system so that it can shift to the previous functional

35

relationship could then reduce the dysregulation in that system. As an example, if the CORT

secretion has reduced telomerase production to a level where oxidative stress can lead classes of

cells to premature senescence, reduction of CORT with likely not re-regulate this area (Serrano

& Blasco, 2002). Increases in factors leading neurogenesis, re-regulation of telomerase and

increased antioxidants could begin the process of interrupting the cascade of cell death that was

established by the dysregulation of cellular senescence. Increased REM sleep could help to

increase neurogenesis and re-regulate any disruptions to the acytocholine system established by

the elevations of CORT (Mirescu & Gould, 2006; Cameron & McKay, 1999; Mueller, Pollock,

Lieblich, Epp, Galae, & Mistlberger, 2008; Mohapela, Giampiero, Kokaiaa, & Lindvalla, 2005;

Vazquez & Baghdoyan, 2001).

It is important to note that there are many ways to affect any given system and the many

effects that any given system can have. This implies that the above formulation is only a guide

for possible interventions and modeling. If the main dysregulation was in neuroplasticity and not

CORT there would be multiple other types of interventions and the systems that are subsequently

affected would differ. Taking a systems approach to treatment and working with the health in the

system, it may be possible to reverse some of the loss of functioning and extend the health and

mental life for individuals with and without cognitive impairment till much closer to the end of

their life. This could enhance the quality of life across the lifespan.

This description of Alzheimer’s disorder is meant as an example of a broader class of

disorders of regulation and ways to map cases of AD that have other causal events leading to the

main dysregulation. Disorders of regulation are marked by changes in auto-regulation that can

lead to disruptions in the functioning of multiple systems in the body, brain and mind.

Alzheimer’s disorder, like other disorders of regulation, can have multiple events that lead to its

36

onset. These events lead to disruption in functional dynamics and destabilization of the system.

A complex functioning system like the human brain and body also has many processes that help

establish and maintain healthy systemic functioning. Just as this class of disorders can be created

by the body’s own mechanisms working out of synchronization, they likely can be healed

through re-establishment of the functional regulators of the biological system.

37

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