A Matter of Balance

“As the twig is bent, so grows the tree.”

(The following understanding of PD arose from a three-year collaboration between myself and  French surgeon and PWP Anne Frobert of Lyon, France, and to whom half the credit must flow.)

There is a branch of science called Chaos Theory which studies the order which exists in systems which we perceive as lacking organization. Order is found throughout the Universe. It is often hidden from us and exists as a potential. The moving water molecules at a temperature of thirty-three degrees Fahrenheit give no hint of the order that is realized at thirty-one degrees. Yet, it is there as a potential. Remove a little energy and the potential collapses into reality and we take advantage of it to cool our beverage of choice.

The water molecules at a temperature of two-hundred and twelve degress have a similar potential but require much more energy transfer to collapse into the reality of a cold drink on a hot day.

In a similar manner we are each born with a collection of potentials that influence our future health. Genetics is just a part of it. Encounters with out environment is another. Yet another that has more recently begun to gain recognition is the ancestral influences of epigenetics. The events of yesterday influence tomorrow even over the span of generations.

A Chaotic System has an overriding characteristic – tiny changes in the initial conditions have large and unpredictable effects upon the future of that system.

And so it is with Young Onset Parkinson’s Disease. There is no “cause” that resulted in 100,000 people developing PD in the same sense that there is no “cause” for 100,000 deaths in automobile accidents. In the latter, some had bad brakes, some had bad luck. Some resulted from careless maintenance and some rolled off the assembly line missing a critical bolt. Some were due to a bush that blocked a “stop” sign and others were due to an engineer missing an important class at University forty years ago.

In YOPD, it is to a certain extent how we are made, but it is also a matter of certain events occurring at critical times, or “bad luck.” It is a whiff of an environmental toxin that our liver cannot deal with. It is a bacterial toxin that washes over our fetus on a critical day. And, it is how our great-grandfather treated our great-grnndmother which ultimately determined how our own reponse to stress evolved.

It is all these things and more. We enter the world with a potential to develop PD determined by our ancestors, our genetics, our gestation…

As Life unfolds that potential is increased or decreased as we interact with our environment and the inevitable stressors of living.

PD is not a “disease” that develops where there was none. It is a “condition” that gradually manifests over the course of decades. To ask where it begins is like asking the same question about a river and to ask when it becomes PD is like asking when the river becomes the sea. There are no hard lines to guide us, only mists and moonlight.

It is this view of PD that we put forward. It is the one that goes furthest in explaining the seemingly unconnected observations and thereby holds out the greatest hope for progress in dealing with it. We do not ask that any of this be taken on faith but only that the evidence presented be examined. We are fully aware that much of the research noted below has been based on animal models, but are also aware of the fact that much of the current view is as well.  Finally, while we are limited in our ability to present original research, we feel that in most cases our points reflect the preponderance of the evidence in a sizable body of data published in peer reviewed journals.

Early Life Origins of Parkinson’s Disease:

Key Concepts:

1. Prenatal conditions and events have major effects upon the adult.

2. One such possible event is fetal exposure to the bacterial endotoxin lipopolysaccharide (LPS).

3. Such exposure, if at the proper point in development, alters the brain in a pro-PD manner.

4. The same exposure alters the immune system in a manner that results in hypersensitivity to future exposure to LPS.

5. Furthermore, the endocrine system is altered by the same exposure thereby disrupting the adult stress response.

6. The endocrine system can be further altered by exposure to maternal stress hormones.

7. Maternal levels of stress hormones are determined by life events and the reaction to them which is, in part, determined by multi-generational influences.

8. In the adult offspring, stress increases the immune response and inflammation increases the endocrine response in a positive feedback loop.

9. This feedback loop lies at the heart of PD, generating numerous effects including neuronal loss in the substantia nigra, poorly controlled stress response, disruption of neurofunction, and gastrointestinal malfunctions.

10. Thus, this hypothesis describes PD as an interwoven malfunction of the central nervous system, the immune system, the endocrine system, and the gastrointestinal system.

Comment:

• Over the last few decades it has become accepted  that the adult is formed in the womb in part by the process of “fetal programming”.  This lifelong influence upon the just-formed fetus can come from many sources and have many effects. The proper influences at the proper time within the proper genetic framework along with the proper physical conditions followed by the proper childhood family structure along with the proper life experiences all may combine to bring into being a state that may become Parkinson’s Disease at some point in the future. Given the proper trigger.
• This string of variables provides an explanation for the fact that, while PD is common, not everyone gets it. They must fall into place one-by-one and in the proper sequence within a person with a particular disposition. And so, as if PD wasn’t already frustrating enough, a certain measure of old-fashioned “bad luck” is required.

Resouces:

• Prenatal programming of postnatal endocrine responses by glucocorticoids
• Impact of Early Life Experiences on Brain and Behavioral Development
• Developmental Programming Through Epigenetic Changes
• The Role of Early Life Environmental Risk Factors in Parkinson Disease

Research:

(Note: Points directly related to the Concepts above will be highlighted and underlined.)-

“During the past decade, a considerable body of evidence has emerged showing that circumstances during the fetal period may have lifelong programming effects on different body functions with a considerable impact on disease susceptibility.”  Kajantee 2006

“During development, there are critical periods of vulnerability to suboptimal conditions when programming may permanently modify disease susceptibility. Programming involves structural changes in important organs; altered cell number, imbalance in distribution of different cell types within the organ, and altered blood supply or receptor numbers. Compensatory efforts by the fetus may carry a price. Effects of programming may pass across generations by mechanisms that do not necessarily involve structural gene changes. Programming often has different effects in males and females.”  Nathanielsz 2008

“The content of dopamine in the nucleus accumbens was found to be lower in prenatally stressed (PS) adult males. Furthermore, prenatal exposure to maternal immune challenge was associated with lower locomotor activity in elevated plus maze and increased number of skips in the beam-walking test, as observed in female offspring.” Jezova 2004

“Excess circulating maternal stress hormones alter the programming of foetal neurons, and together with genetic factors, the postnatal environment and quality of maternal attention, determine the behaviour of the offspring.”  Weinstock 2008

Comment: As noted above, during the critical periods of vulnerability, small insults to the fetus can produce great changes in the adult. The nervous system’s levels of neurotransmitters can be permanently altered by the endocrine system’s response to fetal stress and its locomotor activity permanently changed by the immune system. The programming of previous generations influences the outcomes, as well. Nothing exists in isolation.

Resources:

• Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of         neuroinflammation
• Lipopolysaccharide: Definition

Research:

“We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson’s disease.” Carvey 2004

“The possibility that prenatal toxin exposure may contribute to the development of a neurodegenerative disease of the aged raises interesting new pathogenic questions and draws attention to the possibility that in utero exposure to neurotoxins may represent a here to fore unrecognized cause of PD.”  Ling 2003

“These data suggest that pre-existing  neuroinflammation prolongs the inflammatory response that occurs with a second                  toxic exposure, which may be responsible for progressive DA neuron loss.” Carvey 2006

“These findings suggest that maternal infections may lead to an unbalanced inflammatory reaction in the fetal environment that activates the fetal stress axis.“  Ross 2004

“Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude.”  Lightman 2000

“This study demonstrates that a T cell-mediated immune response as well as an endotoxic challenge during pregnancy can induce anomalies in HPA axis function in adulthood. Clinically, it may be postulated that disturbed fetal brain development due to prenatal immune challenge increases the vulnerability to develop mental illness involving inadequate responses to stress.”  Holsboer  1994

“Exposure to infectious agents during early postnatal life often alters glucocorticoid responses to stress and immune outcomes in adulthood.” Maier 2005

Comment: Early-life exposure to LPS can create a hypersensitivity to subsequent encounters. This sensitivity can trigger an immune response within the brain which leads to neuronal loss. This same immune system activity can impact the HPA axis – the heart of the endocrine system’s stress circuitry.  Nervous, immune, and endocrine systems intertwine and begin a slow dance of self-destruction.

Resources:

• ~ Development of affective disorders: The legacy of prenatal stress

Research:

“Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring.“ Maccari 1999

“These results demonstrate that prenatal stress induces a long-lasting astroglial reaction and a reduced dendritic arborization, with synaptic loss in the brain of adult offspring.“  Antonelli 2006

“Further, a single aversive life event showed capable of changing the reactivity of prenatally stressed offspring, whereas offspring of dams going through a less stressful gestation was largely unaffected by this event. This suggests that circumstances dating back to the very beginning of life affect the individual’s sensitivity towards experiences in life after birth.“  Lund 2005

“Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner.”  Matthews 2006

” Thus, prenatal stress altered subsequent cognitive, endocrine, and neurochemical responses in a sex-specific manner. These data reinforce the view that prenatal stress affects multiple aspects of brain development, interfering with the expression of normal behavioral, neuroendocrine, and neurochemical sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic endocrine and neurological disorders.”  Luine 2004

“The brain not only encodes information and controls the behavioral responses but it is also changed structurally by those experiences.” McEwen 2006

Comment: An immune challenge in the form of maternal infection alters the future immune and endocrine systems. An endocrine challenge in the form of fetal exposure to stress hormones produces similar results. The two begin a dance that lasts a lifetime with ongoing effects throughout the body.

In summary: It cannot be overstated. Parkinson’s Disease is not a neurological disease in the way it is normally understood. It is a disorder of the immune and endocrine systems which, over time, damages the nervous system. That is the core of our hypothesis. There are a hundred things which follow from this, but here is where it begins.