In Part One we have presented evidence from peer reviewed work by multiple researchers that supports a model of YOPD which begins in the first stages of life itself and involving not only the nervous system, but also the immune and endocrine systems. In fact, the nervous system is almost in a secondary role in the early stages, although it claims its place as the disorder progresses.
Most of these factors are in dynamic relationships with one another and fall on a gradient with a wide range of values. Thus a child born after an immune challenge of major impact but with minimal endocrine involvement will stand to develop a different set of symptoms than one who has suffered both immune and endocrine challenge. While it is beyond our ability to precisely define the limits of these effects, it is important to note that this wide variation of possible problems is precisely what is observed in PD and one reason for the frustration associated with it.
Our own belief, while admittedly speculative, is that the immune response and hypersensitivity to LPS will be found to be central with the endocrine response being intimately bound in a manner that influences the speed and severity of the decline. Around the boundaries of this core are numerous factors such as genetics, environment, life events, etc. which further affect the course of the individual.
The following two terms are essential to understanding these issues. In fact, if you can master these two concepts you will have mastered the majority of what we have to say.
Definition: Neuroinflammation and microglia
Definition: HPA Axis
Many of the ideas advanced here are controversial and we will take some time to examine them in more detail before moving on to examine some implications of this model and assessing just how well the hypothesis measures up against the reality of PD.
Early Life Programming of the Adult
This is one of those ideas that, in retrospect, seems obvious. As a fetus develops into a child, trillions of cells form and seek out their rightful place. A certain amount of interference occurs, is anticipated, and corrected or prevented. An elaborate line of defenses and repair capabilities are built in and do their job very well. But, inevitably, sometimes things go awry. Some of the tiny cells are, for example, designed to serve as the foundation of important parts of the future immune system. If they are adversely impacted during their formative period, there will be an effect upon their eventual nature. A similar circumstance can arise with the forming endocrine tissues if they encounter high levels of stress hormones. These effects may not be readily apparent and may, in fact, not show up until late in life.
Preconception Period
As hard-to-believe as it may seem at first, things that occurred long before one’s birth can directly impact the endocrine system. One’s mother’s experiences before she became pregnant affect the offspring in a manner similar to that experienced during gestation, but once removed. This can occur when the original happenstance has sufficient impact as to indirectly result in a higher level of stress hormones than would have otherwise been observed. A similar but even more diffuse effect can be observed in the various aspects of life that affect maternal stress response such as social support, economic status, family and spousal support, etc.
…preconceptual stress to the dam, even well before pregnancy, influences affective and social behavior in her adult offspring, depending on how long before conception it occurred, the behavior tested, and sex. Leshem 2009
LPS as a Programming Agent
LPS is a common substance in the body with fluctuating levels reflecting the bacterial presence in the environment. If those levels peak at a critical time of gestation, the fetus can be exposed to them in such a way as to have a number of effects that tip things toward PD. Those effects include structural changes such as a lower density of dopaminergic neurons, behavioral changes such as low novelty-seeking, and an exaggerated sensitivity to further exposure to LPS, particularly post-puberty.
Gluccocorticoids as Programming Agents
Just as LPS programs the immune response and associated systems, so, too, do hormones such as cortisol affect the developing endocrine and associated systems. Because these hormones can cross the fetal barriers at the placenta and the blood brain barrier itself, even small increases can affect the child. In fact, this is probably an advantage when it is in reaction to a chronic stressful life environment since it allows the fetus to adapt prenatally. However, similar reasoning would indicate that abrupt spikes in levels of these hormones in an otherwise sedate existence could create a less-than-ideal adaptation under particular circumstances.
Hormonal imprinting develops at the first encounter between the target hormone and its developing receptor in the perinatal critical period. This determines the binding and response capacity of the receptor-signal transduction system and hormone production of cells for life. Molecules similar to the hormone and excess or absence of the target hormone cause faulty imprinting with lifelong consequences. Prenatal or neonatal imprinting with opiates, other drugs and prenatal stress have harmful consequences on the adult brain. Tekes 2005
“Intimate” Relationship of Programming Agents
Stress (an endocrine response) and neuroinflammation (an immune response) go hand in hand – where you find one you will find the other. While there are obviously areas where they act independently, this is not one of those. Stress increases neuroinflammation which increases stress which increases inflammation which….. Around and around in a self-sustaining loop. This begins in the womb as exposure to LPS as noted above, not only affects the immune system but also affects the endocrine system’s stress related HPA Axis. Similarly, exposure to maternal stress hormones as noted above, not only affects the endocrine system’s HPA Axis but also affects the immune system’s inflammatory systems. This is a critical point not just in the womb but throughout the life of a Parkinson’s patient.
We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. 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… Shanks 2000
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
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
Effects of Programming Agents
Different individuals exhibit differint sensitivities to both LPS and cortisol and these are, in part, set by early life programming. Since both factors are ubiquitous, a hypersensitivity to either or both presents an ongoing problem. The effects are not limited to the early years but, in fact, are a lifelong companion and maintain a steady wear and tear upon the system. Stories of acute stressors just before symptom emergence are common, as are those preceding a worsening of such. Infections increase neuroinflammation with similar effects upon symptoms. In the early years of PD, the immune effects are most obvious as damage to the substantia nigra produces motor difficulties, but as the disorder progresses, endocrine-based “non-motor symptoms increase. Most telling of the latter is the extreme sensitivity to everyday stress which comes into play.
The activation of the hypothalamo-pituitary-adrenocortical (HPA) axis plays a pivotal role in the stress response. While the short-term activation of the HPA axis allows adaptive responses to the challenge, in the long run this can be devastating for the organism. In particular, life events occurring during the perinatal period have strong long-term effects on the behavioral and neuroendocrine response to stressors. Maccari 2008
A Summary to this Point
There is ample evidence that a fetus acquires features during gestation that determine much about the adult. There is similar evidence that among the things that define those features are maternal stress hormones originating in the endocrine system and exposure to bacterial endotoxin and the resulting effects on the immune system. The evidence further makes it clear that these two systems are altered as a pair, even as a single system. It is also clear that the effects of these twin influences include results that would be expected to predispose to Parkinson’s Disease.
In Part 3 we will take these early beginnings and carry them forward in search of effects that point more closely to Parkinson’s Disease and begin to test the hypothesis.