(The following post references the chart called “The Parkinson’s Cascade” which can be viewed here.)
This is one of a series of attempts to explain my view of Parkinson’s Disease in hopes of stimulating research into new areas. I freely admit to errors in this work and hope that those will be brought to my attention.
At the head of the Parkinson’s Cascade lies an unexpected beginning – “Family Emotional Heritage”. This refers to one of the “roots” of not only Parkinson’s Disease but any number of additional maladies. The “FEH” is used here to describe the attitudes of previous generations toward women and how they affect a child born today.
And they do, indeed, echo down over decades and even centuries. From the peasant hut of a hundred years ago, crossing an ocean and a century, the voice raised in anger, or quietly offering support, is heard in the cry of the newborn child in the modern delivery room. It may be difficult for many to believe that a journey of this sort can be more than imagination, but it is very real.
The understanding of two concepts is necessary for this discussion. These are the developmental origins of the adult and “epigenetic” transfer of experience across generations.
“Developmental programming is defined as the response by the developing mammalian organism to a specific challenge during a critical time window that alters the trajectory of development with resulting persistent effects on phenotype…..During development, there are critical periods of vulnerability to suboptimal conditions when programming may permanently modify disease susceptibility…..Effects of programming may pass across generations by mechanisms that do not necessarily involve structural gene changes.” Nathanielsz 2008
To understand this a bit better, a return to the Cascade may help. The “Severity of the Maternal Stress Response” is the effect that stressors have upon the hormonal chemistry of a pregnant woman. This cocktail is a very powerful brew and “Prenatal Exposure to Maternal Stress Hormones” can affect development in ways that determine the fate of the adult.
“Maternal distress during pregnancy increases plasma levels of cortisol and corticotrophin releasing hormone in the mother and foetus. These may contribute to insulin resistance and behaviour disorders in their offspring that include attention and learning deficits, generalized anxiety and depression….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
A similar result can originate at this stage of life due to “Prenatal Exposure to Environmental Toxins”.
“Together, our data point out the unique sensitivity of the developing organism to endocrine-disrupting chemicals, the occurrence of long-term effects after developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations.” Jefferson 2006
These events share developmental paths that allow the fetus to adapt to the waiting “Life Circumstances” of the external world. For example, a child born into a war zone may live longer if he startles easily.
“Prenatal stress has been associated with a variety of alterations in the offspring. The presented observations suggest that rather than causing changes in the offspring per se, prenatal stress may increase the organism’s vulnerability to aversive life events…..maternal glucocorticoids may be a determining factor for changes in the regulatory mechanisms of the acoustic startle response. 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
These effects manifest in “Dysregulation of the HPAA” – the hypothalamus-pituitary-adrenal axis.
“Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring.” Maccari 1999
“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. …. exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. …. including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function…… Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.” Mathews 2006
The HPAA is, in a sense, the master control that guides the body toward balance, or homeostasis. Dysregulation, or poor control, of this guidance leads to “Disruption of Neuroendocrine Systems”, “Impaired Neurogenesis”, and a “Hypersensitivity to Stress”.
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. In male and female rats exposed to prenatal restraint stress (PRS), these effects include a long-lasting hyperactivation of the HPA response associated with an altered circadian rhythm of corticosterone secretion.” Maccari 2008
“Stress hormones have potent growth-inhibiting effects on a variety of peripheral tissues. Consistent with this general function, stress has been shown to inhibit cell proliferation and, ultimately, neurogenesis in the hippocampus.” Gould 2006
“Exposure of the developing brain to severe and/or prolonged stress may result in hyper-activity of the stress system, defective glucocorticoids-negative feedback, altered cognition, novelty seeking, increased vulnerability to addictive behaviour, and mood-related disorders. Therefore, stress-related events that occur in the perinatal period can permanently change brain and behaviour of the developing individual.” Morley-Fletcher 2007
This latter effect, in turn, produces a “Chronic Exaggerated Stress Response” and a resulting “Elevated Level of Stress Hormones”.
All this feeds into the “Self-Perpetuating Immuno-Endocrine Interaction” which lies at the heart of PD and which will be discussed later.