Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases?
Introduction
Parkinson disease (PD) and Alzheimer disease (AD) are diseases of unknown etiology that appear late in life. Nongenetic causes are suspected in both, with most investigations of etiology centered on the adult period. However, as Wordsworth [1] noted, “The child is father of the man,” and disease may be no exception to this observation. Barker [2] first espoused the controversial concept that very early life events play a causative role in disease in his articles on the fetal origins of coronary heart disease (CHD) [2], [3], [4]. The prior prevailing belief was that CHD was determined by an unhealthy Western lifestyle in combination with genetics. The “Barker hypothesis” challenged this orthodoxy by showing consistent associations of CHD with low birth weight (LBW), LBW being a surrogate and not the cause. A number of studies examining the “fetal origins of adult disease” (FOAD) hypothesis have found associations between LBW and indices of disease risk or actual disease prevalence for ischemic heart disease, hypertension, obesity, insulin resistance, and depression. The FOAD has expanded into the more general “developmental origins of health and disease” (DOHaD), allowing a consideration of infant and childhood events in adult disease etiology [5].
Although controversial, the Barker hypothesis now is more generally considered to be plausible and clinically relevant even by those initially skeptical [3], [4]. Possibly, the intrauterine environment can “program the fetus” with developmental plasticity, allowing the expression of a wide range of phenotypes in response to different environments. Poor developmental conditions may cause adaptations that allow fetal survival; but this long-lasting programming may have adverse consequences in the adult. Thus, adult type 2 diabetes mellitus could be due to a “thrifty phenotype” instigated in the womb by inadequate nutrition, subsequently altering metabolic machinery and rendering it ineffective in dealing with the abundant food supply in developed countries.
The DOHaD has implications for many diseases other than cardiovascular disease, among them type 2 diabetes mellitus, obesity, depression, cancer, and osteoporosis [2], [4]. The realization that adult disease may have developmental origins has driven a belief in the importance of a life-course approach when studying chronic disease. In determining etiology, attempts should be made to specify all factors that act across the life span and to identify periods of vulnerability for them as well [6]. Typical investigations of neurodegenerative disease etiology have concentrated on midlife factors. Although the major growth of brain occurs during the pre- and early postnatal periods, key maturation processes, marked by myelination and an increasing complexity of connectivity, continue through late adolescence. This prolonged period provides ample opportunity for various insults to interfere with brain development, although compromised function may not be expressed until later life [7]. The DOHaD hypothesis has received some attention by those interested in the etiology of PD and AD, and here we will explore the supportive evidence [8], [9], [10]. Early life encompasses fetal, infant, and early childhood; and suspect events can include poor nutrition, infections like intrauterine influenza, as well as chemical and pesticide exposure.
Section snippets
Definition
Parkinson disease or idiopathic parkinsonism is of unknown etiology, and few cases can be directly attributed to well-defined genetic or environmental causes; it is the most frequent neurodegenerative disorder after AD. There is no explicit biochemical test or progression biomarker for PD, and the diagnosis is clinical and uses the exclusion of secondary causes; this may impede epidemiologic investigation because not all persons clinically identified as having PD are found to have the disease
Definition
Sporadic AD, the most common cause of dementia in the elderly (50%-60% of the cases are older than 65 years, with a doubling of risk every 5 years after 65 years), has been described for over a century; but its cause is still unknown and widely debated [9], [30], [31]. AD, like PD, is a progressive neurodegenerative disorder; it is characterized by an ever-worsening memory impairment accompanied by a declining ability to perform important daily behaviors. AD is complex; to date, there are no
Conclusions
The available evidence strongly suggests the need for further study of early-life events that affect the development of late-life neurodegenerative diseases like PD and AD. This is a challenging task because of (1) the long latency between early-life insult and disease manifestation; (2) the limited number of complete birth, growth, and other life-stage records for epidemiologic evaluation; (3) the lack of homology within groups, for example, infants with the same birth weight may have achieved
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STATEMENT OF CONFLICT OF INTEREST: The authors are members of the Scientific Committee of the Collége International de Reserche Servier (CIRS).