Neurodegenerative diseases (NDDs) comprise perhaps half a dozen well-known and hundreds of rare conditions characterized by the loss of function over time and the eventual death of nerve cells. Manifestations of NDDs include cognitive deficits, sensory-motor decline, or both.
According to the National Institutes of Neurological Disorders and Stroke, more than 600 diseases of the nervous system affect 50 million Americans every year. Assuming an annual cost of about $46,000 to care for a single patient, the societal cost of NDDs in the U.S. alone is $243 billion.
Approximately 5.4 million Americans live with Alzheimer’s disease, and close to a million are affected by Parkinson’s disease, the two most prevalent neurodegenerative disorders. Alzheimer’s represents approximately 70% of all dementias.
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New ideas and novel approaches are gaining ground though, as multidisciplinary teams seek to better understand the fundamental biology of neurodegeneration and ultimately uncover new therapeutic strategies.Other common neurodegenerative diseases include multiple sclerosis (400,000 patients), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (30,000 cases each). Prion diseases, motor neuron disease, spinocerebellar ataxia, and spinal muscular dystrophy are examples of less common neurodegenerative diseases.
Risk factors
Virtually every review article on NDDs cites age as a significant risk factor for developing these disorders. For example, Alzheimer’s disease is rare in individuals younger than 50 but prevalence begins rising an additional 0.5% per year after age 65, increasing to about 8% per year after age 85. Similarly rare before the sixth decade of life, Parkinson’s disease prevalence may be as high as 2% for individuals over age 65, increasing every year thereafter.
Recent evidence suggests that the accumulation of senescent nervous system cells, a natural consequence of aging, may predispose individuals toward developing NDDs or accelerate progression of these diseases once they take hold. Investigating the link between senescence and NDDs has been hindered by the lack of universal markers for senescent neuronal cells.
Age is not the only risk factor for Parkinson’s, as the lifetime risk for developing the disease is 4.4% for men and 3.7% for women. A recent paper suggested that “sex might constitute an important factor for AD [Alzheimer’s disease] patient stratification and personalized treatment.”
Sex differences related to immune responses to neurodegeneration, affecting both susceptibility and disease progression, are also apparent in multiple sclerosis, which women develop more frequently than men, but which progresses more slowly and less frequently in females.
Similarly, a 2018 article reviewing nearly 300 papers on sex differences and cognitive decline in Alzheimer’s disease confirmed that women “are at significantly higher risk of developing” Alzheimer’s, and that their cognitive outcomes were poorer than men’s. Moreover, the degree to which underlying health issues such as obesity, cardiovascular disease, and lifestyle factors affect the course of various dementias also varies by sex. While females are at greater risk for developing Alzheimer’s, men are more susceptible to vascular dementia.
The underlying mechanisms of these differences are still unknown. Part of the answer might lie in the physiological differences in gray matter composition that persist between the sexes from birth throughout life. Females have a higher gray matter density than men but significantly lower gray matter volume and mass, and these differences prevail in all relevant regions of the brain.
Underlying causes
However, to say that age and sex are risk factors for NDDs, or even that these disorders are a result of neuronal cell death, is to duck the question of etiology. Considerable debate centers on the relative contributions of nature and nurture, or genes and environment.
Huntington’s disease, as well as several rare neurologic disorders, are clearly inherited as an autosomal dominant trait, while other NDDs occur as autosomal recessive, X-linked, or maternally inherited traits. Approximately 10% of Parkinson’s, Alzheimer’s, and ALS cases are inherited.
Chemical exposure has been linked to the occurrence of several NDDs, or syndromes that closely resemble the sporadically arising disorders. Evidence comes from studies of geographic areas and professions. PD-ALS complex, which occurs in certain tribal regions of Guam, is believed to be caused by ingestion of the allegedly medicinal plant Cycas circinalis, while ingestion of certain pyridine derivatives causes a disease that is indistinguishable from Parkinson’s. However, no chemical “missing link” has been uncovered for most cases of NDDs.
Inflammation has been a prime suspect in the etiology of NDDs since the early 2000s. A 2017 article noting the differential adaptive vs. innate immune responses evident in Alzheimer’s, Parkinson’s, and multiple sclerosis observed that these immune processes not only drive progression of these diseases, but may serve as therapeutic targets. One approach might involve suppression of immune responses acting on the central nervous system, while another may harness immunity to clearly implicated biomolecular or cellular agents.
And what might those biochemical agents be? A paper published online in late 2019, which will appear in print in early 2020, notes the potential of proteins that are either misfolded or which undergo undesirable post-translational modifications to become neurotoxic. The authors cite the classic examples of Alzheimer’s, Parkinson’s, and Lewy body dementia, which are characterized by the intra- or intercellular accumulation of proteins in the central nervous system. These proteins undergo “profound modifications in their structural folding, thereby forming small oligomeric or large fibrillary aggregates...” leading to “...self-association, elongation, and precipitation” within the brain.
Should inflammatory processes turn out to be the smoking gun in NDD progression, a host of therapeutic options already exists. A great deal of pharmacologic crosstalk has been exploited, for example, in the use of steroidal and nonsteroidal anti-inflammatory compounds, organ-rejection drug regimens, and biological immune modulators.
If this brief introduction has one take-home lesson, it is that sufficient mystery still surrounds our understanding of many NDDs. Moreover, the existence of clear genetic and toxicologic etiologies alongside apparently idiopathic NDDs, suggests that, like many cancers, what appears to be a single disease may in fact be several distinguishable illnesses. Fortunately, the emergence of molecular techniques for characterizing biochemical phenomena in living systems has progressed and continues to develop rapidly, thereby compressing what were once “normal” timelines for acquiring basic knowledge and translating that information into actionable therapies and diagnostics.
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