Neuronal loss has broad downstream effects
Neurodegenerative diseases cause progressive irreversible neuronal loss that has broad downstream effects.
The neuroendocrine system regulates homeostasis of circuits that control critical functions (such as stress response, metabolism, reproduction, fluid balance and glucose control.) These systems are frequently disrupted in neurodegenerative disorders—though often overlooked in clinical practice.
Aiming to broaden how clinicians think about these illnesses and provide care, two colleagues at Massachusetts General Hospital searched the literature from the past 30 years (2,022 articles from January 1988, to November 2018) to synthesize data about these disturbances in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia.
Neuroendocrine disturbances, they report, may be a precursor to the illness, a part of the primary pathophysiology, a direct consequence of the disease, or independent of it. Such disturbances “have the potential to further understanding of the disease, exacerbate the underlying pathology, or provide therapeutic benefit.”
Disrupted neural circuitry often involves systemic disturbances that extend beyond the diseased territory in the brain.
The neuroendocrine system is the interface between the central and peripheral endocrine systems, and is a principal system affected by neuronal loss, “though the relationship is rarely discussed,” say the authors.
When functioning properly, this system helps maintain homeostatic balance in response to external signals. When disrupted, there can be broad downstream effects:
Alzheimer’s disease The hypothalamic-pituitary-adrenal (HPA) axis has many functions, though it is felt primarily to modulate stress response. The hypothalamus secretes corticotropin-releasing hormone which stimulates the anterior pituitary to release adrenocorticotropic hormone. This then signals the adrenal glands to release cortisol, which has many metabolic effects.
Studies suggest heightened HPA axis activity in Alzheimer’s disease, which may serve as a marker of the disease, contribute to underlying pathology, and serve as a target for therapeutic intervention.
Parkinson’s disease There is conflicting evidence regarding HPA axis activity related to Parkinson’s disease; both hyperactivity and hypoactivity have been found. Heightened activity has been demonstrated with elevated levels of plasma interleukin-2, a cytokine relevant in the immune response.
Treatment with levodopa reduces interleukin-2 levels, suggesting that the heightened immunoreactivity is related to altered dopaminergic signaling. The hypothalamus releases hormones that have stimulating and inhibiting effects on the anterior pituitary. When activated, the anterior pituitary releases growth hormone that primarily exerts effect on the liver. In response, the liver releases insulin-like growth factor-1 (IGF-1), which has broad downstream effects on bone growth, muscle development, cardiovascular function, as well as on the brain.
Huntington’s disease Most studies have demonstrated HPA axis hyperactivity that may manifest early in the disease process. This is thought to have potential influence on the metabolic hyperactivity and subsequent weight loss seen in the disease.
Amyotrophic lateral sclerosis Plasma levels of arginine vasopressin have been shown to decrease in patients with the disease.
Frontotemporal dementia Little is written about the interplay between the neuroendocrine system and frontotemporal dementia. One article, however, summarizes various physiological disturbances, such as eating, metabolism, sleep, and autonomic functioning. The authors hypothesize that most of these effects are mediated by disrupted circuitry involving the hypothalamus and its projections.
“Broadly speaking, thinking about these various illnesses with a neuroendocrine lens may have implications for risk assessment, diagnosis, and treatment,” say the authors.
“For example, there might be an element of subclinical Cushing’s syndrome in those with rapidly progressive Alzheimer’s disease; if so, this could be screened for and potentially treated.
“Behaviors such as exercise might have protective benefit due to their stress reduction and anti-inflammatory effects.
“Perhaps we should be taking a more thorough history of symptoms of hypogonadism and menopause when assessing for Alzheimer’s. If thyrotropin-releasing hormone confers neuroprotection in Alzheimer’s, the pathway could be mimicked. Perhaps further studies of IGF-1 agents will demonstrate more robust therapeutic benefit in Alzheimer’s.
“Bone health could become a component of Parkinson’s management. In those with subjective memory complaints, we might more aggressively recommend better glucose control. Targeting the HPA axis hyperactivity in Huntington’s might slow progression of disease, as it has been theorized that the metabolic consequence of elevated cortisol levels may contribute to weight loss and death.
“Perhaps evaluating neuroendocrine status should be a larger part of generating a risk prediction model, similar to those commonly utilized in assessing cardiovascular disease risk. These models typically combine data (such as age, sex, blood pressure, lipid values, smoking habits, and comorbidities) to generate an individual’s risk score.
“Perhaps a similar approach could be used with dementias. For example, an algorithm combining cortisol, A1C, estrogen, and exercise level might be able to generate a risk score for Alzheimer’s. With better risk assessment, there may be more avenues to modify outcomes preemptively.
“Finally, given the growing impact of these diseases and increasing knowledge of neurodegenerative disorders, perhaps a visit to the clinic would not be limited to a neurological exam and bedside cognitive testing, but would include addressing bone health, diabetes, and HPA axis imbalance.”
“Perhaps evaluating neuroendocrine status should be a larger part of generating a risk prediction model, similar to those commonly utilized in assessing cardiovascular disease risk.”
The authors conclude: “As we await additional research with definitive answers to queries, we recommend considering how the evidence available can be incorporated into current practice. Checking vitamin D levels and hemoglobin A1C are relatively simple ways to start. Asking about menopause can initiate dialogue about estrogen replacement therapy and its relevance in Alzheimer’s. Familiarizing oneself with the different diabetes medications and their neurologic relevance will likely prove useful.”
The paper, Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review, by Amy Newhouse, MD, Massachusetts General Hospital, Psychiatry and Medicine/Harvard Medical School, Psychiatry; and Zeina El-Chemali, MD, MPH, Massachusetts General Hospital/Harvard Medical School, Psychiatry and Neurology, is published in full in the March/April issue of Psychosomatics.