Chapter 109
Neurodegeneration — 15
Even more encouraging are the consistent findings from three randomized trials of our new friends the GLP-1 drugs. Lixisenatide compared with placebo stopped progression of the motor signs for people with early Parkinson’s. Exenatide showed significant benefit for motor symptom score in a smaller placebo-controlled trial. Another randomized trial of exenatide with longer follow-up found similar benefit with the conclusion, by Thomas Foltynie of University College of London and coauthors: “There is a strong indication that GLP-1 receptor agonists may have a useful role in future treatment of Parkinson’s disease.” In these trials, the benefit endured after the GLP-1 drugs stopped, and the advantage may further widen during extended follow-up.
Although not as palatable or practical as a drug treatment, fecal microbial transplant from healthy donors has been assessed in a small randomized trial (compared with placebo) of early Parkinson’s. Like the GLP-1 drugs and α-synuclein trials, there was evidence for slowing the progression of motor symptoms. Indeed, benefit of a healthy person’s fecal transplant highlights the role of the gut microbiome for this disorder. Beyond these three interventions with some success in small trials, there has been a tenfold acceleration of discovery of potent α-synuclein small molecule (pill) blockers with the help from AI.
Other approaches that are being assessed include cell therapy with induced pluripotent stem cells that can be tailored to whatever subtype of the disease the patient happens to have. Early clinical trials are giving us cause for optimism. Like Alzheimer’s disease, there are ongoing vaccine clinical trials, directed against α-synuclein. Their success will ride, at least in part, on the ability to determine high-risk individuals.
As reviewed with Alzheimer’s disease, a far better path than treatment once Parkinson’s disease has taken hold would be prevention. The parallel strategy I’ve laid out for Alzheimer’s (fig. 7.5) with partitioning high risk, close monitoring, and starting interventions early should be possible to assess in the near future.
KEEPING THE BRAIN YOUNG
There has been considerable attention to new ways, beyond lifestyle+ factors, to preserve our brain health, and even achieve rejuvenation to a level of function well below our chronological age. That interest is justified given multiple new studies that suggest this may someday be attainable.
Normal brain aging, without neurodegenerative disease, has many hallmarks that include neuronal dysfunction, especially in the hippocampus (where memory is choreographed); neuroinflammation (with microglia and astrocyte activation); blood-brain barrier leakage and vascular changes; and a precipitous decline in ability to regenerate nerve cells. We’ve also learned that chronic inflammation, such as occurs with degenerative knee osteoarthritis, accelerates brain aging. Intriguing are the rare brain “super agers” who at age eighty have the memory of people aged twenty or twenty years younger. By imaging, these individuals have less atrophy of brain white matter than their same-aged peers but little difference of lifestyle+ factors.
In mice, many of these hallmarks of aging can be replicated by giving old blood or plasma or transplanting aged blood (hematopoietic) stem cells to young mice. That is also the case with parabiosis, surgically connecting the blood circulation of old and young mice. There are many potential blood and cellular factors that may account for accelerating brain aging in young mice. When the opposite experiments are done, young to old mice, whether it be by parabiosis, plasma, blood, or bone marrow transplantation, there are improvements in neuronal, regenerative (new neurons, neurogenesis), and cognitive function, with less inflammation and more vascular density. These same benefits are simulated by exercise and caloric restriction. The pro-youthful blood factors that have been linked to improving brain-aging function include Klotho, platelet factor 4, and gonadotrophin releasing hormone (GnRH).