Ever since Parkinson’s Disease (PD) was officially described as a neurological syndrome by the English surgeon, geologist, and paleontologist, Dr. James Parkinson, over two centuries ago in an 1817 treatise entitled, “An Essay on the Shaking Palsy”, the only way to diagnose PD has been through the use of clinical diagnostic criteria.
Until now, that is.
According to a large study in The Lancet Neurology published on April 12th, 2023 involving over 1000 participants, a technique known as the α-synuclein seeding amplification assay (αSyn-SAA) or SynTap detects with high accuracy the build-up of an abnormally folded protein called alpha-synuclein (α-synuclein) in the cerebral spinal fluid (CSF) not only when PD is present, but also, more importantly, prior to its development in genetically at-risk individuals. The study also included healthy controls, and participants with possible precursor or prodromal symptoms such as sleep disturbance or loss of smell, which may herald the onset of Parkinson’s disease.
Like Alzheimer’s Disease, in which an insoluble protein called beta amyloid abnormally accumulates in the brain, the defining feature of PD is pathologic deposits of α-synuclein in neurons. These deposits are known as Lewy bodies (LBs). The commercially available SynTap test, which may also help to diagnose other neurodegenerative diseases such as Lewy body dementia and Multiple System Atrophy is based on the amplification of tiny amounts of α-synuclein in the CSF.
Despite its “game-changing” potential, as the Michael J. Fox Foundation describes it, and the short frisson of excitement that we experienced as neurodegenerative researchers, SynTap requires an invasive lumbar puncture or spinal tap to collect cerebral spinal fluid, which makes the assay impractical for broader community screening. However, more convenient SAA blood tests are reportedly in development.
So, while earlier and more definitive diagnosis is a decidedly positive development, in the opinion of many the lack of so-called disease-modifying treatments to reverse or arrest the course of Parkinson’s Disease strikes a note of dissonance and makes this a case where the glass is both half full and half empty.
Currently the standard treatment for PD is dopamine replacement with L-DOPA (levodopa) or other dopamine agonists, which are symptomatic but not disease-modifying therapies. Another potential treatment is deep brain stimulation (DBS), which is also not disease modifying. Moreover, as levodopa lacks long-term efficacy and as DBS is complication-prone and fails to address non-motor symptoms like cognitive decline, depression, anxiety, and loss of sleep, other less toxic therapies that modify the trajectory of the disease are desperately needed.
One therapeutic class that potentially meets these criteria is direct NLRP3 inflammasome inhibitors, of which RRx-001 from EpicentRx is the most clinically advanced, since chronic inflammation may underlie the pathogenesis and progression of neurodegenerative diseases, including PD. In contrast to acute inflammation, which usually resolves in a few days, chronic inflammation may last for months or years. Inflammasome inhibitors act to dampen or repress the inflammatory response, which when it is chronic may lead to damage, dysfunction, and disease.
To date, RRx-001, which has anti-inflammatory and antioxidant properties, has been well tolerated in over 300 patients. And so, for us at least, the promise of RRx-001, which, hopefully, we have a good handle on, and the potential for early treatment with it (and possibly other agents in development) as a result of SynTap or, ideally, another less invasive test, makes the glass in PD more than three-quarters full.
Quick facts about Parkinson’s Disease (PD):
- As the fastest-growing neurodegenerative disorder in the world, and the second most common after Alzheimer’s Disease, PD is tantamount to a “pandemic”.
- With aging, an even more meteoric rise in prevalence is expected.
- More males than females are affected, which is probably related to the protective effects of estrogen.
- The term “neurodegenerative” refers to the progressive and irreversible loss or degeneration of the structure and function of the neurons of the brain.
- PD involves the dopamine-producing (“dopaminergic”) neurons in a specific area of the brain called substantia nigra.
- The diagnosis of it is mainly a clinical one with rest tremor, rigidity, bradykinesia (slowed movement), and postural instability (uncoordination) as the four main telltale symptoms.
- Primarily a disease of the elderly, PD may nevertheless strike much earlier in life, as it did in the case of actor and advocate, Michael J. Fox, diagnosed when he was 29 years old.
- Risk factors include genetic mutations, positive family history, chronic inflammation, the formation of free radicals, and several environmental toxins including pesticides.
- Resting tremor is the most recognized symptom.
- The mainstay of treatment is levodopa, which increases levels of the neurotransmitter, dopamine whose loss is responsible for the core features of PD.
- An early sign of PD is loss of smell or hyposmia.