Parkinsons has been cured many times in animals. When will something work in humans?
Recent clinical trials may vindicate a new approach.
Research into Alzheimer's, Parkinson's, and other neurodegenerative diseases has been slow and disappointing. That's partly because we don't really know how these diseases work, so it is difficult to design useful animal models to test. Researchers also may have been aiming at the wrong target.
Amyloid plaques seemed to be an obvious part of the problem in Alzheimer's, but therapies that cleared the amyloid plaques turned out not to cure the disease.
The situation was similar with Parkinson's. Alpha-synuclein is a protein that accumulates in Parkinson's disease. But last summer we learned from clinical trials that two drugs that cleared the alpha-synuclein in Parkinson's patients -- Prasinezumab and Cinpanemab -- did not halt the disease
Indeed, there are no treatments that delay or halt the progression of the symptoms of Parkinson's disease.
So researchers have been thinking about new approaches.
Parkinson's may not be just one thing, so it might be better to pursue therapies that address multiple disease processes. Also, it might be better not only to strike at the cause of neurodegeneration, but also to strengthen the neurons' defenses against degeneration.
Among the processes typically associated with Parkinson's disease are
Defective protein synthesis, and
Inflammation in the brain
A treatment aimed at preventing those three problems from occurring, or aimed at strengthening neurons in the brain against the negative effects of those processes when they do occur, could be promising.
Could It Be NAD+?
Increasing NAD levels has the potential to achieve both objectives, because in other contexts NAD replenishment has been shown to help neurons function better, and can also improve mitochondrial dysfunction and reduce inflammation.
NAD levels are an obvious target for another reason, too. NAD levels decrease with age, and age is the single biggest risk factor for neurodegenerative diseases.
Plus, tests with human brain tissue have shown that in Parkinson's disease, mitochondrial dysfunction is linked to defects in NAD metabolism.
Histone hyperacetylation can be induced by mitochondrial respiratory complex-I deficiency, a pathological feature found throughout the Parkinson's disease brain, [which] is thought to be [caused] by decreased NAD+...[which reduces the activity of] sirtuins....our results open the possibility that agents targeting [histone acetylation and NAD metabolism] may have therapeutic potential for Parkinson's disease and should be further explored. (emphasis added)
The Clinical Tests of NAD and Parkinson's
A Phase 1 clinical test of nicotinamide riboside (NR) in Parkinson's patients was called the NADPARK study (because they were replenishing NAD levels in PARKinson's disease). The results were published in Cell Metabolism in March, 2022.
The NADPARK study divided 30 newly diagnosed Parkinson's patients who had received no Parkinson's medication into two groups of 15 who received either 1,000 mg of nicotinamide riboside or a placebo for 30 days.
Using brain scanning equipment, and other measures (they even biopsied muscles), the researchers were able to determine that oral NR increased NAD levels in the brains of individuals with Parkinson's disease, and that the NR altered the cerebral metabolism in Parkinson's disease and reduced inflammation, not only in the blood but in the spinal fluid, which suggested a potential effect against neuroinflammation. Moreover, although it was only a short, 30-day test, mild-but-significant clinical improvements in the test group corresponded with the observed metabolic improvements.
We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD)...NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement...Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.
Actually, although all the participants who took NR in the NADPARK study showed metabolic improvements, only about two-thirds of the test group specifically had their brain NAD levels elevated after taking NR. But it was in that two-thirds that the mild-but-significant clinical improvements were noted, in both the cognitive and motor portions of the Parkinson's disease rating scale, which strengthened the inference of a causal connection between NR and the clinical gains.
But the primary findings were that oral NR does increase NAD in the human brain, and the treatment is safe and potentially neuroprotective -- promising enough to warrant further study.
Based on this positive result, these researchers are moving forward fast. They have already begun a much larger Phase 2 trial. The Phase 2 study, called the "NOPARK" study will follow 400 patients for 52 weeks to determine the efficacy of NAD replenishment therapy by oral NR in delaying the progression of Parkinson's disease. This study will tell us whether NR has a neuroprotective effect in Parkinson's disease, or not. But the study won't be complete before the end of 2024.
The researchers are also attempting to determine the optimal dose of NR. Both the NADPARK and NOPARK studies used 1,000 mg. But a separate phase 2 clinical study called "N-DOSE" will compare 1,000 mg, 2,000 mg, and 3,000 mg across 80 participants for 90 days. A separate clinical test determined the safety of a 3,000 mg dose.
Beyond Parkinson's, this research team is also reportedly hoping to begin in 2023 to clinically test NAD replenishment in the context of another disease similar to Parkinson's, but more rare and much worse, called Progressive Supranuclear Palsy or PSP. Actor Dudley Moore died of complications related to PSP, and singer Linda Ronstadt was diagnosed with it.
Another group is also clinically testing NAD replenishment for Parkinson's disease. In a pre-print published in 2021, researchers testing a cocktail of metabolic activators that also included 1,000 mg of nicotinamide riboside (the other ingredients were L-serine, L-carnitine, and NAC), reported the completion of an 84-day Phase 2 study, showing significant improvement in cognitive but not motor scores among individuals with Parkinson's disease.
Although that Parkinson's study does not appear yet to be finally published in a peer-reviewed journal, another Phase 2 test with the same metabolic cocktail including NR, but for Alzheimer's disease instead of Parkinson's, showed promising results and was published in Translational Neurodegeneration in January, 2023.
Another clinical trial testing the effect of niacin on Parkinson's disease for one year had somewhat mixed results, with some clinical measures improving, others steady or declining, which might or might not have been a benefit of the vitamin. This could sound a note of caution, but niacin also might not have reasonably been expected to work very well for this purpose, because unlike NR, niacin relies on the Preiss-Handler pathway to replenish NAD, and that pathway is not well-expressed in neurons, and therefore not in the brain.
It's still early innings. The animal models look good, and the early clinical results are promising. But we won't be able to have proper confidence until we see the results of much larger human trials. Happily, the Phase 2 NOPARK trial is already underway, and it will involve 10x+ more participants than NADPARK, and watch them for 10x+ longer.
Alas, we will likely have to wait at least two more years for the results.