Potential approaches for disease modification in PD and iRBD
| Mechanisms | Agents | Comments |
| Immunisation | Monoclonal antibodies directed toward the toxic conformations of synuclein | Several ongoing phase I and II trials of passive and active immunisation (RO7046015, PASADENA trial; BIIB054, SPARK trial)70 |
| Blockers of synuclein misfolding or aggregation |
NPT088, glycerol phenylbutyrate, squalamine, 71
nilotinib, selective c-Abl inhibitors,72 epigallocatechin gallate73 | |
| Neuroinflammation modifiers | ||
| Anti-inflammatory | Ibuprofen | Lower PD risk in people receiving non-steroidal anti-inflammatory agents74; alpha-synuclein increases inflammation |
| AZD3241 (selective, irreversible myeloperoxidase inhibitor)75 | Benefit on microglia brain imaging in a short-term trial in PD 75 | |
| Antibiotics | Doxycycline, tetracycline | Protective in PD animal models76; Rosacea is associated with higher PD risk, treatment with doxycycline reduces this risk77 |
| Oxidative stress | Melatonin (antioxidant) |
Symptomatic effect in RBD
18
Neuroprotective in various animal PD models78 |
| Glutathione (antioxidant) | N-acetylcysteine (glutathione precursor) trial79
Troloxamide-quinone trial (NCT02462603) | |
| Apamin (from bee venom) | Protective in a PD mouse model80 | |
| Iron | Deferiprone (iron chelator) | FAIRPARKI: small randomised double-blind delayed start trial in treated patients with PD81 SKY and FAIRPARKII ongoing trials |
| Adrenergic system | Beta-2 adrenergic receptor (B2R) agonist | B2R agonists: lower PD risk71; B2R regulates the alpha-synuclein gene82 |
| Modafinil: common and safe stimulant in narcolepsy | Neuroprotective in MPTP parkinsonism marmosets and cats83
Some patients with RBD are sleepy 84 | |
| Glucagon-like peptide-1 | Exenatide (antidiabetics) | May reduce DA neurons apoptosis85 |
| Glucocerebrosidase activity (GBA mutation) | Glucosylceramide synthase inhibitors; GBA-modifying drugs (ambroxol) | Tailored treatment in GBA mutation carriers or in sporadic PD with low GBA activity (NCT0294182) GBA mutations in 10% of patients with iRBD 86 |
| Reduce α-synuclein fibrillation and decrease parthenatos cell-death pathway | Poly(adenosine 5′-diphosphate-ribose) polymerase 1 (PARP1) inhibitors | Olaparib, rucaparib, niraparib, talazoparib are all FDA approved for certain cancers |
| Increasing DA activity | Nicotine | Lower PD risk in smokers87
But higher RBD risk in smokers 88 Trial NIC-PD, n=160: ongoing |
| Lifestyle modifiers | ||
| Diet: selective increased consumption | Caffeine (black tea, coffee) | Lower PD risk in heavy coffee drinkers89
No lower RBD risk 88 |
| Diet: selective increased consumption | Eating edible solanaceae (tomatoes, peppers, potatoes) containing nicotine | Epidemiological evidence for lower PD risk when eating these foods90 |
| Diet: selective increased consumption | Eating more omega 3 polyunsaturated fatty acids | But no neuroprotection in mild cognitive impairment (MAPT study)91 |
| Diet: selective decreased consumption | Reducing milk consumption | Increased PD risk when drinking fresh milk92 |
| Diet: selective decreased consumption | Avoid eating tropical fruits/food containing annonacin (soursop) | Associated with atypical PD93
RBD in up to 55% of patients with parkinsonism of French West Indies 94 |
| Diet: selective increased consumption | Yerba mate tea | Inverse association between yerba mate consumption and PD in South America95 96 |
| Lifestyle: decreasing exposure (food, air) | Avoid exposure to pesticides |
RBD is more frequent in workers using pesticides
88
PD is more frequent in workers using pesticides |
| Exercise and physical activity | Exercise and physical therapy | Anti-inflammatory, antioxidant, promitochondrial, trophic and anti-synuclein effects97–99 |
In italics: human trials in PD; in bold: data in iRBD. Most details can be found in a recent review.142 As for lifestyle changes, details can be obtained from a recent review on RBD risk factors.4
c-Abl, Abelson non-receptor tyrosine kinase ; DA, dopamine; FDA, Food and Drug Administration; GBA, glucocerebrosidase ; iRBD, isolated rapid eye movement sleep behavioural disorder; MAPT, microtubule-associated protein tau; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; RBD, rapid eye movement sleep behavioural disorder.