Table 3.

Potential approaches for disease modification in PD and I RBD (In italics: human trials in PD; in bold: data in iRBD) Most details can be found in a recent review [100]. As for lifestyle changes, details can be obtained from a recent review on RBD risk factors [4].

Mechanisms	Agents	Comments
Immunization	Monoclonal antibodies directed toward the toxic conformations of synuclein	Several ongoing phase I and II trials of passive and active immunization (R07046015, PASADENA trial; BIIB054, SPARK trial) [70]
Neuroinflammation modifiers	Blockers of synuclein misfolding or aggregation	NPT088, glycerol phenylbutyrate, squalamine [71] Nilotinib, selective c-Abl Inhibitors [72], epigallocatechin gallate [73]
Anti-inflammatory	Ibuprofen	Lower PD risk in people receiving nonsteroidal anti-inflammatory agents [74]; 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 models[76]; Rosacea is associated with higher PD risk, treatment with doxycycline reduces this risk [77]
Oxidative stress	Melatonin (antioxidant)	Symptomatic effect in RBD [18] Neuroprotective in various animal PD models [78]
	Glutathione (antioxidant)	N acetylcysteine (glutathione precursor) trial [79] Troloxamide-quinone trial (NCT02462603)
	Apamin (from bee venom)	Protective in a PD mouse model [80]
Iron	Deferiprone (iron chelator)	FAIRPARKI: small randomized double-blind delayed start trial in treated PD patients [81] SKY and FAIRPARKII ongoing trials
Adrenergic system	Beta-2 adrenergic receptor (B2R) agonist	B2R agonists: lower PD risk [71]; B2R regulates the alpha-synuclein gene [82]
	Modafinil: common and safe stimulant in narcolepsy; NAd reuptake inhibition?	Neuroprotective in MPTP parkinsonism marmosets and cats [83] Some RBD patients are sleepy [84]
Glucagon-like peptide-1	Exenatide (antidiabetics)	May reduce DA neurons apoptosis [85]
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 -synuclein fibrillation and decrease parthenatos cell-death pathway	poly(adenosine 5′-diphosphate-ribose) polymerase 1 (PARP1 inhibitors (Kam, Science 2018)	Olaparib, Rucaparib, Niraparib, Talazoparib are all FDA-approved for certain cancers.
Increasing DA activity	Nicotine	Lower PD risk in smokers [87] 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 drinkers [89] 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 foods [90]
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 milk [92]
Diet: Selective decreased consumption	Avoid eating tropical fruits/food containing annonacin (soursop)	Associated with atypical PD [93] 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 America [95 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 effects [97–99]