How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease?

References

• Dorsey ER, Sherer T, Okun MS, et al. The emerging evidence of the parkinson pandemic. J Parkinsons Dis. 2018;8:S3–S8. Brundin P, Langston JW, Bloem BR, editors.
   PubMedGoogle Scholar
• Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795–808.
   PubMed Web of Science ®Google Scholar
• Rajput AH, Uitti RJ, Rajput AH, et al. Timely levodopa (LD) administration prolongs survival in Parkinson’s disease. Parkinsonism Relat Disord. 1997;3(3):159–165.
   PubMedGoogle Scholar
• Myers PS, Jackson JJ, Clover AK, et al. Distinct progression patterns across Parkinson disease clinical subtypes. Ann Clin Transl Neurol. 2021;8(8):1695–1708.
   PubMed Web of Science ®Google Scholar
• Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence‐based medicine review. Mov Disord. 2019;34(2):180–198.
   PubMed Web of Science ®Google Scholar
• Fahn S. The 200-year journey of Parkinson disease: reflecting on the past and looking towards the future. Parkinsonism Relat Disord. 2018;46:S1–S5.
   PubMed Web of Science ®Google Scholar
• Höllerhage M, Klietz M, Höglinger GU. Disease modification in Parkinsonism: obstacles and ways forward. J Neural Transm. 2022;129(9):1133–1153.
   PubMed Web of Science ®Google Scholar
• McFarthing K, Rafaloff G, Baptista M, et al. Parkinson’s disease drug therapies in the clinical trial pipeline: 2022 update. J Parkinsons Dis. 2022;12(4):1073–1082.
   PubMedGoogle Scholar
• Vijiaratnam N, Simuni T, Bandmann O, et al. Progress towards therapies for disease modification in Parkinson’s disease. Lancet Neurol. 2021;20(7):559–572.
   PubMed Web of Science ®Google Scholar
• Vijayakumar D, Jankovic J. Slowing Parkinson’s disease progression with vaccination and other immunotherapies. CNS Drugs. 2022;36(4):327–343.
   PubMed Web of Science ®Google Scholar
• Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(10291):2284–2303.
   PubMed Web of Science ®Google Scholar
• Lungu C, Cedarbaum JM, Dawson TM, et al. Seeking progress in disease modification in Parkinson disease. Parkinsonism Relat Disord. 2021;90:134–141.
   PubMed Web of Science ®Google Scholar
• Schaeffer E, Postuma RB, Berg D. Prodromal PD: a new nosological entity. Prog Brain Res. 2020;252:331–356.
   PubMed Web of Science ®Google Scholar
• Berg D, Borghammer P, Fereshtehnejad S-M, et al. Prodromal Parkinson disease subtypes — key to understanding heterogeneity. Nat Rev Neurol. 2021;17(6):349–361.
   PubMed Web of Science ®Google Scholar
• Mahlknecht P, Marini K, Werkmann M, et al. Prodromal Parkinson’s disease: hype or hope for disease-modification trials? Transl Neurodegener. 2022;11(1):11.
   PubMed Web of Science ®Google Scholar
• Pinto M, Nissanka N, Peralta S, et al. Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation. Mol Neurodegener. 2016;11(1):25.
   PubMedGoogle Scholar
• Cleren C, Yang L, Lorenzo B, et al. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism. J Neurochem. 2008;104(6):1613–1621.
   PubMed Web of Science ®Google Scholar
• Janssen Daalen JM, Schootemeijer S, Richard E, et al. Lifestyle Interventions for the prevention of Parkinson disease. Neurology. 2022;99(7 Supplement 1):42–51.
   PubMed Web of Science ®Google Scholar
• Crotty GF, Schwarzschild MA. Chasing protection in Parkinson’s disease: does exercise reduce risk and progression? Front Aging Neurosci. 2020;12. DOI:10.3389/fnagi.2020.00186
   PubMed Web of Science ®Google Scholar
• Ahlskog JE. Aerobic exercise: evidence for a direct brain effect to slow Parkinson disease progression. Mayo Clin Proc. 2018;93(3):360–372.
   PubMed Web of Science ®Google Scholar
• Murata H, Barnhill LM, Bronstein JM. Air pollution and the risk of Parkinson’s disease: a review. Mov Disord. 2022;37(5):894–904.
   PubMed Web of Science ®Google Scholar
• Jo S, Kim Y-J, Park KW, et al. Association of NO 2 and other air pollution exposures with the risk of Parkinson disease. JAMA Neurol. 2021;78(7):800.
   PubMed Web of Science ®Google Scholar
• Costello S, Cockburn M, Bronstein J, et al. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol. 2009;169(8):919–926.
   PubMed Web of Science ®Google Scholar
• Hancock DB, Martin ER, Mayhew GM, et al. Pesticide exposure and risk of Parkinson’s disease: a family-based case-control study. BMC Neurol. 2008;8(1):6.
   PubMedGoogle Scholar
• Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Res Rev. 2018;42:72–85.
   PubMed Web of Science ®Google Scholar
• Hill EJ, Robak LA, Al-Ouran R, et al. Genome sequencing in the Parkinson disease clinic. Neurol Genet. 2022;8(4):e200002.
   PubMed Web of Science ®Google Scholar
• Funayama M, Nishioka K, Li Y, et al. Molecular genetics of Parkinson’s disease: contributions and global trends. J Hum Genet. 2022. DOI:10.1038/s10038-022-01058-5.
   Web of Science ®Google Scholar
• Aleksovski D, Miljkovic D, Bravi D, et al. Disease progression in Parkinson subtypes: the PPMI dataset. Neurol Sci. 2018;39(11):1971–1976.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease. JAMA. 2020;323(6):548.
   PubMed Web of Science ®Google Scholar
• Konno T, Deutschländer A, Heckman MG, et al. Comparison of clinical features among Parkinson’s disease subtypes: a large retrospective study in a single center. J Neurol Sci. 2018;386:39–45.
   PubMed Web of Science ®Google Scholar
• Sauerbier A, Jenner P, Todorova A, et al. Non motor subtypes and Parkinson’s disease. Parkinsonism Relat Disord. 2016;22:S41–S46.
   PubMed Web of Science ®Google Scholar
• Thenganatt MA, Jankovic J. Parkinson disease subtypes. JAMA Neurol. 2014;71(4):499.
   PubMed Web of Science ®Google Scholar
• Merola A, Romagnolo A, Dwivedi AK, et al. Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications. J Neurol. 2020;267(10):2949–2960.
   PubMed Web of Science ®Google Scholar
• Saunders-Pullman R, Mirelman A, Alcalay RN, et al. Progression in the LRRK2 -associated Parkinson disease population. JAMA Neurol. 2018;75(3):312.
   PubMed Web of Science ®Google Scholar
• Lee MJ, Pak K, Kim H-K, et al. Genetic factors affecting dopaminergic deterioration during the premotor stage of Parkinson disease. Npj Park Dis. 2021;7(1):104.
   PubMed Web of Science ®Google Scholar
• Sauerbier A, Lenka A, Aris A, et al. Nonmotor symptoms in Parkinson’s disease: gender and ethnic differences. Int Rev Neurobiol. 2017;133:417–446.
   PubMed Web of Science ®Google Scholar
• Reekes TH, Higginson CI, Ledbetter CR, et al. Sex specific cognitive differences in Parkinson disease. Npj Park Dis. 2020;6(1):7.
   PubMed Web of Science ®Google Scholar
• Cerri S, Mus L, Blandini F. Parkinson’s disease in women and men: what’s the difference? J Parkinsons Dis. 2019;9(3):501–515.
   PubMedGoogle Scholar
• Hassin-Baer S, Molchadski I, Cohen OS, et al. Gender effect on time to levodopa-induced dyskinesias. J Neurol. 2011;258(11):2048–2053.
   PubMed Web of Science ®Google Scholar
• Oh SS, Galanter J, Thakur N, et al. Diversity in clinical and biomedical research: a promise yet to be fulfilled. PLOS Med. 2015;12(12):e1001918.
   PubMed Web of Science ®Google Scholar
• Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498–2508.
   PubMed Web of Science ®Google Scholar
• Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380(4):315–324.
   PubMed Web of Science ®Google Scholar
• NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 2015;14(8):795–803.
   PubMed Web of Science ®Google Scholar
• Beal MF, Oakes D, Shoulson I, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease. JAMA Neurol. 2014;71(5):543.
   PubMed Web of Science ®Google Scholar
• Mischley LK, Lau RC, Shankland EG, et al. Phase IIb study of intranasal glutathione in Parkinson’s disease. J Parkinsons Dis. 2017;7(2):289–299.
   PubMedGoogle Scholar
• Monti DA, Zabrecky G, Kremens D, et al. N‐acetyl cysteine is associated with dopaminergic improvement in Parkinson’s disease. Clin Pharmacol Ther. 2019;106(4):884–890.
   PubMed Web of Science ®Google Scholar
• Schwarzschild MA, Ascherio A, Beal MF, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease. JAMA Neurol. 2014;71(2):141.
   PubMed Web of Science ®Google Scholar
• Schwarzschild MA, Ascherio A, Casaceli C, et al. Effect of urate-elevating inosine on early Parkinson disease progression: the SURE-PD3 randomized clinical trial. JAMA. 2021;326(10):926–939.
   PubMed Web of Science ®Google Scholar
• Pagan FL, Hebron ML, Wilmarth B, et al. Nilotinib effects on safety, tolerability, and potential biomarkers in Parkinson disease. JAMA Neurol. 2020;77(3):309.
   PubMed Web of Science ®Google Scholar
• Simuni T, Fiske B, Merchant K, et al. Efficacy of nilotinib in patients with moderately advanced Parkinson disease. JAMA Neurol. 2021;78(3):312.
   PubMed Web of Science ®Google Scholar
• Pagano G, Taylor KI, Anzures-Cabrera J, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J Med. 2022;387(5):421–432.
   PubMed Web of Science ®Google Scholar
• Lang AE, Siderowf AD, Macklin EA, et al. Trial of cinpanemab in early Parkinson’s disease. N Engl J Med. 2022;387(5):408–420.
   PubMed Web of Science ®Google Scholar
• Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176–183.
   PubMed Web of Science ®Google Scholar
• Lin C, Chang C, Tai C, et al. A double‐blind, randomized, controlled trial of lovastatin in Parkinson’s disease. Mov Disord. 2021;36(5):1229–1237.
   PubMed Web of Science ®Google Scholar
• Devos D, Labreuche J, Rascol O, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med. 2022;387(22):2045–2055.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Hauser RA, Gauguster L, et al. The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol. 1995;38(5):771–777.
   PubMed Web of Science ®Google Scholar
• Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002;59(12):1937–1943.
   PubMed Web of Science ®Google Scholar
• Palhagen S, Heinonen E, Hagglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology. 2006;66(8):1200–1206.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–1278.
   PubMed Web of Science ®Google Scholar
• Hattori N, Takeda A, Takeda S, et al. Rasagiline monotherapy in early Parkinson’s disease: a phase 3, randomized study in Japan. Parkinsonism Relat Disord. 2019;60:146–152.
   PubMed Web of Science ®Google Scholar
• Parkinson Study Group STEADY-PD III Investigators. Isradipine versus placebo in early Parkinson disease: a randomized trial. Ann Intern Med. 2020;172(9):591–598.
   PubMed Web of Science ®Google Scholar
• Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664–1675.
   PubMed Web of Science ®Google Scholar
• Gabathuler R. Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiol Dis. 2010;37(1):48–57.
   PubMed Web of Science ®Google Scholar
• Cheng G, Liu Y, Ma R, et al. Anti-Parkinsonian therapy: strategies for crossing the blood–brain barrier and nano-biological effects of nanomaterials. Nano-Micro Lett. 2022;14(1):105.
   PubMed Web of Science ®Google Scholar
• Karakatsani ME, Blesa J, Konofagou EE. Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson’s disease. Mov Disord. 2019;34(9):1252–1261.
   PubMed Web of Science ®Google Scholar
• Fishman PS, Fischell JM. Focused ultrasound mediated opening of the blood-brain barrier for neurodegenerative diseases. Front Neurol. 2021;12. DOI:10.3389/fneur.2021.749047
   PubMed Web of Science ®Google Scholar
• Pineda‐Pardo JA, Gasca‐Salas C, Fernández‐Rodríguez B, et al. Striatal blood–brain- barrier opening in Parkinson’s disease dementia: a pilot exploratory study. Mov Disord. 2022;37(10):2057–2065.
   PubMed Web of Science ®Google Scholar
• D’Haese P-F, Ranjan M, Song A, et al. β-amyloid plaque reduction in the hippocampus after focused ultrasound-induced blood–brain barrier opening in Alzheimer’s disease. Front Hum Neurosci. 2020;14. DOI:10.3389/fnhum.2020.593672.
   PubMed Web of Science ®Google Scholar
• Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nat Commun. 2021;12(1):779.
   PubMed Web of Science ®Google Scholar
• Marras C, Chaudhuri KR. Nonmotor features of Parkinson’s disease subtypes. Mov Disord. 2016;31(8):1095–1102.
   PubMed Web of Science ®Google Scholar
• Shulman LM, Gruber-Baldini AL, Anderson KE, et al. The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol. 2010;67(1). DOI:10.1001/archneurol.2009.295.
   PubMedGoogle Scholar
• Horváth K, Aschermann Z, Ács P, et al. Minimal clinically important difference on the motor examination part of MDS-UPDRS. Parkinsonism Relat Disord. 2015;21(12):1421–1426.
   PubMed Web of Science ®Google Scholar
• Horváth K, Aschermann Z, Kovács M, et al. Minimal clinically important differences for the experiences of daily living parts of movement disorder society-sponsored unified Parkinson’s disease rating scale. Mov Disord. 2017;32(5):789–793.
   PubMed Web of Science ®Google Scholar
• Macklin EA, Coffey CS, Brumm MC, et al. Statistical considerations in the design of clinical trials targeting prodromal Parkinson disease. Neurology. 2022;99(7 Supplement 1):68–75.
   PubMed Web of Science ®Google Scholar
• Do J, McKinney C, Sharma P, et al. Glucocerebrosidase and its relevance to Parkinson disease. Mol Neurodegener. 2019;14(1):36.
   PubMed Web of Science ®Google Scholar
• Tolosa E, Vila M, Klein C, et al. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020;16(2):97–107.
   PubMed Web of Science ®Google Scholar
• Balestrino R, Tunesi S, Tesei S, et al. Penetrance of Glucocerebrosidase (GBA) mutations in Parkinson’s disease: a Kin Cohort study. Mov Disord. 2020;35(11):2111–2114.
   PubMed Web of Science ®Google Scholar
• Iwaki H, Blauwendraat C, Makarious MB, et al. Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score. Mov Disord. 2020;35(5):774–780.
   PubMed Web of Science ®Google Scholar
• Mullin S, Beavan M, Bestwick J, et al. Evolution and clustering of prodromal parkinsonian features in GBA1 carriers. Mov Disord. 2019;34(9):1365–1373.
   PubMed Web of Science ®Google Scholar
• Mirelman A, Saunders-Pullman R, Alcalay RN, et al. Application of the movement disorder society prodromal criteria in healthy G2019S - LRRK2 carriers. Mov Disord. 2018;33(6):966–973.
   PubMed Web of Science ®Google Scholar
• Menozzi E, Schapira AHV. Exploring the genotype–phenotype correlation in GBA-Parkinson disease: clinical aspects, biomarkers, and potential modifiers. Front Neurol. 2021;12. DOI:10.3389/fneur.2021.694764
   PubMed Web of Science ®Google Scholar
• Rocha EM, Keeney MT, Di Maio R, et al. LRRK2 and idiopathic Parkinson’s disease. Trends Neurosci. 2022;45(3):224–236.
   PubMed Web of Science ®Google Scholar
• Hustad E, Aasly JO. Clinical and imaging markers of prodromal Parkinson’s disease. Front Neurol. 2020;11. DOI:10.3389/fneur.2020.00395
   PubMed Web of Science ®Google Scholar
• Picillo M, Barone P, MT P. Merging clinical and imaging biomarkers to tackle Parkinson’s disease. Mov Disord Clin Pract. 2017;4(5):652–662.
   PubMedGoogle Scholar
• Heinzel S, Berg D, Gasser T, et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov Disord. 2019;34(10):1464–1470.
   PubMed Web of Science ®Google Scholar
• Jennings D, Huntwork-Rodriguez S, Henry AG, et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci Transl Med. 2022;14(648). DOI:10.1126/scitranslmed.abj2658.
   PubMed Web of Science ®Google Scholar
• Senkevich K, Rudakou U, Gan-Or Z. New therapeutic approaches to Parkinson’s disease targeting GBA, LRRK2 and Parkin. Neuropharmacology. 2022;202:108822.
   PubMed Web of Science ®Google Scholar
• Diaz-Ortiz ME, Seo Y, Posavi M, et al. GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein. Science. 2022;377(6608). DOI:10.1126/science.abk0637.
   PubMed Web of Science ®Google Scholar
• Mollenhauer B, von Arnim CAF. Toward preventing Parkinson’s disease. Science. 2022;377(6608):818–819.
   PubMed Web of Science ®Google Scholar
• Martinez‐Valbuena I, Visanji NP, Olszewska DA, et al. Combining skin α‐synuclein real‐time quaking‐induced conversion and circulating neurofilament light chain to distinguish multiple system atrophy and Parkinson’s disease. Mov Disord. 2022;37(3):648–650.
   PubMed Web of Science ®Google Scholar
• Mammana A, Baiardi S, Quadalti C, et al. RT‐QuIC detection of pathological α‐synuclein in skin punches of patients with lewy body disease. Mov Disord. 2021;36(9):2173–2177.
   PubMed Web of Science ®Google Scholar
• Donadio V, Wang Z, Incensi A, et al. In Vivo diagnosis of Synucleinopathies. Neurology. 2021;96(20):e2513–e2524.
   PubMed Web of Science ®Google Scholar
• Iranzo A, Fairfoul G, Ayudhaya ACN, et al. Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study. Lancet Neurol. 2021;20:203–212.
   PubMed Web of Science ®Google Scholar
• Kuzkina A, Bargar C, Schmitt D, et al. Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study. Npj Park Dis. 2021;7(1):99.
   PubMedGoogle Scholar
• Han Y, Wu D, Wang Y, et al. Skin alpha-synuclein deposit patterns: a predictor of Parkinson’s disease subtypes. eBioMedicine. 2022;80:104076.
   PubMed Web of Science ®Google Scholar
• Berg D, Crotty GF, Keavney JL, et al. Path to Parkinson disease prevention. Neurology. 2022;99(7 Supplement 1):76–83.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019;142(3):744–759.
   PubMed Web of Science ®Google Scholar
• Fang X, Han D, Cheng Q, et al. Association of levels of physical activity with risk of Parkinson disease. JAMA Network Open. 2018;1(5):e182421.
   PubMed Web of Science ®Google Scholar
• Clarke CE. Are delayed-start design trials to show neuroprotection in Parkinson’s disease fundamentally flawed? Mov Disord. 2008;23(6):784–789.
   PubMed Web of Science ®Google Scholar
• Wang D, Robieson W, Zhao J, et al. Statistical considerations in a delayed-start design to demonstrate disease modification effect in neurodegenerative disorders. Pharm Stat. 2019;18(4):407–419.
   PubMed Web of Science ®Google Scholar
• Javidnia M, Frasier M, Shoulson I, et al. Innovative approaches for slowing disease progression in Parkinson’s disease: takeaways from the 14th annual international society for central nervous system clinical trials and methodology scientific meeting. Innov Clin Neurosci. 2020;17(1–3):14–19.
   PubMedGoogle Scholar
• Crotty GF, Schwarzschild MA. What to test in Parkinson disease prevention trials? Neurology. 2022;99(7 Supplement 1):34–41.
   PubMed Web of Science ®Google Scholar
• Johansson ME, Cameron IGM, Van der Kolk NM, et al. Aerobic exercise alters brain function and structure in Parkinson’s disease: a randomized controlled trial. Ann Neurol. 2022;91(2):203–216.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Gagnon JF, Vendette M, et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology. 2009;72(15):1296–1300.
   PubMed Web of Science ®Google Scholar
• Mirelman A, Siderowf A, Chahine L. Outcome assessment in Parkinson disease prevention trials. Neurology. 2022;99(7 Supplement 1):52–60.
   PubMed Web of Science ®Google Scholar
• Espay AJ, Hausdorff JM, Sánchez‐Ferro Á, et al. A roadmap for implementation of patient‐centered digital outcome measures in Parkinson’s disease obtained using mobile health technologies. Mov Disord. 2019;34(5):657–663.
   PubMed Web of Science ®Google Scholar
• Bouça-Machado R, Fernandes A, Ranzato C, et al. Measurement tools to assess activities of daily living in patients with Parkinson’s disease: a systematic review. Front Neurosci. 2022;16. DOI:10.3389/fnins.2022.945398.
   PubMed Web of Science ®Google Scholar
• Seibyl JP, Kuo P. What is the role of dopamine transporter imaging in Parkinson prevention clinical trials? Neurology. 2022;99(7 Supplement 1):61–67.
   PubMed Web of Science ®Google Scholar
• Korat Š, Bidesi NSR, Bonanno F, et al. Alpha-synuclein PET tracer development—an overview about current efforts. Pharmaceuticals. 2021;14(9):847.
   Web of Science ®Google Scholar
• Matuskey D, Tinaz S, Wilcox KC, et al. Synaptic changes in Parkinson disease assessed with in vivo Imaging. Ann Neurol. 2020;87(3):329–338.
   PubMed Web of Science ®Google Scholar
• Ofori E, Pasternak O, Planetta PJ, et al. Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease. Brain. 2015;138(8):2322–2331.
   PubMedGoogle Scholar
• Gaurav R, Yahia‐Cherif L, Pyatigorskaya N, et al. Longitudinal changes in neuromelanin MRI signal in Parkinson’s disease: a progression marker. Mov Disord. 2021;36(7):1592–1602.
   PubMed Web of Science ®Google Scholar
• Javidnia M, Arbatti L, Hosamath A, et al. Predictive value of verbatim Parkinson’s disease patient-reported symptoms of postural instability and falling. J Parkinsons Dis. 2021;11(4):1957–1964.
   PubMedGoogle Scholar
• Martinez-Martin P, Rodriguez-Blazquez C, Frades-Payo B. Specific patient-reported outcome measures for Parkinson’s disease: analysis and applications. Expert Rev Pharmacoecon Outcomes Res. 2008;8(4):401–418.
   PubMedGoogle Scholar
• Savitt D, Jankovic J. Targeting α-synuclein in Parkinson’s disease: progress towards the development of disease-modifying therapeutics. Drugs. 2019;79(8):797–810.
   PubMed Web of Science ®Google Scholar
• Oliveira LMA, Gasser T, Edwards R, et al. Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease. Npj Park Dis. 2021;7:65.
   PubMed Web of Science ®Google Scholar
• Sulzer D, Edwards RH. The physiological role of α‐synuclein and its relationship to Parkinson’s disease. J Neurochem. 2019;150(5):475–486.
   PubMed Web of Science ®Google Scholar
• Espay AJ, Okun MS. Abandoning the proteinopathy paradigm in Parkinson disease. JAMA Neurol. 2022;80(2):123–124.
   Web of Science ®Google Scholar
• Höglinger GU. Does the Anti-Tau strategy in progressive supranuclear palsy need to be reconsidered? No. Mov Disord Clin Pract. 2021;8(7):1038–1040.
   PubMed Web of Science ®Google Scholar
• Kwan ATH, Arfaie S, Therriault J, et al. Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord. 2020;49(4):334–348.
   PubMed Web of Science ®Google Scholar
• Whone A. Monoclonal antibody therapy in Parkinson’s disease — the end? N Engl J Med. 2022;387(5):466–467.
   PubMed Web of Science ®Google Scholar
• Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an Anti–α-synuclein monoclonal antibody, in patients with Parkinson disease. JAMA Neurol. 2018;75(10):1206.
   PubMed Web of Science ®Google Scholar
• Tan E-K, Chao Y-X, West A, et al. Parkinson disease and the immune system — associations, mechanisms and therapeutics. Nat Rev Neurol. 2020;16(6):303–318.
   PubMed Web of Science ®Google Scholar
• Volc D, Poewe W, Kutzelnigg A, et al. Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson’s disease: a randomised, single-blinded, phase 1 trial. Lancet Neurol. 2020;19(7):591–600.
   PubMed Web of Science ®Google Scholar
• Smit JW, Basile P, Prato MK, et al. Phase 1/1b studies of UCB0599, an oral inhibitor of α-Synuclein misfolding, including a randomized study in Parkinson’s disease. Mov Disord. 2022;37(10):2045–2056.
   PubMed Web of Science ®Google Scholar
• Kamath T, Abdulraouf A, Burris SJ, et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease. Nat Neurosci. 2022;25(5):588–595.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Perez AI, Sucunza D, Pedrosa MA, et al. Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death. Neurotherapeutics. 2018;15(4):1063–1081.
   PubMed Web of Science ®Google Scholar
• Lin H-C, Tseng Y-F, Shen A-L, et al. Association of angiotensin receptor blockers with incident Parkinson disease in patients with hypertension: a retrospective cohort study. Am J Med. 2022;135(8):1001–1007.
   PubMed Web of Science ®Google Scholar
• Jo Y, Kim S, Ye BS, et al. Protective effect of renin-angiotensin system inhibitors on Parkinson’s disease: a nationwide cohort study. Front Pharmacol. 2022;13. DOI:10.3389/fphar.2022.837890.
   Web of Science ®Google Scholar
• Lee Y-C, Lin C-H, Wu R-M, et al. Antihypertensive agents and risk of Parkinson’s disease: a nationwide cohort study. PLoS One. 2014;9(6):e98961. Morishita R, editor.
   PubMed Web of Science ®Google Scholar
• Engelender S, Stefanis L, Oddo S, et al. Can we treat neurodegenerative proteinopathies by enhancing protein degradation? Mov Disord. 2022;37(7):1346–1359.
   PubMed Web of Science ®Google Scholar
• Robak LA, Jansen IE, van Rooij J, et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain. 2017;140(12):3191–3203.
   PubMed Web of Science ®Google Scholar
• Senkevich K, Gan-Or Z. Autophagy lysosomal pathway dysfunction in Parkinson’s disease; evidence from human genetics. Parkinsonism Relat Disord. 2020;73:60–71.
   PubMed Web of Science ®Google Scholar
• Cai R, Zhang Y, Simmering JE, et al. Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases. J Clin Invest. 2019;129(10):4539–4549.
   PubMed Web of Science ®Google Scholar
• Simmering JE, Welsh MJ, Liu L, et al. Association of glycolysis-enhancing α-1 blockers with risk of developing Parkinson disease. JAMA Neurol. 2021;78(4):407.
   PubMed Web of Science ®Google Scholar
• Schultz JL, Brinker AN, Xu J, et al. A pilot to assess target engagement of terazosin in Parkinson’s disease. Parkinsonism Relat Disord. 2022;94:79–83.
   PubMed Web of Science ®Google Scholar
• Marks WJ, Ostrem JL, Verhagen L, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2–neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol. 2008;7(5):400–408.
   PubMed Web of Science ®Google Scholar
• Marks WJ, Baumann TL, Bartus RT. Long-term safety of patients with Parkinson’s disease receiving rAAV2-Neurturin (CERE-120) gene transfer. Hum Gene Ther. 2016;27(7):522–527.
   PubMed Web of Science ®Google Scholar
• Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59(3):459–466.
   PubMed Web of Science ®Google Scholar
• Sidorova YA, Saarma M. Can growth factors cure Parkinson’s disease? Trends Pharmacol Sci. 2020;41(12):909–922.
   PubMed Web of Science ®Google Scholar
• Gosselet F, Loiola RA, Roig A, et al. Central nervous system delivery of molecules across the blood-brain barrier. Neurochem Int. 2021;144:104952.
   PubMed Web of Science ®Google Scholar
• Khatri DK, Preeti K, Tonape S, et al. Nanotechnological advances for nose to brain delivery of therapeutics to improve the Parkinson therapy. Curr Neuropharmacol. 2022;20.
   Google Scholar
• Stefani A, Pierantozzi M, Cardarelli S, et al. Neurotrophins as therapeutic agents for Parkinson’s disease; New chances from focused ultrasound? Front Neurosci. 2022;16. DOI:10.3389/fnins.2022.846681.
   PubMed Web of Science ®Google Scholar
• Schaeffer E, Rogge A, Nieding K, et al. Patients’ views on the ethical challenges of early Parkinson disease detection. Neurology. 2020;94(19):e2037–e2044.
   PubMed Web of Science ®Google Scholar
• Millum J, Grady C. The ethics of placebo-controlled trials: methodological justifications. Contemp Clin Trials. 2013;36(2):510–514.
   PubMed Web of Science ®Google Scholar
• Fu KA, Saver JL, Perlman S. Emerging subspecialties in neurology: a career as a clinical trialist in neurology. Neurology. 2022;98:940–944.
   PubMed Web of Science ®Google Scholar