Progress of non-motor symptoms in early-onset Parkinson's disease

Abstract

Parkinson's disease (PD) is a common degenerative disease of the central nervous system that is characterized by movement disorders and non-motor symptoms (NMSs). The associated NMSs primarily include neuropsychiatric symptoms, autonomic dysfunction, sleep-wake disorders, pain, fatigue, and hyposmia. These NMSs can occur at any stage of PD, especially before the onset of motor symptoms, and may affect a patient's quality of life more than motor symptoms. Although PD is most commonly diagnosed in people over 65 years, some patients exhibit symptom onset before the age of 50, which is clinically known as early-onset Parkinson's disease (EOPD). The high heterogeneity and incidence of EOPD-associated NMSs can lead to the misdiagnosis of EOPD as other neurodegenerative diseases. In this review, we discuss the research progress related to NMSs in patients with EOPD, focusing on neuropsychiatric disorders, autonomic dysfunction, sleep disorders, and sensory impairment, and outline the association of NMSs with different genotypic alterations, with the aim of providing assistance in the clinical management of patients.

Keywords

autonomic dysfunction / early-onset Parkinson's disease / late-onset Parkinson's disease / neuropsychiatric symptoms / non-motor symptoms

References

[1] Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020; 323(6):548-560.

[2] Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006; 5(4):355-363.

[3] Camerucci E, Stang CD, Turcano P, et al. Deep brain stimulation and treatment outcomes of young- and late-onset (≤55 Years) Parkinson's disease: a population-based study. Front Neurol. 2021; 12:784398.

[4] Zheng Z, Lv Y, Rong S, Sun T, Chen L. Physical frailty, genetic predisposition, and incident parkinson disease. JAMA Neurol. 2023; 80:455.

[5] Ferguson LW, Rajput AH, Rajput A. Early-onset vs. late-onset parkinson's disease: a clinical-pathological study. Can J Neurol Sci/J Can des Sci Neurol. 2016; 43(1):113-119.

[6] Maggi G, Vitale C, Cerciello F, Santangelo G. Sleep and wakefulness disturbances in Parkinson's disease: a meta-analysis on prevalence and clinical aspects of REM sleep behavior disorder, excessive daytime sleepiness and insomnia. Sleep Med Rev. 2023; 68:101759.

[7] Li K, Xu S, Wang R, et al. Electroacupuncture for motor dysfunction and constipation in patients with Parkinson's disease: a randomised controlled multi-centre trial. EClinicalMed. 2023; 56:101814.

[8] Markopoulou K, Aasly J, Chung SJ, et al. Longitudinal monitoring of Parkinson's disease in different ethnic cohorts: the DodoNA and LONG-PD study. Front Neurol. 2020; 11:548.

[9] Jankovic J, Tan EK. Parkinson's disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020; 91(8):795-808.

[10] Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003; 24(2):197-211.

[11] Pihlstrøm L, Shireby G, Geut H, et al. Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology. Nat Commun. 2022; 13(1):4932.

[12] Herman S, Djaldetti R, Mollenhauer B, Offen D. CSF-derived extracellular vesicles from patients with Parkinson's disease induce symptoms and pathology. Brain. 2023; 146(1):209-224.

[13] Ahnaou A, Drinkenburg WHIM. REM sleep behavior and olfactory dysfunction: enhancing the utility and translation of animal models in the search for precision medicines for Parkinson's disease. Neurosci Biobehav Rev. 2022; 143:104897.

[14] Attems J, Toledo JB, Walker L, et al. Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study. Acta Neuropathol. 2021; 141(2):159-172.

[15] Braak H, Rüb U, Jansen Steur ENH, Del Tredici K, de Vos RAI. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology. 2005; 64(8):1404-1410.

[16] Ray Chaudhuri K, Leta V, Bannister K, Brooks DJ, Svenningsson P. The noradrenergic subtype of Parkinson disease: from animal models to clinical practice. Nat Rev Neurol. 2023; 19:333-345.

[17] Weintraub D, Simuni T, Caspell-Garcia C, et al. Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease. Mov Disorders. 2015; 30(7):919-927.

[18] Hinkle JT, Perepezko K, Rosenthal LS, et al. Markers of impaired motor and cognitive volition in Parkinson's disease: correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias. Parkinsonism Rel Disord. 2018; 47:50-56.

[19] Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017; 18(7):435-450.

[20] Hanganu A, Bruneau MA, Degroot C, et al. Depressive symptoms in Parkinson's disease correlate with cortical atrophy over time. Brain Cogn. 2017; 111:127-133.

[21] Walter U, Dressler D, Wolters A, Wittstock M, Benecke R. Transcranial brain sonography findings in clinical subgroups of idiopathic Parkinson's disease. Mov Disorders. 2007; 22(1):48-54.

[22] Pagano G, Ferrara N, Brooks DJ, Pavese N. Age at onset and Parkinson disease phenotype. Neurology. 2016; 86(15):1400-1407.

[23] Zhou MZ, Gan J, Wei YR, Ren XY, Chen W, Liu ZG. The association between non-motor symptoms in Parkinson's disease and age at onset. Clin Neurol Neurosurg. 2013; 115(10):2103-2107.

[24] Starkstein SE, Berthier ML, Bolduc PL, Preziosi TJ, Robinson RG. Depression in patients with early versus late onset of Parkinson's disease. Neurology. 1989; 39(11):1441.

[25] Fereshtehnejad SM, Hadizadeh H, Farhadi F, Shahidi GA, Delbari A, Lökk J. Comparison of the psychological symptoms and disease-specific quality of life between early- and typical-onset Parkinson's disease patients. Parkinson's Disease. 2014; 2014:819260.

[26] Ou R, Wei Q, Hou Y, et al. Suicidal ideation in early-onset Parkinson's disease. J Neurol. 2021; 268(5):1876-1884.

[27] Weintraub D, Aarsland D, Chaudhuri KR, et al. The neuropsychiatry of Parkinson's disease: advances and challenges. Lancet Neurol. 2022; 21(1):89-102.

[28] Sbolli M, Fiuzat M, Cani D, O'Connor CM. Depression and heart failure: the lonely comorbidity. Eur J Heart Fail. 2020; 22(11):2007-2017.

[29] Castrioto A, Lhommée E, Moro E, Krack P. Mood and behavioural effects of subthalamic stimulation in Parkinson's disease. Lancet Neurol. 2014; 13(3):287-305.

[30] Tao Y, Vermilyea SC, Zammit M, et al. Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys. Nature Med. 2021; 27(4):632-639.

[31] Chaudhuri KR, Schapira AH. Non-motor symptoms of parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009; 8(5):464-474.

[32] Kim R, Shin JH, Park S, Kim HJ, Jeon B. Longitudinal evolution of non-motor symptoms according to age at onset in early Parkinson's disease. J Neurol Sci. 2020; 418:117157.

[33] Špica V, Pekmezović T, Svetel M, Kostić VS. Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease. J Neurol. 2013; 260(1):131-137.

[34] Broen MPG, Narayen NE, Kuijf ML, Dissanayaka NNW, Leentjens AFG. Prevalence of anxiety in Parkinson's disease: a systematic review and meta-analysis. Mov Disorders. 2016; 31(8):1125-1133.

[35] Sagna A, Gallo JJ, Pontone GM. Systematic review of factors associated with depression and anxiety disorders among older adults with Parkinson's disease. Parkinsonism Rel Disord. 2014; 20(7):708-715.

[36] Magnard R, Vachez Y, Carcenac C, et al. What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease? Transl Psychiatry. 2016; 6(3):e753.

[37] Walter U, Hoeppner J, Prudente-Morrissey L, Horowski S, Herpertz SC, Benecke R. Parkinson's disease-like midbrain sonography abnormalities are frequent in depressive disorders. Brain. 2007; 130(Pt 7):1799-1807.

[38] Nemade D, Subramanian T, Shivkumar V. An update on medical and surgical treatments of Parkinson's disease. Aging Dis. 2021; 12(4):1021-1035.

[39] Brubacher JR, Chan H, Erdelyi S, Zed PJ, Staples JA, Etminan M. Medications and risk of motor vehicle collision responsibility in British Columbia, Canada: a population-based case-control study. The Lancet Public Health. 2021; 6(6):e374-e385.

[40] Monastero R, Cicero CE, Baschi R, et al. Mild cognitive impairment in Parkinson's disease: the Parkinson's disease cognitive study (PACOS). J Neurol. 2018; 265(5):1050-1058.

[41] Tang H, Huang J, Nie K, et al. Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease. Int J Neurosci. 2016; 126(3):227-234.

[42] Dubois B, Pillon B, Sternic N, Lhermitte F, Agid Y. Age-induced cognitive disturbances in Parkinson's disease. Neurology. 1990; 40(1):38.

[43] Lin MK, Farrer MJ. Genetics and genomics of Parkinson's disease. Genome Med. 2014; 6(6):48.

[44] Rozzini L, Vicini Chilovi B, Conti M, et al. Efficacy of SSRIs on cognition of Alzheimer's disease patients treated with cholinesterase inhibitors. Int Psychogeriatr. 2010; 22(1):114-119.

[45] Jiang W, Wu Z, Wen L, et al. The efficacy of high- or low-frequency transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia. Adv Ther. 2022; 39(1):286-295.

[46] Wickremaratchi MM, Ben-Shlomo Y, Morris HR. The effect of onset age on the clinical features of Parkinson's disease. Eur J Neurol. 2009; 16(4):450-456.

[47] Joza S, Hu MT, Jung KY, et al. Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study. Brain. 2023; 146:3258-3272.

[48] Kasongo DW, de Leo G, Vicario N, Leanza G, Legname G. Chronic α-synuclein accumulation in rat hippocampus induces lewy bodies formation and specific cognitive impairments. eNeuro. 2020; 7(3):ENEURO.0009-20.2020.

[49] Lanskey JH, McColgan P, Schrag AE, et al. Can neuroimaging predict dementia in Parkinson's disease? Brain. 2018; 141(9):2545-2560.

[50] Brandão PRP, Munhoz RP, Grippe TC, et al. Cognitive impairment in Parkinson's disease: a clinical and pathophysiological overview. J Neurol Sci. 2020; 419:117177.

[51] Bohnen NI, Albin RL, Müller MLTM, et al. Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects. JAMA Neurol. 2015; 72(2):194-200.

[52] Liu SY, Wu JJ, Zhao J, et al. Onset-related subtypes of Parkinson's disease differ in the patterns of striatal dopaminergic dysfunction: a positron emission tomography study. Parkinsonism Rel Disord. 2015; 21(12):1448-1453.

[53] Malchow B, Levold K, Labusga M, et al. Effects of three months of aerobic endurance training on motor cortical excitability in schizophrenia patients and healthy subjects. Neuropsychobiology. 2018; 79:100-107.

[54] Morrin H, Fang T, Servant D, Aarsland D, Rajkumar AP. Systematic review of the efficacy of non-pharmacological interventions in people with lewy body dementia. Int Psychogeriatr. 2018; 30(3):395-407.

[55] Baba T, Takeda A, Murakami A, et al. Effect of donepezil for dementia prevention in Parkinson's disease with severe hyposmia (The DASH-PD study): a randomized long-term placebo-controlled trial. EClinicalMedicine. 2022; 51:101571.

[56] Levine SZ, Yoshida K, Goldberg Y, et al. Linking the mini-mental state examination, the Alzheimer's disease assessment Scale-Cognitive subscale and the severe impairment battery: evidence from individual participant data from five randomised clinical trials of donepezil. Evidence Based Mental Health. 2021; 24(2):56-61.

[57] Voon V, Napier TC, Frank MJ, et al. Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update. Lancet Neurol. 2017; 16(3):238-250.

[58] Sharp ME, Caccappolo E, Mejia-Santana H, et al. The relationship between obsessive-compulsive symptoms and PARKIN genotype: the CORE-PD study. Mov Disorders. 2015; 30(2):278-283.

[59] Vargas AP, Cardoso FEC. Impulse control and related disorders in Parkinson's disease. Arq Neuropsiquiatr. 2018; 76(6):399-410.

[60] Vela L, Martínez Castrillo JC, García Ruiz P, et al. The high prevalence of impulse control behaviors in patients with early-onset Parkinson's disease: a cross-sectional multicenter study. J Neurol Sci. 2016; 368:150-154.

[61] Averbeck BB, O'Sullivan SS, Djamshidian A. Impulsive and compulsive behaviors in Parkinson's disease. Annu Rev Clin Psychol. 2014; 10:553-580.

[62] Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical spectrum of impulse control disorders in Parkinson's disease. Mov Disorders. 2015; 30(2):121-127.

[63] Holtz NA, Tedford SE, Persons AL, Grasso SA, Napier TC. Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2016; 70:77-84.

[64] Merola A, Romagnolo A, Comi C, et al. Prevalence and burden of dysautonomia in advanced Parkinson's disease. Mov Disorders. 2017; 32(5):796-797.

[65] Postuma RB, Gagnon JF, Pelletier A, Montplaisir J. Prodromal autonomic symptoms and signs in Parkinson's disease and dementia with Lewy bodies. Mov Disorders. 2013; 28(5):597-604.

[66] Umehara T, Oka H, Nakahara A, Matsuno H, Toyoda C. High norepinephrinergic orthostatic hypotension in early Parkinson's disease. Parkinsonism Rel Disord. 2018; 55:97-102.

[67] Bhanu C, Nimmons D, Petersen I, et al. Drug-induced orthostatic hypotension: a systematic review and meta-analysis of randomised controlled trials. PLoS Med. 2021; 18(11):e1003821.

[68] Usnich T, Hanssen H, Lohmann K, et al. Pronounced orthostatic hypotension in GBA-related Parkinson's disease. Journal of Parkinson's Disease. 2022; 12(5):1539-1544.

[69] Yoritaka A, Shimo Y, Hatano T, Hattori N. Motor/nonmotor symptoms and progression in patients with Parkinson's disease: prevalence and risks in a longitudinal study. Parkinson's Disease. 2020; 2020:1-13.

[70] Espay AJ, LeWitt PA, Hauser RA, Merola A, Masellis M, Lang AE. Neurogenic orthostatic hypotension and supine hypertension in Parkinson's disease and related synucleinopathies: prioritisation of treatment targets. Lancet Neurol. 2016; 15(9):954-966.

[71] Fanciulli A, Campese N, Goebel G, et al. Association of transient orthostatic hypotension with falls and syncope in patients with Parkinson disease. Neurology. 2020; 95(21):e2854-e2865.

[72] Zhu S, Li H, Xu X, et al. The pathogenesis and treatment of cardiovascular autonomic dysfunction in Parkinson's disease: what we know and where to go. Aging Dis. 2021; 12(7):1675-1692.

[73] Wood H. A new scale to assess gastrointestinal dysfunction in Parkinson disease. Nat Rev Neurol. 2021; 17(8):462.

[74] Klingelhoefer L, Reichmann H. Pathogenesis of Parkinson disease--the gut-brain axis and environmental factors. Nat Rev Neurol. 2015; 11(11):625-636.

[75] Esteves AR, Munoz-Pinto MF, Nunes-Costa D, et al. Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria. Gut. 2023; 72(1):73-89.

[76] Yang X, Zhou R, Di W, He Q, Huo Q. Clinical therapeutic effects of probiotics in patients with constipation associated with Parkinson disease: a protocol for systematic review and meta-analysis. Medicine. 2021; 100(44):e27705.

[77] Fasano A, Visanji NP, Liu LWC, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 2015; 14(6):625-639.

[78] Rodríguez-Violante M, de Saráchaga AJ, Cervantes-Arriaga A, et al. Self- perceived pre-motor symptoms load in patients with Parkinson's disease: a retrospective study. J Parkinsons Dis. 2016; 6(1):183-190.

[79] Pellegrini C, Fornai M, D'Antongiovanni V, Antonioli L, Bernardini N, Derkinderen P. The intestinal barrier in disorders of the central nervous system. Lancet Gastroenterol Hepatol. 2023; 8(1):66-80.

[80] Huang H, Xu H, Luo Q, et al. Fecal microbiota transplantation to treat Parkinson's disease with constipation: a case report. Medicine. 2019; 98(26):e16163.

[81] Tian H, Wang J, Feng R, et al. Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-richardson's syndrome: a phase 2, single centre, randomised clinical trial. EClinicalMedicine. 2023; 58:101888.

[82] Uchiyama T, Sakakibara R, Yamamoto T, et al. Urinary dysfunction in early and untreated Parkinson's disease. J Neurol Neurosurg Psychiatry. 2011; 82(12):1382-1386.

[83] Scott GD, Lim MM, Drake MG, Woltjer R, Quinn JF. Onset of skin, gut, and genitourinary prodromal Parkinson's disease: a study of 1.5 million veterans. Mov Disorders. 2021; 36(9):2094-2103.

[84] Guo X, Song W, Chen K, et al. Gender and onset age-related features of non-motor symptoms of patients with Parkinson's disease--a study from southwest China. Parkinsonism Rel Disord. 2013; 19(11):961-965.

[85] Özcan T, Benli E, Özer F, Demir EY, Kaya Y, Ayyıldız A. The association between symptoms of sexual dysfunction and age at onset in Parkinson's disease. Clin Auton Res. 2016; 26(3):205-209.

[86] Peelaerts W, Mercado G, George S, et al. Urinary tract infections trigger synucleinopathy via the innate immune response. Acta Neuropathol. 2023; 145(5):541-559.

[87] Ng YF, Chen CYT, Chia GTH, Tan BBJW, Chan LL, Tan EK. The association between Parkinson's disease and sexual dysfunction: clinical correlation and therapeutic implications. Ageing Res Rev. 2022; 79:101665.

[88] Diaconu Ş, Falup-Pecurariu C. Personalized assessment of insomnia and sleep quality in patients with Parkinson's disease. J Pers Med. 2022; 12(2):322.

[89] Fifel K, Yanagisawa M, Deboer T. Mechanisms of sleep/wake regulation under hypodopaminergic state: insights from MitoPark mouse model of Parkinson's disease. Adv Sci. 2023; 10(5):e2203170.

[90] Stefani A, Högl B. Sleep disorders in Parkinson disease. Sleep Med Clin. 2021; 16(2):323-334.

[91] Arnulf I. Ideas that come at night: on sleep research in 2022. Lancet Neurol. 2023; 22(1):23-24.

[92] Mahale R, Yadav R, Pal PK. Rapid eye movement sleep behaviour disorder in young- and older-onset Parkinson disease: a questionnaire-based study. Sleep Med. 2014; 15(6):642-646.

[93] Mahale R, Yadav R, Pal PK. Quality of sleep in young onset Parkinson's disease: any difference from older onset Parkinson's disease. Parkinsonism Rel Disord. 2015; 21(5):461-464.

[94] Jurcau A, Nunkoo VS. Clinical markers May identify patients at risk for early Parkinson's disease dementia: a prospective study. Am J Alzheimers Dis Other Demen. 2021; 36:153331752110213.

[95] Koychev I, Okai D. Cognitive-behavioural therapy for non-motor symptoms of Parkinson's disease: a clinical review. Evidence Based Mental Health. 2017; 20(1):15-20.

[96] Bohnen NI, Yarnall AJ, Weil RS, et al. Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches. The Lancet Neurol. 2022; 21(4):381-392.

[97] Ricciardi L, Bove F, Espay KJ, et al. 24-Hour infusion of levodopa/carbidopa intestinal gel for nocturnal akinesia in advanced Parkinson's disease. Mov Disorders. 2016; 31(4):597-598.

[98] Suzuki K. Current update on clinically relevant sleep issues in Parkinson's disease: a narrative review. J Parkinsons Dis. 2021; 11(3):971-992.

[99] Luppi PH, Clément O, Sapin E, et al. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev. 2011; 15(3):153-163.

[100] Pena-Pereira MA, Sobreira-Neto MA, Sobreira E, et al. Validation of the Brazilian Portuguese version of the rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ-BR). Arq Neuropsiquiatr. 2020; 78(10):629-637.

[101] Zhou Z, Zhou X, Xiang Y, et al. Subtyping of early-onset Parkinson's disease using cluster analysis: a large cohort study. Front Aging Neurosci. 2022; 14:1040293.

[102] Zhou X, Liu Z, Zhou X, et al. The Chinese Parkinson's disease registry (CPDR): study design and baseline patient characteristics. Mov Disorders. 2022; 37(7):1335-1345.

[103] Byun JI, Shin YY, Seong YA, et al. Comparative efficacy of prolonged-release melatonin versus clonazepam for isolated rapid eye movement sleep behavior disorder. Sleep Breathing. 2023; 27(1):309-318.

[104] Hadi F, Agah E, Tavanbakhsh S, et al. Safety and efficacy of melatonin, clonazepam, and trazodone in patients with Parkinson's disease and sleep disorders: a randomized, double-blind trial. Neurol Sci. 2022; 43(10):6141-6148.

[105] Hershey LA, Coleman-Jackson R. Pharmacological management of dementia with Lewy bodies. Drugs Aging. 2019; 36(4):309-319.

[106] Shen Y, Yu WB, Shen B, et al. Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice. Brain. 2020; 143(11):3374-3392.

[107] Yang X, Liu B, Shen H, et al. Prevalence of restless legs syndrome in Parkinson's disease: a systematic review and meta-analysis of observational studies. Sleep Med. 2018; 43:40-46.

[108] Laslett LL, Honan C, Turner JA, et al. Poor sleep and multiple sclerosis: associations with symptoms of multiple sclerosis and quality of life. J Neurol Neurosurg Psychiatry. 2022; 93:1162-1165.

[109] Achebe MO, Mandell E, Jolley K, et al. Pagophagia and restless legs syndrome are highly associated with iron deficiency and should be included in histories evaluating anemia. Am J Hematol. 2023; 98(1):E8-e10.

[110] Calne SM, Lidstone SC, Kumar A. Psychosocial issues in young-onset Parkinson's disease: current research and challenges. Parkinsonism Rel Disord. 2008; 14(2):143-150.

[111] Winkelman JW, Wipper B, Zackon J. Long-term safety, dose stability, and efficacy of opioids for patients with restless legs syndrome in the National RLS opioid registry. Neurology. 2023; 100(14):e1520-e1528.

[112] Bezard E. Models of hyperkinetic disorders in primates. J Neurosci Methods. 2020; 332:108551.

[113] Santos-García D, Aneiros-Díaz A, Macias-Arribi M, Llaneza-González MA, Abella-Corral J, Santos-Canelles H. Sensory symptoms in Parkinson's disease. Rev Neurol. 2010; 50(suppl 2):S65-S74.

[114] Schrag A, Bohlken J, Dammertz L, et al. Widening the spectrum of risk factors, comorbidities, and prodromal features of Parkinson disease. JAMA Neurol. 2023; 80(2):161-171.

[115] Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ESrecommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013; 20(1):16-34.

[116] He R, Zhao Y, He Y, et al. Olfactory dysfunction predicts disease progression in Parkinson's disease: a longitudinal study. Front Neurosci. 2020; 14:569777.

[117] Casjens S, Eckert A, Woitalla D, et al. Diagnostic value of the impairment of olfaction in Parkinson's disease. PLoS One. 2013; 8(5):e64735.

[118] Doty RL. Olfaction in Parkinson's disease and related disorders. Neurobiol Dis. 2012; 46(3):527-552.

[119] Landis BN, Burkhard PR. Rhinorrhea and olfaction in Parkinson disease. Neurology. 2008; 71(13):1041-1042 author reply 1042

[120] Quinn NP, Rossor MN, Marsden CD. Olfactory threshold in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1987; 50(1):88-89.

[121] Santin R, Fonseca VF, Bleil CB, Rieder CRM, Hilbig A. Olfactory function and Parkinson's disease in Southern Brazil. Arq Neuropsiquiatr. 2010; 68(2):252-257.

[122] Kim W, Tripathi M, Kim C, et al. An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models. Nat Commun. 2023; 14(1):4283.

[123] Valkovic P, Minar M, Singliarova H, et al. Pain in Parkinson's disease: a cross-sectional study of its prevalence, types, and relationship to depression and quality of life. PLoS One. 2015; 10(8):e0136541.

[124] Tinazzi M, Recchia S, Simonetto S, et al. Muscular pain in Parkinson's disease and nociceptive processing assessed with CO₂ laser-evoked potentials. Mov Disorders. 2010; 25(2):213-220.

[125] Brown CA, El-Deredy W, Jones AKP. When the brain expects pain: common neural responses to pain anticipation are related to clinical pain and distress in fibromyalgia and osteoarthritis. Eur J Neurosci. 2014; 39(4):663-672.

[126] Defazio G, Tinazzi M, Berardelli A. How pain arises in Parkinson's disease? Eur J Neurol. 2013; 20(12):1517-1523.

[127] Eryilmaz IE, Erer S, Zarifoglu M, et al. Contribution of functional dopamine D2 and D3 receptor variants to motor and non-motor symptoms of early onset Parkinson's disease. Clin Neurol Neurosurg. 2020; 199:106257.

[128] Ashkan K, Rogers P, Bergman H, Ughratdar I. Insights into the mechanisms of deep brain stimulation. Nat Rev Neurol. 2017; 13(9):548-554.

[129] Florin E, Koschmieder KC, Schnitzler A, Becker S. Recovery of impaired endogenous pain modulation by dopaminergic medication in Parkinson's disease. Mov Disorders. 2020; 35(12):2338-2343.

[130] Campos ACP, Berzuino MB, Hernandes MS, Fonoff ET, Pagano RL. Monoaminergic regulation of nociceptive circuitry in a Parkinson's disease rat model. Exp Neurol. 2019; 318:12-21.

[131] Hannaway N, Zarkali A, Leyland LA, et al. Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2023; 94:742-750.

[132] Zarkali A, McColgan P, Leyland LA, Lees AJ, Weil RS. Longitudinal thalamic White and grey matter changes associated with visual hallucinations in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2022; 93(2):169-179.

[133] Tang L, Xu N, Huang M, et al. A primate nigrostriatal Atlas of neuronal vulnerability and resilience in a model of Parkinson's disease. Nat Commun. 2023; 14(1):7497.

[134] Alves JN, Westner BU, Højlund A, Weil RS, Dalal SS. Structural and functional changes in the retina in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2023; 94(6):448-456.

[135] Feitosa-Santana C, Fernandes Costa M, Ballalai Ferraz H, et al. Visual losses in early-onset and late-onset Parkinson's disease. J Opt Soc Am A. 2020; 37(5):A285-A293.

[136] Gasser T. Genetic basis of Parkinson's disease: inheritance, penetrance, and expression. Appl Clin Genet. 2011; 4:67-80.

[137] Song J, Shen B, Yang YJ, et al. Non-motor symptoms in Parkinson's disease patients with parkin mutations: more depression and less executive dysfunction. J Mol Neurosci. 2020; 70(2):246-253.

[138] Wang Y, Wu JJ, Liu FT, et al. Olfaction in parkin carriers in Chinese patients with Parkinson disease. Brain Behav. 2017; 7(5):e00680.

[139] Imberechts D, Kinnart I, Wauters F, et al. DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy. Brain. 2022; 145(12):4368-4384.

[140] Riboldi GM, Vialle RA, Navarro E, et al. Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease. Mol Neurodegener. 2022; 17(1):52.

[141] Li R, Lu Y, Zhang Q, et al. Piperine promotes autophagy flux by P2RX4 activation in SNCA/α-synuclein-induced Parkinson disease model. Autophagy. 2022; 18(3):559-575.

[142] Abu Manneh R, Chairta PP, Mitsi E, et al. Genetic study of early onset Parkinson's disease in Cyprus. Int J Mol Sci. 2022; 23(23):15369.

[143] Xu Q, Guo H, Zhang X, et al. Hypoxia regulation of ATP13A2 (PARK9) gene transcription. J Neurochem. 2012; 122(2):251-259.

[144] Simuni T, Uribe L, Cho HR, et al. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's progression markers initiative (PPMI): a cross-sectional study. Lancet Neurol. 2020; 19(1):71-80.

[145] Quadalti C, Palmqvist S, Hall S, et al. Clinical effects of Lewy body pathology in cognitively impaired individuals. Nat Med. 2023; 29:1964-1970.

[146] Hattori N, Mizuno Y. Pathogenetic mechanisms of parkin in Parkinson's disease. The Lancet. 2004; 364(9435):722-724.

[147] Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol. 2001; 50(3):293-300.

[148] Kalinderi K, Bostantjopoulou S, Fidani L. The genetic background of Parkinson's disease: current progress and future prospects. Acta Neurol Scand. 2016; 134(5):314-326.

[149] Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet. 2000; 25(3):302-305.

[150] van de Warrenburg BPC, Lammens M, Lücking CB, et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology. 2001; 56(4):555-557.

[151] Chung KKK, Zhang Y, Lim KL, et al. Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature Med. 2001; 7(10):1144-1150.

[152] Samaranch L, Lorenzo-Betancor O, Arbelo JM, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain. 2010; 133(Pt 4):1128-1142.

[153] Xiao B, Tan EK. Thalamic pathways mediating motor and non-motor symptoms in a Parkinson's disease model. Trends Neurosci. 2023; 46(1):1-2.

[154] Angelopoulou E, Bozi M, Simitsi A-M, et al. Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: data analysis of the hellenic biobank of Parkinson's disease. J Neurol Sci. 2022; 442:120405.

[155] De Carolis L, Galli S, Bianchini E, et al. Age at onset influences progression of motor and non-motor symptoms during the early stage of Parkinson's disease: a monocentric retrospective study. Brain Sci. 2023; 13(2):157.

[156] Zhang Z, Liu G, Wang D, et al. Effect of onset age on the levodopa threshold dosage for dyskinesia in Parkinson's disease. Neurol Sci. 2022; 43(5):3165-3174.

[157] de Carvalho Aguiar P, Lessa PS, Junior Jr., CG, et al. Genetic and environmental findings in early-onset Parkinson's disease Brazilian patients. Mov Disorders. 2008; 23(9):1228-1233.

[158] Liu J, Leng J, Zhang X, et al. Investigation of non-motor symptoms in first-degree relatives of patients with Parkinson's disease. Parkinsonism Rel Disord. 2018; 52:62-68.

[159] Sun YM, Yu HL, Zhou XY, et al. Disease progression in patients with parkin-related Parkinson's disease in a longitudinal cohort. Mov Disorders. 2021; 36(2):442-448.

[160] Xiao Y, Ou R, Yang T, et al. Different associated factors of subjective cognitive complaints in patients with early- and late-onset Parkinson's disease. Front Neurol. 2021; 12:749471.

[161] Santos García D, de Deus Fonticoba T, Cores C, et al. Predictors of clinically significant quality of life impairment in Parkinson's disease. npj Parkinson's Disease. 2021; 7(1):118.

[162] Dadu A, Satone V, Kaur R, et al. Identification and prediction of Parkinson's disease subtypes and progression using machine learning in two cohorts. npj Parkinson's Disease. 2022; 8(1):172.

[163] Gavelin HM, Domellöf ME, Leung I, et al. Computerized cognitive training in Parkinson's disease: a systematic review and meta-analysis. Ageing Res Rev. 2022; 80:101671.

[164] Broxmeyer L. Parkinson's: another look. Med Hypotheses. 2002; 59(4):373-377.

[165] Berstad K, Berstad JER. Parkinson's disease; the hibernating spore hypothesis. Med Hypotheses. 2017; 104:48-53.

[166] Caputi V, Giron MC. Microbiome-gut-brain axis and toll-like receptors in Parkinson's disease. Int J Mol Sci. 2018; 19(6):1689.

[167] Ahmad MH, Rizvi MA, Ali M, Mondal AC. Neurobiology of depression in Parkinson's disease: insights into epidemiology, molecular mechanisms and treatment strategies. Ageing Res Rev. 2023; 85:101840.

[168] Zhang W, Deng B, Xie F, et al. Efficacy of repetitive transcranial magnetic stimulation in Parkinson's disease: a systematic review and meta-analysis of randomised controlled trials. EClinicalMedicine. 2022; 52:101589.

[169] Titova N, Chaudhuri KR. Non-motor Parkinson disease: new concepts and personalised management. Med J Aust. 2018; 208(9):404-409.

[170] Bang Y, Lim J, Choi HJ. Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson's disease: clues to early diagnosis and effective treatment. Arch Pharmacal Res. 2021; 44(6):588-604.

[171] Abou Kassm S, Naja W, Haddad R, Pelissolo A. The relationship between anxiety disorders and Parkinson's disease: clinical and therapeutic issues. Curr Psychiatry Rep. 2021; 23(4):20.

[172] Fabbri M, Caldas AC, Ramos JB, et al. Moving towards home-based community-centred integrated care in Parkinson's disease. Parkinsonism Rel Disord. 2020; 78:21-26.

[173] Meira B, Lhommée E, Schmitt E, et al. Early Parkinson's disease phenotypes tailored by personality, behavior, and motor symptoms. J Parkinsons Dis. 2022; 12(5):1665-1676.

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