No CrossRef data available.
Article contents
Prodromal Association of Non-Motor Symptomatology in Adults With Neurodegenerative Diseases
Published online by Cambridge University Press: 22 September 2025
Abstract
Background:
Early diagnosis of neurodegenerative diseases (NDs) is a priority with the advent of disease-modifying therapies. The study of prodromal non-motor symptoms (NMS) in ND could help guide early diagnosis, facilitating adequate treatment. The primary objective of this study was to determine the prodromal association between NMS and ND.
Methods:
A retrospective cohort study was planned. Records of subjects attending the movement disorders and NDs unit from Hospital Civil de Guadalajara “Fray Antonio Alcalde,” from 2012 to January 2025, were evaluated. Subjects with NMSQuest questionnaire in ND were included. Descriptive and inferential parametric statistics (Student’s t-test for independent samples and ANOVA) were used, and odds ratios (OD) with 95% confidence interval were calculated using binary logistic regression. A p value < 0.05 was considered significant.
Results:
The most frequent prodromal NMS in ND were depression, constipation, insomnia, anxiety and pain. There was an average of 7.7 ± 7.6 years of prodromal NMS prior to the diagnosis of ND. Prodromal depression [OR 1.9 (1.1–3.5 p < 0.001) and confusion/delusional thoughts [OR 7.2 (1.3–39.2) p = 0.02] were associated with dementia (time onset prior to diagnosis 9.9 ± 12.2 and 5.5 ± 9.7 years, respectively). Prodromal restless legs syndrome was associated with movement disorders [OR 3.3 (1.1–9.7) p = 0.02] (time onset 4.7 ± 6.9 years prior to diagnosis).
Conclusion:
Evidence points to a potential association of prodromal NMS in ND. Prospective studies are required to confirm and characterize the association between prodromal NMS and ND, as their early identification may contribute to the timely diagnosis of ND.
Résumé
Association avec des symptômes non moteurs en phase prodromique chez des adultes atteints de maladies neurodégénératives.
Le diagnostic précoce des maladies neurodégénératives (MND) est une priorité avec l’avènement des traitements modificateurs de la maladie (TMM). L’étude des symptômes non moteurs (SNM) en phase prodromiques dans le cas des MND pourrait aider à orienter les diagnostics précoces, facilitant ainsi un traitement adéquat. L’objectif principal de cette étude était donc, dans le cas des MND, de déterminer l’association avec des SNM en phase prodromique.
Une étude de cohorte rétrospective a été planifiée. Les dossiers de sujets ayant fréquenté de 2012 à janvier 2025 le service des troubles du mouvement et des MND de l’hôpital Fray Antonio Alcalde de Guadalajara ont été évalués. Les sujets ayant répondu au Non-Motor Symptoms Questionnaire (NMSQ) dans le cas de la maladie de Parkinson ont été inclus. Des statistiques paramétriques descriptives et inférentielles (test de Student pour des échantillons indépendants et ANOVA) ont été utilisées, tandis que le rapport de cotes (RC) avec un intervalle de confiance à 95 % a été calculé à l’aide d’une régression logistique binaire. Une valeur de p < 0,05 a été considérée comme significative.
Dans le cas de la maladie de Parkinson (MP), les SNM les plus fréquents en phase prodromique étaient la dépression, la constipation, l’insomnie, l’anxiété et la douleur. La durée moyenne de ces SNM avant un diagnostic de MP était de 7,7 ± 7,6 ans. La dépression en phase prodromique [RC 1,9 (1,1 – 3,5) ; p < 0,001 , de même que la confusion et des pensées délirantes [RC 7,2 (1,3 – 39,2) ; p = 0,02] étaient associées à la démence (début avant le diagnostic de 9,9 ± 12,2 et 5,5 ± 9,7 ans respectivement). Le syndrome des jambes sans repos en phase prodromique était par ailleurs associé à des troubles du mouvement [RC 3,3 (1,1 – 9,7) ; p = 0,02] dont les débuts étaient de 4,7 ± 6,9 ans avant un diagnostic.
Les données disponibles indiquent une association potentielle entre les SNM en phase prodromique et les MND. Des études prospectives sont certes nécessaires pour confirmer et caractériser cette association, car leur identification précoce pourrait contribuer au diagnostic précoce des MND.
Information
- Type
- Original Article
- Information
- Copyright
- © The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation
References
Willson, DM, Cookson, MR, Den Bosch, LV, Zetterberg, H, Holtzman, DM. Hallmarks of neurodegenerative diseases. CellPress. 2023;186(4):693–714. https://doi.org/10.1016/j.cell.2022.12.032.Google Scholar
Steinmetz, JD, Seeher, KM, Schiess, N, et al. GBD 2021 Nervous System Disorders Collaborators. “Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet Neurol. 2024;23(4):344–381. https://doi.org/10.1016/S1474-4422(24)00038-3.Google Scholar
World Health Organization. Dementia,” WHO. [Online]. Accessed 31 Octubre 2024. https://www.who.int/news-room/fact-sheets/detail/dementia.Google Scholar
Tanner, CM, Ostrem, JL. Parkinsons disease. N Engl J Med. 2024;391(5):442–452. https://doi.org/10.1056/NEJMra2401857.Google Scholar
Rodriguez-Blazquez, C, Schrag, A, Rizos, A, Chudhuri, KR, Martínez-Martín, P, Weintraub, D. Prevalence of non-motor symptoms and non-motor fluctuations in parkinsons disease using the MDS-NMS. Mov Disord Clin Pract. 2020;8(2):231–239. https://doi.org/10.1002/mdc3.13122.Google Scholar
Chaudhuri, KR, Martínez Martin, P, Schapira, A, et al. International multicenter pilon study of the first comprehensive self-completed nonmotor symptoms questionnaire for parkinsons disease: the NMSQuest study. Movement Disord. 2006;21(7):916–923. https://doi.org/10.1002/mds.20844.Google Scholar
Rios Romenets, S, Wolfson, C, Galatas, C, et al. Validation of the non-motor symptoms questionnaire (NMS-quest). Parkinsonism and Relat Disord. 2012;18(1):54–58. https://doi.org/10.1016/j.parkreldis.2011.08.013.Google Scholar
Feng, Q, Liu, H, Zhang, H, et al. Objetive assessment of hyposmia in alzheimer’s disease from image and behavior by combining pleasant odor with unpleasant odor. Front Neurol. 2021;12:697487. https://doi.org/10.3389/fneur.2021.697487.Google Scholar
Bollinger, R, Keleman, A, Thompson, R, et al. Falls: a marker of preclinical alzheimer disease: a cohort study protocol. BMJ Open. 2021;11(9):e050820. https://doi.org/10.1136/bmjopen-2021-050820.Google Scholar
Nakase, T, Tatewaki, Y, Thyreau, B, et al. Impact of constipation on progression of alzheimer’s disease: a retrospective study. Cns Neurosci Ther. 2022;28(12):1964–1973. https://doi.org/10.1111/cns.13940.Google Scholar
Khalid, S, Sambamoorthi, U, Umer, A, Lilly, CL, Gross, DK, Innes, KE. Increased odds of incident alzheimers disease and related dementias in presence of common non-cancer chronic pain conditions in appalachian older adults. J Aging Health. 2022;34(2):158–172. https://doi.org/10.1177/08982643211036219.Google Scholar
Galbiati, A, Carli, G, Hensley, M, Ferini-Strambi, L. REM sleep behavior disorder and alzheimers disease: definitely no relationship? J Alzheimers Dis. 2018;63(1):1–11. https://doi.org/10.3233/JAD-171164.Google Scholar
Johanssson, M, Stomrud, E, Lindberg, O, et al. Apathy and anxiety are early markers of alzheimer’s disease. Neurobiol Aging. 2020;85:74–82. https://doi.org/10.1016/j.neurobiolaging.2019.10.008.Google Scholar
Bronner, G, Aharon-Peretz, J, Hassin-Baer, S. Sexuality in patients with parkinsons disease, alzheimers disease, and other dementias. Handb Clin Neurol. 2015;130(17):297–323. Chapter 17. https://doi.org/10.1016/B978-0-444-63247-0.00017-1.Google Scholar
Morrow, CB, Leousakos, J, Yan, H, Onyike, C, Kamath, V. Weight change and neuropsychiatric symptoms in alzheimers disease and frontotemporal dementia: associations with cognitive decline. J Alzheimers Dis Rep. 2023;7(1):767–774. https://doi.org/10.3233/ADR-230034.Google Scholar
Moscovich, M, Heinzel, S, Postuma, RB, et al. How specific ar non-motor symptoms in the prodrome of parkinsons disease compared to other movement disorders? Parkinsonism Relat Disord. 2020;81:213–218. https://doi.org/10.1016/j.parkreldis.2020.10.003.Google Scholar
Isik, AT, Kocyigit, SE, Aydin, AE, Soysal, P. A comparison of the prevalence of orthostatic hypotension between older patients with alzheimer’s disease, Lewy body dementia, and without dementia. Exp Gerontol. 2019;124:110628. https://doi.org/10.1016/j.exger.2019.06.001.Google Scholar
Campese, N, Caliò, B, Leys, F, et al. Pain in multiple system atrophy a systematic review and meta-analysis. Mov Disord Clin Pract. 2023;10(12):1738–1749. https://doi.org/10.1002/mdc3.13897.Google Scholar
Painous, C, Martí, MJ, Simonet, C, et al. Prediagnostic motor and non-motor symptoms in progressive supranuclear palsy: the step-back PSP study. Parkinsonism Relat Disord. 2020;74:67–73. https://doi.org/10.1016/j.parkreldis.2020.03.003.Google Scholar
Shojaie, A, Rota, S, Al Khleifat, A, Chaudhuri, KR, Al-Chalabi, A. Non-motor symptoms in amyotrophic lateral sclerosis: lessons from parkinsons disease. Amyotroph La Scl Fr Degeneration. 2023;24(7–8):562–571. https://doi.org/10.1080/21678421.2023.2220748.Google Scholar
Beakelandt, V, Lobbestael, E. Disease-modifying targets in neurodegenerative disorders. Paving the way for disease-modifying therapies, scienceDirect. Elsevier Inc; 2017.Google Scholar
Carvalho, DZ, St. Louis, EK, Boeve, BF, et al. Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middle-aged and older adults. Sleep Med. 2017;32:236–243. https://doi.org/10.1016/j.sleep.2016.08.023.Google Scholar
Ashraf Hamad, A, Ehab Amer, B, Bushara Abbas, N, Zakria Alnajjar, A, Meshref, M. Prevalence and correlates of fatigue in amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2024;45(2):485–493. https://doi.org/10.1007/s10072-023-07119-7.Google Scholar
Cófreces, P, Ofman, SD, Estay, JA, Hermida, PD. Parkinsons disease: a bibliographic update of psychosocial aspects. Revista de la Facultad de Ciencias Médicas de Córdoba. 2022;79(2):181–187. https://doi.org/10.31053/1853.0605.v79.n2.33610.Google Scholar
Jaakkola, E, Joutsa, J, Mäkinen, E, et al. Burden of non-motor symptoms in unclear parkinsonism and tremor: a study with [123I]FP-CIT SPECT. J Neurol Sci. 2019;404:124–127. https://doi.org/10.1016/j.jns.2019.07.025.Google Scholar
Raj, J, Beena, V, George, J. Assessment of non motor symptoms in parkinsonism syndromes. J Neurol Sci. 2021;429: 118056. https://doi.org/10.1016/j.jns.2021.119596.Google Scholar
Livingston, G, Huntley, J, Liu, KY, et al. Dementia prevention, intervention, and care: 2024 report of the lancet standing commission. The Lancet Commissions. 2024;404(10452):572–628. https://doi.org/10.1016/S0140-6736(24)01296-0.Google Scholar
McKeith, IG, Ferman, TJ, Thomas, AJ, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94(17):743–755. https://doi.org/10.1212/WNL.0000000000009323.Google Scholar
Stella, F, Radanovic, M, Balthazar, MLF, Canineu, PR, de Souza, LC, Forlenza, OV. Neuropsychiatric symptoms in the prodromal stages of dementia. Curr Opin Psychiatr. 2014;27(3):230–235. https://doi.org/10.1097/YCO.0000000000000050.Google Scholar
De Silva, R, Makawita, C, Al-Sami, Y, Aslanyan, A, Ananthavarathan, P, Malek, N. Non-motor symptoms (NMS) in progresive cerebellar ataxia. J Neurol Sci. 2023;455:121048. https://doi.org/10.1016/j.jns.2023.121141.Google Scholar
Peall, KJ, Kuiper, A, de Koning, TJ, Tijssen, MAJ. Non-motor symptoms in genetically defined dystonia: homogenous groups require systematic assessment. Parkinsonism Relat Disord. 2015;21(9):1031–1040. https://doi.org/10.1016/j.parkreldis.2015.07.003.Google Scholar
Louis, ED. Non-motor symptoms in essential tremor: a review of the current data aand state of the field. Parkinsonism Relat Disord. 2016;22Suppl 1(01):S115–S118. https://doi.org/10.1016/j.parkreldis.2015.08.034.Google Scholar