Abstract
The background of this study is to investigate whether striatal dopamine depletion patterns (selective involvement in the sensorimotor striatum or asymmetry) are associated with motor deficits in Parkinson’s disease (PD). We enrolled 404 drug-naïve patients with early stage PD who underwent dopamine transporter (DAT) imaging. After quantifying DAT availability in each striatal sub-region, principal component (PC) analysis was conducted to yield PCs representing the spatial patterns of striatal dopamine depletion. Subsequently, multivariate linear regression analysis was conducted to investigate the relationship between striatal dopamine depletion patterns and motor deficits assessed using the Unified PD Rating Scale Part III (UPDRS-III). Mediation analyses were used to evaluate whether dopamine deficiency in the posterior putamen mediated the association between striatal dopamine depletion patterns and parkinsonian motor deficits. Three PCs indicated patterns of striatal dopamine depletion: PC1 (overall striatal dopamine deficiency), PC2 (selective dopamine loss in the sensorimotor striatum), and PC3 (symmetric dopamine loss in the striatum). Multivariate linear regression analysis revealed that PC1 (β = − 1.605, p < 0.001) and PC2 (β = 3.201, p < 0.001) were associated with motor deficits (i.e., higher UPDRS-III scores in subjects with severe dopamine depletion throughout the whole striatum or more selective dopamine loss in the sensorimotor striatum), whereas PC3 was not (β = − 0.016, p = 0.992). Mediation analyses demonstrated that the effects of PC1 and PC2 on UPDRS-III scores were indirectly mediated by DAT availability in the posterior putamen, with a non-significant direct effect. Dopamine deficiency in the posterior putamen was most relevant to the severity of motor deficits in patients with PD, while the spatial patterns of striatal dopamine depletion were not a key determinant.
Similar content being viewed by others
References
Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington Clinical, morphological and neurochemical correlations. J Neurol Sci 20(4):415–455
Bezard E, Gross CE (1998) Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach. Prog Neurobiol 55(2):93–116. https://doi.org/10.1016/s0301-0082(98)00006-9
Bezard E, Boraud T, Bioulac B, Gross CE (1997) Compensatory effects of glutamatergic inputs to the substantia nigra pars compacta in experimental parkinsonism. Neuroscience 81(2):399–404. https://doi.org/10.1016/s0306-4522(97)00226-1
Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21(17):6853–6861. https://doi.org/10.1523/jneurosci.21-17-06853.2001
Bezard E, Gross CE, Brotchie JM (2003) Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci 26(4):215–221. https://doi.org/10.1016/s0166-2236(03)00038-9
Blesa J, Juri C, Garcia-Cabezas MA, Adanez R, Sanchez-Gonzalez MA, Cavada C, Obeso JA (2011) Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson’s disease. Front Syst Neurosci 5:92. https://doi.org/10.3389/fnsys.2011.00092
Blesa J, Trigo-Damas I, Dileone M, Del Rey NL, Hernandez LF, Obeso JA (2017) Compensatory mechanisms in Parkinson’s disease: Circuits adaptations and role in disease modification. Exp Neurol 298(Pt B):148–161. https://doi.org/10.1016/j.expneurol.2017.10.002
Bruck A, Aalto S, Rauhala E, Bergman J, Marttila R, Rinne JO (2009) A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson’s disease shows nonlinear progression in the putamen. Mov Disord 24(7):1009–1015. https://doi.org/10.1002/mds.22484
Bu M, Farrer MJ, Khoshbouei H (2021) Dynamic control of the dopamine transporter in neurotransmission and homeostasis. Npj Parkinson’s Disease. https://doi.org/10.1038/s41531-021-00161-2
Chung SJ, Kim HR, Jung JH, Lee PH, Jeong Y, Sohn YH (2020a) Identifying the Functional Brain Network of Motor Reserve in Early Parkinson’s Disease. Mov Disord 35(4):577–586. https://doi.org/10.1002/mds.28012
Chung SJ, Lee JJ, Lee PH, Sohn YH (2020b) Emerging Concepts of Motor Reserve in Parkinson’s Disease. J Mov Disord 13(3):171–184. https://doi.org/10.14802/jmd.20029
Chung SJ, Lee S, Yoo HS, Lee YH, Lee HS, Choi Y, Lee PH, Yun M, Sohn YH (2020c) Association of the non-motor burden with patterns of striatal dopamine loss in de novo Parkinson’s Disease. J Parkinsons Dis 10(4):1541–1549. https://doi.org/10.3233/jpd-202127
Chung SJ, Yoo HS, Lee YH, Jung JH, Baik K, Ye BS, Sohn YH, Lee PH (2020d) White matter hyperintensities and risk of levodopa-induced dyskinesia in Parkinson’s disease. Ann Clin Transl Neurol 7(2):229–238. https://doi.org/10.1002/acn3.50991
Chung SJ, Yoo HS, Lee YH, Lee HS, Lee PH, Sohn YH (2020e) Initial motor reserve and long-term prognosis in Parkinson’s disease. Neurobiol Aging 92:1–6. https://doi.org/10.1016/j.neurobiolaging.2020.02.028
Chung SJ, Lee PH, Sohn YH, Kim YJ (2021) Glucocerebrosidase Mutations and Motor Reserve in Parkinson’s Disease. J Parkinsons Dis 11(4):1715–1724. https://doi.org/10.3233/jpd-212758
Colloby SJ, McParland S, O’Brien JT, Attems J (2012) Neuropathological correlates of dopaminergic imaging in Alzheimer’s disease and Lewy body dementias. Brain 135(Pt 9):2798–2808. https://doi.org/10.1093/brain/aws211
Djaldetti R, Lorberboym M, Karmon Y, Treves TA, Ziv I, Melamed E (2011) Residual striatal dopaminergic nerve terminals in very long-standing Parkinson’s disease: a single photon emission computed tomography imaging study. Mov Disord 26(2):327–330. https://doi.org/10.1002/mds.23380
Fass B, Butcher LL (1981) Evidence for a crossed nigrostriatal pathway in rats. Neurosci Lett 22(2):109–113. https://doi.org/10.1016/0304-3940(81)90072-0
Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301. https://doi.org/10.1093/brain/114.5.2283
Fiorenzato E, Antonini A, Bisiacchi P, Weis L, Biundo R (2021) Asymmetric dopamine transporter loss affects cognitive and motor progression in Parkinson’s Disease. Mov Disord 36(10):2303–2313. https://doi.org/10.1002/mds.28682
German DC, Manaye KF, Sonsalla PK, Brooks BA (1992) Midbrain dopaminergic cell loss in Parkinson’s disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. Ann N Y Acad Sci 648:42–62
Ham JH, Lee JJ, Kim JS, Lee PH, Sohn YH (2015) Is Dominant-Side Onset Associated With a Better Motor Compensation in Parkinson’s Disease? Mov Disord 30(14):1921–1925. https://doi.org/10.1002/mds.26418
Helmich RC, Derikx LC, Bakker M, Scheeringa R, Bloem BR, Toni I (2009) Spatial remapping of cortico-striatal connectivity in Parkinson’s Disease. Cereb Cortex 20(5):1175–1186. https://doi.org/10.1093/cercor/bhp178
Helmich RC, Thaler A, van Nuenen BF, Gurevich T, Mirelman A, Marder KS, Bressman S, Orr-Urtreger A, Giladi N, Bloem BR, Toni I (2015) Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers. Neurology 84(4):399–406. https://doi.org/10.1212/wnl.0000000000001189
Hilker R, Schweitzer K, Coburger S, Ghaemi M, Weisenbach S, Jacobs AH, Rudolf J, Herholz K, Heiss WD (2005) Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch Neurol 62(3):378–382. https://doi.org/10.1001/archneur.62.3.378
Honkanen EA, Saari L, Orte K, Gardberg M, Noponen T, Joutsa J, Kaasinen V (2019) No link between striatal dopaminergic axons and dopamine transporter imaging in Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.27777
Jeong SH, Lee HS, Jung JH, Baik K, Lee YH, Yoo HS, Sohn YH, Chung SJ, Lee PH (2021) White matter hyperintensities, dopamine loss, and motor deficits in de novo Parkinson’s disease. Mov Disord 36(6):1411–1419
Kang YW, Na DL, Hahn SH (1997) A validity study on the korean mini-mental state examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 15(2):300–308
Kang GA, Bronstein JM, Masterman DL, Redelings M, Crum JA, Ritz B (2005) Clinical characteristics in early Parkinson’s disease in a central California population-based study. Mov Disord 20(9):1133–1142. https://doi.org/10.1002/mds.20513
Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease Pathophysiologic and clinical implications. N Engl J Med 318(14):876–880. https://doi.org/10.1056/nejm198804073181402
Knable MB, Jones DW, Coppola R, Hyde TM, Lee KS, Gorey J, Weinberger DR (1995) Lateralized differences in iodine-123-IBZM uptake in the basal ganglia in asymmetric Parkinson’s disease. J Nucl Med 36(7):1216–1225
Kojovic M, Kassavetis P, Bologna M, Parees I, Rubio-Agusti I, Berardelli A, Edwards MJ, Rothwell JC, Bhatia KP (2015) Transcranial magnetic stimulation follow-up study in early Parkinson’s disease: A decline in compensation with disease progression? Mov Disord 30(8):1098–1106. https://doi.org/10.1002/mds.26167
Kraemmer J, Kovacs GG, Perju-Dumbrava L, Pirker S, Traub-Weidinger T, Pirker W (2014) Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts. Mov Disord 29(14):1767–1773. https://doi.org/10.1002/mds.25975
Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, Wudel J, Pal PK, de la Fuente-Fernandez R, Calne DB, Stoessl AJ (2000) In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 47(4):493–503
Lee CS, Schulzer M, de la Fuente-Fernandez R, Mak E, Kuramoto L, Sossi V, Ruth TJ, Calne DB, Stoessl AJ (2004) Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis. Arch Neurol 61(12):1920–1925. https://doi.org/10.1001/archneur.61.12.1920
Liu SY, Wu JJ, Zhao J, Huang SF, Wang YX, Ge JJ, Wu P, Zuo CT, Ding ZT, Wang J (2015) Onset-related subtypes of Parkinson’s disease differ in the patterns of striatal dopaminergic dysfunction: A positron emission tomography study. Parkinsonism Relat Disord 21(12):1448–1453. https://doi.org/10.1016/j.parkreldis.2015.10.017
Liu FT, Ge JJ, Wu JJ, Wu P, Ma Y, Zuo CT, Wang J (2018) Clinical, dopaminergic, and metabolic correlations in Parkinson Disease: a dual-tracer PET study. Clin Nucl Med 43(8):562–571. https://doi.org/10.1097/rlu.0000000000002148
Mounayar S, Boulet S, Tandé D, Jan C, Pessiglione M, Hirsch EC, Féger J, Savasta M, François C, Tremblay L (2007) A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery. Brain 130(Pt 11):2898–2914. https://doi.org/10.1093/brain/awm208
Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, Lee CS, McKenzie J, McCormick S, Samii A, Troiano A, Ruth TJ, Sossi V, de la Fuente-Fernandez R, Calne DB, Stoessl AJ (2009) Longitudinal progression of sporadic Parkinson’s disease: a multi-tracer positron emission tomography study. Brain 132(Pt 11):2970–2979. https://doi.org/10.1093/brain/awp209
Narang N, Hunt ME, Pundt LL, Alburges ME, Wamsley JK (1993) Unilateral ibotenic acid lesion of the caudate putamen results in D2 receptor alterations on the contralateral side. Exp Neurol 121(1):40–47. https://doi.org/10.1006/exnr.1993.1069
Oh M, Kim JS, Kim JY, Shin KH, Park SH, Kim HO, Moon DH, Oh SJ, Chung SJ, Lee CS (2012) Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med 53(3):399–406. https://doi.org/10.2967/jnumed.111.095224
Perier C, Agid Y, Hirsch EC, Feger J (2000) Ipsilateral and contralateral subthalamic activity after unilateral dopaminergic lesion. NeuroReport 11(14):3275–3278
Pirker W (2003a) Correlation of dopamine transporter imaging with parkinsonian motor handicap: How close is it? Mov Disord 18(S7):S43–S51. https://doi.org/10.1002/mds.10579
Pirker W (2003b) Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it? Mov Disord 18(Suppl 7):S43-51. https://doi.org/10.1002/mds.10579
Roedter A, Winkler C, Samii M, Walter GF, Brandis A, Nikkhah G (2001) Comparison of unilateral and bilateral intrastriatal 6-hydroxydopamine-induced axon terminal lesions: evidence for interhemispheric functional coupling of the two nigrostriatal pathways. J Comp Neurol 432(2):217–229. https://doi.org/10.1002/cne.1098
Saari L, Kivinen K, Gardberg M, Joutsa J, Noponen T, Kaasinen V (2017) Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease. Neurology 88(15):1461–1467. https://doi.org/10.1212/wnl.0000000000003810
Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, Steinling M, Valk J (1993) A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 114(1):7–12. https://doi.org/10.1016/0022-510x(93)90041-v
Schneider JS, Rothblat DS, DiStefano L (1994) Volume transmission of dopamine over large distances may contribute to recovery from experimental parkinsonism. Brain Res 643(1–2):86–91. https://doi.org/10.1016/0006-8993(94)90012-4
Shin H-W, Hong S-W, Youn YC (2022) Clinical aspects of the differential diagnosis of parkinson’s disease and parkinsonism. J Clin Neurol 18(3):259–270
Sun FT, Schriber RA, Greenia JM, He J, Gitcho A, Jagust WJ (2007) Automated template-based PET region of interest analyses in the aging brain. Neuroimage 34(2):608–617. https://doi.org/10.1016/j.neuroimage.2006.09.022
Ter Telgte A, van Leijsen EMC, Wiegertjes K, Klijn CJM, Tuladhar AM, de Leeuw FE (2018) Cerebral small vessel disease: from a focal to a global perspective. Nat Rev Neurol 14(7):387–398. https://doi.org/10.1038/s41582-018-0014-y
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15(1):273–289
van Nuenen BF, van Eimeren T, van der Vegt JP, Buhmann C, Klein C, Bloem BR, Siebner HR (2009) Mapping preclinical compensation in Parkinson’s disease: an imaging genomics approach. Mov Disord 24(Suppl 2):S703-710. https://doi.org/10.1002/mds.22635
Whone A, Moore R, Piccini P, Brooks D (2003) Plasticity of the nigropallidal pathway in Parkinson’s disease. Ann Neurol 53:206–213. https://doi.org/10.1002/ana.10427
Wile DJ, Agarwal PA, Schulzer M, Mak E, Dinelle K, Shahinfard E, Vafai N, Hasegawa K, Zhang J, McKenzie J, Neilson N, Strongosky A, Uitti RJ, Guttman M, Zabetian CP, Ding YS, Adam M, Aasly J, Wszolek ZK, Farrer M, Sossi V, Stoessl AJ (2017) Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol 16(5):351–359. https://doi.org/10.1016/s1474-4422(17)30056-x
Funding
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1I1A1A01059678) and a new faculty research seed money grant of Yonsei University College of Medicine for 2022 (2022–32-0059). Also, this research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HI22C0224).
Author information
Authors and Affiliations
Contributions
Conception of research question/study design (SHJ and SJC); data analysis (SHJ, HSL, and SJC); drafting of manuscript (SHJ and SJC); critical appraisal of manuscript for intellectual content (CWP, YJK, MY, PHL, and YHS). The study sponsors were not involved in the conception of research question/study design, data analysis, and manuscript drafting of critical appraisal of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jeong, S.H., Park, C.W., Lee, H.S. et al. Patterns of striatal dopamine depletion and motor deficits in de novo Parkinson’s disease. J Neural Transm 130, 19–28 (2023). https://doi.org/10.1007/s00702-022-02571-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-022-02571-9