Onset pattern of nigrostriatal denervation in early Parkinson’s disease
Open accessAbstract
The striatal dopaminergic deficit in Parkinson’s disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson’s disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson’s disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson’s disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson’s disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson’s disease and eventually monitor the impact of putative therapies.
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The current understanding of Parkinson's disease pathogenesis suggests that a combination of genetic and environmental factors contributes to progressive neurodegeneration of nigrostriatal dopaminergic neurons in the pars compacta of the substantia nigra, as well as other affected cortical regions.
“The current understanding of PD pathogenesis suggests that a combination of genetic and environmental factors contributes to the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the pars compacta of the substantia nigra, as well as other affected cortical regions [125,126].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [126]
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Cites
Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002) · NeuroImage · doi:10.1006/nimg.2002.1132 · Cited by 11,888 · see citing works
Fast robust automated brain extraction
Smith, S. M. (2002) · Human Brain Mapping · doi:10.1002/hbm.10062 · Cited by 10,496 · see citing works
The organization of the human cerebellum estimated by intrinsic functional connectivity
Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C., & Yeo, B. T. T. (2011) · Journal of Neurophysiology · doi:10.1152/jn.00339.2011 · Cited by 7,304 · see citing works
N4ITK: Improved N3 Bias Correction
Tustison, N. J., Avants, B., Cook, P. A., Zheng, Y., Egan, A., Yushkevich, P. A., & Gee, J. C. (2010) · IEEE Transactions on Medical Imaging · doi:10.1109/tmi.2010.2046908 · Cited by 6,119 · see citing works
The WU-Minn Human Connectome Project: An overview
Van Essen, D. C., Smith, S. M., Barch, D. M., Behrens, T. E. J., Yacoub, E., & Ugurbil, K. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.05.041 · Cited by 5,651 · see citing works
Avants, B., Epstein, C. L., Grossman, M., & Gee, J. C. (2007) · Medical Image Analysis · doi:10.1016/j.media.2007.06.004 · Cited by 5,618 · see citing works
The minimal preprocessing pipelines for the Human Connectome Project
Glasser, M. F., Sotiropoulos, S. N., Wilson, J. A., Coalson, T. S., Fischl, B., Andersson, J. L., Xu, J., Jbabdi, S., Webster, M., Polimeni, J. R., et al. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.04.127 · Cited by 5,253 · see citing works
AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY
FEARNLEY, J. M., & LEES, A. J. (1991) · Brain · doi:10.1093/brain/114.5.2283 · Cited by 3,529 · see citing works
A Bayesian model of shape and appearance for subcortical brain segmentation
Patenaude, B., Smith, S. M., Kennedy, D. N., & Jenkinson, M. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.02.046 · Cited by 2,287 · see citing works
Unbiased nonlinear average age-appropriate brain templates from birth to adulthood
Fonov, V., Evans, A., McKinstry, R. C., Almli, C. R., & Collins, D. L. (2009) · NeuroImage · doi:10.1016/s1053-8119(09)70884-5 · Cited by 2,092 · see citing works
Uneven Pattern of Dopamine Loss in the Striatum of Patients with Idiopathic Parkinson's Disease
Kish, S. J., Shannak, K. S., & Hornykiewicz, O. (1988) · New England Journal of Medicine · doi:10.1056/nejm198804073181402 · Cited by 1,945 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1437 · Cited by 1,772 · see citing works
Patlak, C. S., & Blasberg, R. G. (1985) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1985.87 · Cited by 1,673 · see citing works
Function in the human connectome: task-fMRI and individual differences in behavior
Barch, D. M., Burgess, G. C., Harms, M. P., Petersen, S. E., Schlaggar, B. L., Corbetta, M., Glasser, M. F., Curtiss, S., Dixit, S., Feldt, C., et al. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.05.033 · Cited by 1,529 · see citing works
The primate basal ganglia: Parallel and integrative networks
Haber, S. N. (2003) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2003.10.003 · Cited by 1,479 · see citing works
Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease
Kordower, J. H., Olanow, C. W., Dodiya, H. B., Chu, Y., Beach, T. G., Adler, C. H., Halliday, G. M., & Bartus, R. T. (2013) · Brain · doi:10.1093/brain/awt192 · Cited by 1,294 · see citing works
An Optimized Blockwise Non Local Means Denoising Filter for 3D Magnetic Resonance Images
Barillot, C., Inserm, H. I., & Barillot, C. (2007) · Cited by 1,168 · see citing works
Performance Measurements of the Siemens mMR Integrated Whole-Body PET/MR Scanner
Delso, G., Fürst, S., Jakoby, B., Ladebeck, R., Ganter, C., Nekolla, S. G., Schwaiger, M., & Ziegler, S. I. (2011) · Journal of Nuclear Medicine · doi:10.2967/jnumed.111.092726 · Cited by 870 · see citing works
The organization of the human striatum estimated by intrinsic functional connectivity
Choi, E. Y., Yeo, B. T. T., & Buckner, R. L. (2012) · Journal of Neurophysiology · doi:10.1152/jn.00270.2012 · Cited by 746 · see citing works
Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease
Killiany, R., Gómez‐Isla, T., Moss, M. B., Kikinis, R., Sándor, T., Jolesz, F. A., Tanzi, R. E., Jones, K. J., Hyman, B. T., & Albert, M. (2000) · Annals of Neurology · doi:10.1002/1531-8249(200004)47:4 · Cited by 659 · see citing works
Rodríguez‐Oroz, M. (2001) · Brain · doi:10.1093/brain/124.9.1777 · Cited by 468 · see citing works
The mystery of motor asymmetry in Parkinson's disease
Djaldetti, R., Ziv, I., & Melamed, E. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(06)70549-x · Cited by 412 · see citing works
Metabolic brain networks in neurodegenerative disorders: a functional imaging approach
Eidelberg, D. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.003 · Cited by 389 · see citing works
An [18F]dopa–PET and clinical study of the rate of progression in Parkinson’s disease
Morrish, P., Sawle, G. V., & Brooks, D. J. (1996) · Brain · doi:10.1093/brain/119.2.585 · Cited by 366 · see citing works
Age at onset and Parkinson disease phenotype
Pagano, G., Ferrara, N., Brooks, D. J., & Pavese, N. (2016) · Neurology · doi:10.1212/wnl.0000000000002461 · Cited by 360 · see citing works
Self-citationNandhagopal, R., Kuramoto, L., Schulzer, M., Mak, E., Cragg, J. J., Lee, C. S., McKenzie, J., McCormick, S., Samii, A., Troiano, A. R., et al. (2009) · Brain · doi:10.1093/brain/awp209 · Cited by 262 · see citing works
Clinically deployable Kinesia™ technology for automated tremor assessment
Giuffrida, J. P., Riley, D. E., Maddux, B. N., & Heldman, D. A. (2009) · Movement Disorders · doi:10.1002/mds.22445 · Cited by 251 · see citing works
Filion, M., Tremblay, L., & Bédard, P. J. (1991) · Brain Research · doi:10.1016/0006-8993(91)90586-k · Cited by 236 · see citing works
Somatotopic Organization of the Primate Basal Ganglia
Nambu, A. (2011) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2011.00026 · Cited by 234 · see citing works
Takada, M., Tokuno, H., Nambu, A., & Inase, M. (1998) · Experimental Brain Research · doi:10.1007/s002210050384 · Cited by 213 · see citing works
González‐Escamilla, G., Lange, C., Teipel, S. J., Buchert, R., & Grothe, M. J. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.12.077 · Cited by 183 · see citing works
Paulus, D. H., Quick, H. H., Geppert, C., Fenchel, M., Zhan, Y., Hermosillo, G., Faul, D. D., Boada, F. E., Friedman, K. P., & Koesters, T. (2015) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.156000 · Cited by 175 · see citing works
Romanelli, P., Esposito, V., Schaal, D. W., & Heit, G. (2004) · Brain Research Reviews · doi:10.1016/j.brainresrev.2004.09.008 · Cited by 163 · see citing works
A Cortical Pathogenic Theory of Parkinson’s Disease
Foffani, G., & Obeso, J. A. (2018) · Neuron · doi:10.1016/j.neuron.2018.07.028 · Cited by 161 · see citing works
Self-citationRegional changes in [18F]dopa metabolism in the striatum in Parkinson's disease
Morrish, P., Sawle, G. V., & Brooks, D. J. (1996) · Brain · doi:10.1093/brain/119.6.2097 · Cited by 153 · see citing works
Striatal dopamine in P arkinson disease: A meta‐analysis of imaging studies
Kaasinen, V., & Vahlberg, T. J. (2017) · Annals of Neurology · doi:10.1002/ana.25103 · Cited by 151 · see citing works
Progression of monoaminergic dysfunction in parkinson's disease: a longitudinal 18f-dopa pet study
Pavese, N., Rivero-Bosch, M., Lewis, S. J., Whone, A. L., & Brooks, D. J. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.03.012 · Cited by 145 · see citing works
Self-citationFoot, Hand, Face and Eye Representation in the Human Striatum
Gérardin, E. (2002) · Cerebral Cortex · doi:10.1093/cercor/13.2.162 · Cited by 139 · see citing works
Organization of Corticostriatal Motor Inputs in Monkey Putamen
Nambu, A., Kaneda, K., Tokuno, H., & Takada, M. (2002) · Journal of Neurophysiology · doi:10.1152/jn.2002.88.4.1830 · Cited by 138 · see citing works
Extrastriatal monoamine neuron function in Parkinson’s disease: An 18F-dopa PET study
Moore, R. Y., Whone, A. L., & Brooks, D. J. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.09.004 · Cited by 136 · see citing works
The natural history of parkinson's disease
Poewe, W. H., & Wenning, G. K. (1998) · Annals of Neurology · doi:10.1002/ana.410440703 · Cited by 129 · see citing works
Locations of movement‐related cells in the human subthalamic nucleus in Parkinson's disease
Theodosopoulos, P. V., Marks, W. J., Christine, C. W., et al. (2003) · Movement Disorders · doi:10.1002/mds.10446 · Cited by 126 · see citing works
Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?
Wong, Y. C., Luk, K. C., Purtell, K., Burke, S., Stoessl, A. J., Trudeau, L., Yue, Z., Krainc, D., Oertel, W. H., Obeso, J. A., et al. (2019) · Movement Disorders · doi:10.1002/mds.27823 · Cited by 123 · see citing works
Self-citationDopamine Release and Uptake Dynamics within Nonhuman Primate StriatumIn Vitro
Cragg, S. J., Hille, C. J., & Greenfield, S. A. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-21-08209.2000 · Cited by 120 · see citing works
Correlation of Parkinson Disease Severity and18F-DTBZ Positron Emission Tomography
Hsiao, I., Weng, Y.-H., Hsieh, C., Lin, W., Wey, S., Kung, M., Yen, T., Lu, C., & Lin, K. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.290 · Cited by 118 · see citing works
Eshuis, S. A., Jager, P. L., Maguire, R. P., Jonkman, S., Dierckx, R., & Leenders, K. L. (2008) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-008-0989-5 · Cited by 117 · see citing works
Blesa, J., Pifl, C., Sánchez-González, M. Á., Carlos Juri, C., García‐Cabezas, M. Á., Adánez, R., Iglesias, E., Collantes, M., Peñuelas, I., Sánchez-Hernández, J. J., et al. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.05.018 · Cited by 107 · see citing works
Self-citationHandedness correlates with the dominant Parkinson side: A systematic review and meta‐analysis
van der Hoorn, A., Burger, H., Leenders, K. L., & de Jong, B. M. (2011) · Movement Disorders · doi:10.1002/mds.24007 · Cited by 103 · see citing works
Uitti, R. J., Baba, Y., Wszołek, Z. K., & Putzke, D. J. (2005) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2004.10.007 · Cited by 102 · see citing works
Clinical implications of early caudate dysfunction in Parkinson’s disease
Pasquini, J., Durcan, R., Wiblin, L., Stokholm, M. G., Rochester, L., Brooks, D. J., Burn, D. J., & Pavese, N. (2019) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2018-320157 · Cited by 93 · see citing works
Self-citationBrück, A., Aalto, S., Rauhala, E., et al. (2009) · Movement Disorders · doi:10.1002/mds.22484 · Cited by 91 · see citing works
A probabilistic atlas of the basal ganglia using 7 T MRI
Keuken, M. C., & Forstmann, B. U. (2015) · Data in Brief · doi:10.1016/j.dib.2015.07.028 · Cited by 86 · see citing works
Separating Parkinson's Disease From Normality
Sawle, G. V. (1994) · Archives of Neurology · doi:10.1001/archneur.1994.00540150027011 · Cited by 76 · see citing works
Cragg, S. J., Hille, C. J., & Greenfield, S. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05705.2002 · Cited by 66 · see citing works
Motor Onset Topography and Progression in Parkinson's Disease: the Upper Limb Is First
Monje, M. H. G., Sánchez‐Ferro, Á., Pineda‐Pardo, J. A., Vela, L., Alonso‐Frech, F., & Obeso, J. A. (2021) · Movement Disorders · doi:10.1002/mds.28462 · Cited by 56 · see citing works
Self-citationDo parkinsonian symptoms and levodopa‐induced dyskinesias start in the foot?
Vidailhet, M., Bonnet, A. M., Marconi, R., Gouider‐Khouja, N., & Agid, Y. (1994) · Neurology · doi:10.1212/wnl.44.9.1613 · Cited by 51 · see citing works
Wichmann, T., & Kliem, M. A. (2004) · Journal of Neurophysiology · doi:10.1152/jn.01180.2002 · Cited by 47 · see citing works
Dopaminergic Vulnerability in Parkinson Disease: The Cost of Humans’ Habitual Performance
Hernández, L. F., Obeso, I., Costa, R. M., Redgrave, P., & Obeso, J. A. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.03.007 · Cited by 40 · see citing works
Self-citationA study of subtle motor signs in early Parkinson's disease
Schneider, S. A., Drude, L., Kasten, M., Klein, C., & Hagenah, J. M. (2012) · Movement Disorders · doi:10.1002/mds.25161 · Cited by 27 · see citing works
Rate of 6‐[18F]fluorodopa uptake decline in striatal subregions in Parkinson's disease
Gallagher, C. L., Oakes, T. R., Johnson, S. C., et al. (2011) · Movement Disorders · doi:10.1002/mds.23503 · Cited by 25 · see citing works
Alakurtti, K., Johansson, J. J., Tuokkola, T., Någren, K., & Rinne, J. O. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.05.091 · Cited by 20 · see citing works
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Research works printed but not linked: 3
- [25]25. Coupe P, Yger P, Prima S, Hellier P, Kervrann C, Barillot C. An optimized blockwise nonlocal means denoising filter for 3-D magnetic resonance images. IEEE Trans Med Imaging . 2008;27(4): 425-441.
- [34]34. Glasser MF, Sotiropoulos SN, Wilson JA, et al.; WU-Minn HCP Consortium. The minimal preprocessing pipelines for the HumanConnectome Project. Neuroimage . 2013;80:105-124.
- [47]47. Lee CS, Samii A, Sossi V, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol . 2000;47(4):493-503.
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Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?
Blesa, J., Foffani, G., Dehay, B., Bezard, E., & Obeso, J. A. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00542-9 · Cited by 232 · see citing works
Self-citationDanna, R., Kondle, S., Amar, O., Mabourakh, M., Chen, G., Fadol, W. B., & Mohieldin, A. M. (2025) · Biology · doi:10.3390/biology14121787 · Cited by 2 · see citing works
“The current understanding of PD pathogenesis suggests that a combination of genetic and environmental factors contributes to the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the pars compacta of the substantia nigra, as well as other affected cortical regions [125,126].”
- Authors
- Pineda-Pardo, J. A., Sánchez-Ferro, Á., Monje, M. H. G., Pavese, N., & Obeso, J. A.
- Affiliations
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid , Spain
- Northwestern University (US)
- Aarhus University Hospital (DK)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-01
- Volume
- 145
- Issue
- 3
- Pages
- 1018-1028
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC9351472
- OpenAlex
- W4206682947
- Cited by
- 51
- References
- 61
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 15 · 2023: 8 · 2022: 7 · 2021: 1
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundación MAPFRE
- Ministerio de Ciencia e Innovación (PID2019-111045RB-I00)
- Fundación Hospitales de Madrid
- NIH
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Parkinson's disease, nigrostriatal denervation, putamen, somatotopic organization, 18F-DOPA PET, bradykinesia, disease progression
- MeSH terms
- Child, Preschool, Corpus Striatum, Denervation, Dihydroxyphenylalanine, Dopamine, Humans, Parkinson Disease, Putamen
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