Regional nigral neuromelanin degeneration in asymptomatic leucine-rich repeat kinase 2 gene carrier using MRI

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Abstract

Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.

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Most cited references 48

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Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications.

S J Kish, K Shannak, O. Hornykiewicz (1988)

Autografting of dopamine-producing adrenal medullary tissue to the striatal region of the brain is now being attempted in patients with Parkinson's disease. Since the success of this neurosurgical approach to dopamine-replacement therapy may depend on the selection of the most appropriate subregion of the striatum for implantation, we examined the pattern and degree of dopamine loss in striatum obtained at autopsy from eight patients with idiopathic Parkinson's disease. We found that in the putamen there was a nearly complete depletion of dopamine in all subdivisions, with the greatest reduction in the caudal portions (less than 1 percent of the dopamine remaining). In the caudate nucleus, the only subdivision with severe dopamine reduction was the most dorsal rostral part (4 percent of the dopamine remaining); the other subdivisions still had substantial levels of dopamine (up to approximately 40 percent of control levels). We propose that the motor deficits that are a constant and characteristic feature of idiopathic Parkinson's disease are for the most part a consequence of dopamine loss in the putamen, and that the dopamine-related caudate deficits (in "higher" cognitive functions) are, if present, less marked or restricted to discrete functions only. We conclude that the putamen--particularly its caudal portions--may be the most appropriate site for intrastriatal application of dopamine-producing autografts in patients with idiopathic Parkinson's disease.

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Ageing and Parkinson's disease: substantia nigra regional selectivity.

J Fearnley, A Lees (1991)

The micro-architecture of the substantia nigra was studied in control cases of varying age and patients with parkinsonism. A single 7 mu section stained with haematoxylin and eosin was examined at a specific level within the caudal nigra using strict criteria. The pars compacta was divided into a ventral and a dorsal tier, and each tier was further subdivided into 3 regions. In 36 control cases there was a linear fallout of pigmented neurons with advancing age in the pars compacta of the caudal substantia nigra at a rate of 4.7% per decade. Regionally, the lateral ventral tier was relatively spared (2.1% loss per decade) compared with the medial ventral tier (5.4%) and the dorsal tier (6.9%). In 20 Parkinson's disease (PD) cases of varying disease duration there was an exponential loss of pigmented neurons with a 45% loss in the first decade. Regionally, the pattern was opposite to ageing. Loss was greatest in the lateral ventral tier (average loss 91%) followed by the medial ventral tier (71%) and the dorsal tier (56%). The presymptomatic phase of PD from the onset of neuronal loss was estimated to be about 5 yrs. This phase is represented by incidental Lewy body cases: individuals who die without clinical signs of PD or dementia, but who are found to have Lewy bodies at post-mortem. In 7 cases cell loss was confined to the lateral ventral tier (average loss 52%) congruent with the lateral ventral selectivity of symptomatic PD. It was calculated that at the onset of symptoms there was a 68% cell loss in the lateral ventral tier and a 48% loss in the caudal nigra as a whole. The regional selectivity of PD is relatively specific. In 15 cases of striatonigral degeneration the distribution of cell loss was similar, but the loss in the dorsal tier was greater than PD by 21%. In 14 cases of Steele-Richardson-Olszewski syndrome (SRO) there was no predilection for the lateral ventral tier, but a tendency to involve the medial nigra and spare the lateral. These findings suggest that age-related attrition of pigmented nigral cells is not an important factor in the pathogenesis of PD.

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Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Daniel G Healy, Mario Falchi, Sean S. O’Sullivan … (2008)

Summary Background Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

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Author and article information

Contributors

Rahul Gaurav: rahul.gaurav@icm-institute.org

Stéphane Lehéricy: stephane.lehericy@upmc.fr

Tao Wu: wutao69@gmail.com

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 9 May 2024

Publication date PMC-release: 9 May 2024

Publication date Collection: 2024

Volume: 14

Electronic Location Identifier: 10621

Affiliations

[1 ]GRID grid.417031.0, ISNI 0000 0004 1799 2675, Department of General Practice, , Tianjin Union Medical Center, ; Tianjin, China

[2 ]GRID grid.462844.8, ISNI 0000 0001 2308 1657, Paris Brain Institute – ICM, INSERM U1127, CNRS UMR 7225, Pitié-Salpêtrière Hospital, , Sorbonne Université, ; Paris, France

[3 ]Movement Investigations and Therapeutics Team (MOV’IT), Paris Brain Institute – ICM, ( https://ror.org/050gn5214) Paris, France

[4 ]Center for NeuroImaging Research (CENIR), Paris Brain Institute – ICM, ( https://ror.org/050gn5214) Hôpital Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75013 Paris, France

[5 ]Department of Neurology (H.J.), University Hospital of Heidelberg, ( https://ror.org/013czdx64) Heidelberg, Germany

[6 ]Department of Neurology, Xuanwu Hospital of Capital Medical University, ( https://ror.org/013xs5b60) Beijing, China

[7 ]Department of Neurology, Center for Movement Disorders, Beijing Tiantan Hospital, Capital Medical University, ( https://ror.org/013xs5b60) Beijing, China

[8 ]GRID grid.411617.4, ISNI 0000 0004 0642 1244, China National Clinical Research Center for Neurological Diseases, ; Beijing, China

[9 ]GRID grid.410318.f, ISNI 0000 0004 0632 3409, Department of Radiology, Guang’anmen Hospital, , China Academy of Chinese Medical Sciences, ; Beijing, China

[10 ]Department of Radiology, Xuanwu Hospital of Capital Medical University, ( https://ror.org/013xs5b60) Beijing, China

[11 ]Department of Radiology, Keck School of Medicine, University of Southern California, ( https://ror.org/03taz7m60) Los Angeles, CA 90033 USA

[12 ]Department of Neuroradiology, Pitié-Salpêtrière Hospital, AP-HP, ( https://ror.org/02mh9a093) Paris, France

Article

Publisher ID: 59074

DOI: 10.1038/s41598-024-59074-8

PMC ID: 11087650

PubMed ID: 38729969

SO-VID: 47225474-078c-4b73-9427-e985a98df525

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 29 September 2023

Date accepted : 7 April 2024

Funding

Funded by: Ministry of Science and Technology

Award ID: 2016YFC1306503

Award Recipient : Tao Wu

Funded by: The National Science Foundation of China

Award ID: 82071423

Award ID: 81571228

Award Recipient : Tao Wu

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ScienceOpen disciplines: Uncategorized

Keywords: asymptomatic leucine-rich repeat kinase 2 (lrrk2) gene carrier,parkinson’s disease (pd),mri,neuromelanin,substantia nigra (sn),computational neuroscience,diseases of the nervous system,neuroscience,biomarkers,neurology

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ScienceOpen disciplines: Uncategorized

Keywords: asymptomatic leucine-rich repeat kinase 2 (lrrk2) gene carrier, parkinson’s disease (pd), mri, neuromelanin, substantia nigra (sn), computational neuroscience, diseases of the nervous system, neuroscience, biomarkers, neurology

Regional nigral neuromelanin degeneration in asymptomatic leucine-rich repeat kinase 2 gene carrier using MRI

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Most cited references 48

Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications.

Ageing and Parkinson's disease: substantia nigra regional selectivity.

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

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