Abstract
Parkinson’s disease (PD) is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin (NM)-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional NM loss and iron accumulation within specific areas of SN relate to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and postcommissural putamen by [18F]DOPA PET in 23 Parkinson’s disease patients and 23 healthy control (HC) participants in whom NM content and iron load were assessed in medial and lateral SN, respectively, by NM-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson’s disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial SN. In conclusion, multimodal imaging reveals regionally specific relationships between iron accumulation and depigmentation within the SN of Parkinson’s disease and provides in vivo insights in its neuropathology.
Highlights
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder worldwide and a growing public health issue given population aging[1]
Measurement of striatal [18F]-DOPA uptake by positron emission tomography (PET) is still regarded as one of the most reliable tool for the in vivo diagnosis of PD because it directly probes the nigro-striate synthesis of dopamine[10,11,12], and as such considered as a measure of dopamine terminal loss. [18F]DOPA uptake is decreased in the putamen in virtually all patients with PD, even in the early stage of the disease[12]
In PD, it is expected that R2* would increase in substantia nigra (SN) due to iron accumulation, whereas the signal of NM-sensitive MRI would decrease in SN, due to dopaminergic neuron loss and depigmentation
Summary
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder worldwide and a growing public health issue given population aging[1]. The decline of dopaminergic nigro-striatal neurotransmission is considered as the core mechanism explaining motor symptoms of PD and the diagnosis of PD still mainly relies on the clinical observation of motor signs[6]. The latter only appear when 50–60% of dopaminergic neurons of SN are already lost[7]. Measurement of striatal [18F]-DOPA uptake by positron emission tomography (PET) is still regarded as one of the most reliable tool for the in vivo diagnosis of PD because it directly probes the nigro-striate synthesis of dopamine[10,11,12], and as such considered as a measure of dopamine terminal loss. In PD, it is expected that R2* would increase in SN due to iron accumulation, whereas the signal of NM-sensitive MRI would decrease in SN, due to dopaminergic neuron loss and depigmentation
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