Parkinson’s disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI

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.

Ferroptosis in Parkinson’s disease: glia–neuron crosstalk

“…Several mutations in ferroptosis genes have been linked to PD (Table 1), including DJ-1, autosomal recessive PD gene, that encodes a negative modulator of ferroptosis [16]. Moreover, the characteristics of ferroptosis induction are highly consistent with the pathological changes observed in PD patients, including increased iron content [4,5], lipid peroxidation [17][18][19], and defects in the antioxidant system such as decreased levels of cystine/ glutamate antiporter (xCT) [20], glutathione (GSH) [21], DJ-1 (that maintains cysteine and GSH biosynthesis) [16], and CoQ10 [22]. Furthermore, ferroptosis was observed in different PD cellular and animal models such as SH-SY5Y cells treated with MPP + and 6-OHDA, and MPTP-lesioned mice [8][9][10].…”

“…Activated glia may act as 'double-edged swords' because they can exert neuroprotective effects by releasing neurotrophic factors and phagocytosis, while mediating neuronal damage by releasing proinflammatory cytokines [3]. Brain imaging and pathological studies have shown correlations between iron deposition in the SNpc of PD patient brains and DA neuronal loss [4,5], indicating that imbalance of iron homeostasis may be a factor closely associated with neuronal death in PD. This type of iron-dependent cell death is termed ferroptosis [6].…”

Cerebral Iron Deposition in Neurodegeneration

“…Parkinson Disease ↓ Fe in serum/plasma [107] ↑ Fe in substantia nigra [108,109] ↑ Fe in neurons and adjacent neuropil, microglia, perivascularly in extracellular deposits [110][111][112] Fe bound to neuromelanin in dopaminergic neurons [112,113] Alzheimer Disease ↓ Fe in serum/plasma [114][115][116] ↑ Fe in (mostly temporal) cortex, globus pallidus, caudate, putamen [117][118][119][120][121][122] ↑ Fe in amyloid plaques, microglia, along myelinated fibers [117,[123][124][125] Fe bound to amyloid partially composed of magnetite nanoparticles [126,127] Amyotrophic Lateral Sclerosis ↑ ferritin, ↓ transferrin in serum [128] ↑ Fe in liver, kidneys [129] ↑ Fe in spinal cord [130,131] ↑ Fe in motor cortex, caudate, subthalamic nucleus, globus pallidus, substantia nigra, red nucleus [132][133][134] ↑ Fe in spinal cord neuron nuclei [135] ↑ Fe in microglia in motor cortex [136] n.a.…”

“…Brain regions affected early in PD include SN, LC, olfactory bulb, and dorsal motor neurons of the vagus nuclei [281,282]. However, iron accumulation in PD is limited to SN pars compacta [108,109].…”

Diagnostic Performance for Differential Diagnosis of Atypical Parkinsonian Syndromes from Parkinson’s Disease Using Quantitative Indices of 18F-FP-CIT PET/CT

“…Atypical parkinsonian syndromes (APS), such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB), are other causes of Parkinsonism. Although the clinical progression and pathology can differ between Parkinsonism, there are evident difficulties for achieving confirmed diagnosis based solely on clinical features, particularly in the elderly and in patients at an early stage of disease [ 1 , 2 ]. To date, the therapeutic strategies for these chronic neurodegenerative disorders are based on symptomatic treatments.…”