Abstract
Several studies of Parkinson's disease (PD) have reported dysregulation of cerebral metals, particularly decreases in copper and increases in iron in substantia nigra (SN). However, few studies have investigated regions outside the SN, fewer have measured levels of multiple metals across different regions within the same brains, and there are no currently-available reports of metal levels in Parkinson's disease dementia (PDD). This study aimed to compare concentrations of nine essential metals across nine different brain regions in cases of PDD and controls. Investigated were: primary motor cortex (MCX); cingulate gyrus (CG); primary visual cortex (PVC); hippocampus (HP); cerebellar cortex (CB); SN; locus coeruleus (LC); medulla oblongata (MED); and middle temporal gyrus (MTG), thus covering regions with severe, moderate, or low levels of neuronal loss in PDD. Levels of eight essential metals and selenium were determined using an analytical methodology involving the use of inductively-coupled plasma mass spectrometry (ICP-MS), and compared between cases and controls, to better understand the extent and severity of metal perturbations. Findings were also compared with those from our previous study of sporadic Alzheimer's disease dementia (ADD), which employed equivalent methods, to identify differences and similarities between these conditions. Widespread copper decreases occurred in PDD in seven of nine regions (exceptions being LC and CB). Four PDD-affected regions showed similar decreases in ADD: CG, HP, MTG, and MCX. Decreases in potassium and manganese were present in HP, MTG and MCX; decreased manganese was also found in SN and MED. Decreased selenium and magnesium were present in MCX, and decreased zinc in HP. There was no evidence for increased iron in SN or any other region. These results identify alterations in levels of several metals across multiple regions of PDD brain, the commonest being widespread decreases in copper that closely resemble those in ADD, pointing to similar disease mechanisms in both dementias.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting around 1% of the world’s population above the age of 60 (Tysnes and Storstein, 2017)
We investigated levels of eight essential metals including sodium (Na), magnesium (Mg), potassium (K), calcium (Ca), manganese (Mn), Fe, Cu, zinc (Zn), and selenium (Se), across nine brain regions including the cerebellum at the level of the dentate nucleus (CB), cingulate gyrus (CG), hippocampus (HP), locus coeruleus (LC), motor cortex (MCX), medulla (MED), middle temporal gyrus (MTG), occipital cortex at the level of the primary visual cortex (PVC), and substantia nigra (SN) in nine confirmed cases of PDD and nine age-matched control brains
PDD cases showed a higher incidence of psychiatric symptoms such as anxiety and depression, whereas hypertension and type II diabetes were more common in controls
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting around 1% of the world’s population above the age of 60 (Tysnes and Storstein, 2017). The condition is described as PD with dementia ( known as Parkinson’s disease dementia, and Parkinsonian dementia) and abbreviated as PDD. PD and PDD are characterized by the degeneration of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein in Lewy bodies and neuropil threads (Braak et al, 2003). Research is ongoing on exactly how these inclusions develop or how they lead to neuronal death. Clinical trials targeting the aggregation and binding of α-synuclein, and/or aiming to changes its levels are ongoing, to date no drugs modifying misfolded α-synuclein have been developed (Oliveri, 2019)
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