Brain iron linked with higher risk of cognitive decline in Parkinson’s disease
A UK study of 100 patients with Parkinson’s disease (PD) has found a link between brain tissue iron levels and risk of cognitive decline.
“Dementia affects up to half of patients with PD, but the timing and severity of cognitive involvement vary and useful quantitative tools to track cognitive change in PD are required,” wrote the researchers. [J Neurol Neurosurg Psychiatry 2013;84:1258-1264] “A potential mechanism for selective vulnerability in PD dementia is excess brain iron accumulation.” [Parkinsons Dis 2013;3:461-491]
By using quantitative susceptibility mapping (QSM), an emerging MRI technique that detects local variations in iron content, the researchers identified widespread increases in iron levels along the cortical ribbon in prefrontal cortex in PD patients vs age-matched unaffected controls (false discovery rate [FDR]-corrected p<0.05). “We found unilateral QSM increases in the right rostral putamen and right temporal cortex,” they reported. [J Neurol Neurosurg Psychiatry 2020, doi: 10.1136/jnnp-2019-322042]
QSM regression analysis revealed bilaterally increased (FDR-corrected p<0.05) absolute susceptibility with decreasing Montreal Cognitive Assessment scores in PD patients’ hippocampus, thalamus (including anterior, mediodorsal and posterior nuclei), caudal regions of ventromedial prefrontal cortex, regions of basal forebrain and rostral caudate nucleus.
“These tissue changes, in regions known to be related to cognition, were strikingly obvious, while conventional measures of atrophy showed no relationship,” commented the researchers. Indeed, voxel-based morphometry showed no difference in atrophy between PD patients and controls, or any association with disease severity measured using cognitive, motor scores, risk score for cognitive decline or visual performance. “Behavioural changes, captured by clinical measures, often occur before consistent atrophy is seen in PD,” noted the researchers. [Brain Commun 2019, doi: 10.1093/braincomms/fcz006]
Impaired visuoperception is emerging as a potential predictor of Parkinson’s dementia. Analysis of PD patients with poor vs normal visual performance revealed widespread QSM increases in patients with poor visual performance (FDR-corrected p<0.05). “There was striking overlap of brain iron levels between patients with high dementia risk and those with poor vision scores in prefrontal, anterior cingulate and posterior parietal cortex and precuneus regions, suggesting common underlying substrates,” wrote the researchers.
Indeed, brain iron co-localizes with Alzheimer’s disease pathology, particularly amyloid and tau, which are key predictors of PD dementia. [Brain 2017;140:2112-2119; Brain 2011;134:1493-1505] “Therefore, detecting levels of brain iron could be a sensitive way to identify brain tissue already affected by the earliest processes that ultimately lead to PD dementia,” the researchers proposed. [Brain 2017;140:118-131]
In the putamen, brain iron increases were related to poorer motor function. “These anatomically specific changes were detected where conventional neuroimaging failed to identify atrophy and without requiring predefined regions of interest,” commented the researchers. “Our findings have important potential as neuroimaging markers of disease activity with application in the clinic and in therapeutic trials.”
“In summary, we show that whole-brain measures of iron content can be used to probe key clinical indices of disease activity, with cognitive performance related to hippocampal changes, dementia risk linked to increased brain iron in parietal and frontal cortices, and motor severity co-varying with raised brain iron levels in the putamen,” concluded the authors of the study.