Parkinson’s Disease (PD) is a progressive neurodegenerative disease that causes neurons in the area of the brain that controls movement to weaken or die. Up to 50 percent of patients with PD suffer from dementia. The timing, severity, and effects of that dementia differs — and the reason for the varying vulnerability of different brain regions has remained unclear. A group of researchers at University College London’s Queen Square Institute of Neurology, however, have discovered a potential mechanism for the selective vulnerability: excess brain iron accumulation.
Iron builds up in the brain during normal aging processes, partially due to increased blood-brain–barrier permeability, and it especially affects the basal ganglia. The toxic potential of iron comes from its ability to generate reactive oxygen species (which can damage DNA), irreversibly modify proteins via highly reactive aldehydes, and stimulate the release of additional iron from storage proteins. These processes can lead to iron-mediated cell death.
Iron also accumulates in the brain during the neurodegenerative processes of PD. According to lead study author George Edward Calver Thomas, “Increased iron is seen in the substantia nigra at post mortem in PD and in vivo using transcranial sonography.” That excess brain iron is important in key pathophysiological pathways specific to PD. “Free radical species generated through iron overload interact with alpha-synuclein to promote Lewy-related pathology and produce neurotoxic by-products via catalyzation of dopamine oxidation reactions,” said Thomas.
Brain iron co-localizes with Alzheimer’s Disease (AD) pathology, particularly amyloid and tau, which are key predictors of PD dementia. Therefore, detecting levels of brain iron could be a sensitive way to identify brain tissue already affected by the processes that eventually lead to dementia in PD.
Detecting Iron Levels with QSM
To conduct the study, neuroimaging was needed that could detect early neuroanatomical correlates of cognitive involvement. Traditional MRIs, however, are poor at assessing volume loss caused by neuronal cell death until later disease stages, when that cell death occurs on a larger scale. Techniques sensitive to brain tissue microstructure are more suited to detect brain changes linked to cognitive involvement in PD.
Quantitative susceptibility mapping (QSM) is an emerging MRI technique that detects local variations in iron content. QSM is sensitive to magnetic susceptibility differences between chemical species, which are captured by the signal phase of MRI gradient echo sequences (GREs). This method recovers local susceptibility sources giving rise to magnetic field perturbations that are increased in basal ganglia regions in PD. It has never been used, however, to track cognitive changes throughout the entire brain.
Thomas and his colleagues investigated outcomes related to the progression of cognitive impairment. Their study used risk algorithms combined with clinical information to predict cognitive change over time. The researchers then used QSM to measure those changes in 100 patients with PD who did not have dementia. They hypothesized that magnetic susceptibility values reflecting brain tissue iron would be higher in:
- Mesial temporal structures in relation to poorer cognitive ability
- Posterior and prefrontal cortical regions in relation to higher risk of dementia
- Basal ganglia regions in relation to motor change
Methods and Imaging Protocol
The study, conducted from October 2017–October 2018, consisted of 100 patients within 10 years after PD diagnosis, ages 49–80. The inclusion criterion was a clinical diagnosis of early to mid-stage PD; exclusion criteria were confounding neurological or psychiatric disorders, dementia, or metallic implants unsafe for an MRI. The patients’ usual therapy, including levodopa, was continued throughout all assessments.
The patients underwent a variety of clinical assessments, including the following:
- Cognition was assessed with the Montreal Cognitive Assessment (MoCA).
- Motor function was assessed using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS-III), with patients in the “on” state.
- Risk of cognitive decline was assessed using a validated clinical algorithm that combines age, MDS-UPDRS-III, REM sleep behavior disorder score, sense of smell and depression.
- Visual acuity was assessed using LogMAR.
- Visual perception was assessed using two higher-order visual tasks.
MRI measurements consisting of susceptibility-weighted and T1-weighted MRI scans were performed on a Siemens Prismafit 3T MRI system using a 64-channel receive array coil. Susceptibility-weighted MRI signals were obtained from a 2×1-accelerated, 3D flow-compensated spoiled GRE sequence.
QSM image reconstruction, including phase pre-processing and estimation of susceptibility maps, followed the default QSMbox pipeline for single-echo, coil-combined data. QSM spatial normalization and whole-brain and regional analyses were performed using QSMexplorer. To improve statistical conditioning in cortical regions, whole-brain analyses were performed for absolute QSM data.
The research team used QSM to identify brain tissue iron changes relating to poorer cognition in PD. They showed tissue changes in the hippocampus and thalamus that related to cognitive deficits in PD without dementia, and brain iron increases in the parietal and prefrontal cortices that related to predictors of poor cognitive outcome. Additionally, they showed that brain iron increased in the putamen in relation to decreased motor function.
The team concluded that whole-brain measures of iron content can be used to probe key clinical indices of disease activity. They detected atrophic changes in places where conventional neuroimaging failed — and their methods had the advantage of not requiring predefined regions of interest. The study’s findings have important potential as neuroimaging markers of disease activity, with applications both in the clinic and in therapeutic trials.
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