Abstract
This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson’s disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression.
Highlights
Parkinson’s disease (PD) is a slowly progressing neurodegenerative movement disorder clinically characterized by rigidity, tremor, and bradykinesia that affects about ten million people worldwide [1]
PD patients performed at baseline significantly worse than healthy control (HC) subjects based on clinical measures
The main finding of this study is that PD is associated with higher than normal rates of regional diffusion tensor imaging (DTI) changes that involve primarily the substantia nigra, the thalamus and midbrain regions
Summary
Parkinson’s disease (PD) is a slowly progressing neurodegenerative movement disorder clinically characterized by rigidity, tremor, and bradykinesia that affects about ten million people worldwide [1]. The Parkinson’s Disease Progression Marker Initiative (PPMI) is an observational clinical study that includes brain imaging to validate potential biomarkers of PD [2]. We investigated whether PD patients enrolled in the PPMI exhibit a progressive decline in microstructural integrity—based on magnetic resonance diffusion tensor imaging (DTI)—that could offer a surrogate biomarker of disease progression. Two longitudinal studies have described diffusion changes in the substantia nigra of PD. Ofori et al [7] used a bi-tensor model and found that free-water diffusion increased in the substantia nigra in PD patients over a one year period, whereas the control group showed no significant change. No study before investigated associations between microstructural changes in PD and other potential biomarkers of PD progression, such as variations in dopamine deficits [9] or specific proteins cerebrospinal fluid (CSF) [10]
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