The clinicopathological correlations between aspects of cognition, disease severity and imaging in Parkinson's Disease (PD) have been unclear. We studied cognitive profiles, demographics, and functional connectivity patterns derived from resting-state fMRI data (rsFC) in 31 PD subjects from the Parkinson's Progression Markers Initiative (PPMI) database. We also examined rsFC from 19 healthy subjects (HS) from the Pacific Parkinson's Research Centre. Graph theoretical measures were used to summarize the rsFC patterns. Canonical correlation analysis (CCA) was used to relate separate cognitive profiles in PD that were associated with disease severity and demographic measures as well as rsFC network measures. The CCA model relating cognition to demographics suggested female gender and education supported cognitive function in PD, age and depression scores were anti-correlated with overall cognition, and UPDRS had little influence on cognition. Alone, rsFC global network measures did not significantly differ between PD and controls, yet some nodal network measures, such as network segregation, were distinguishable between PD and HS in cortical “hub” regions. The CCA model relating cognition to rsFC global network values, which was not related to the other CCA model relating cognition to demographic information, suggested modularity, rich club coefficient, and transitivity was also broadly related to cognition in PD. Our results suggest that education, aging, comorbidity, and gender impact cognition more than overall disease severity in PD. Cortical “hub” regions are vulnerable in PD, and impairments of processing speed, attention, scanning abilities, and executive skills are related to enhanced functional segregation seen in PD.

Graphical network characteristics and nonstationary functional connectivity features, both derived from resting‐state functional magnetic resonance imaging (rsfMRI) data, have been associated with cognitive performance in healthy subjects. How these features jointly relate to cognition in diseased states has not been investigated. In this study, 46 relapsing–remitting multiple sclerosis subjects underwent rsfMRI scans and a focused cognitive battery. With a sliding window approach, we examined six dynamic network features that indicated how connectivity changed over time as well as six measures derived from graph theory to reflect static network characteristics. Multiset canonical correlation analysis (MCCA) was then carried out to investigate the relations between dynamic network features, stationary network characteristics, cognitive testing, demographic, disease severity, and mood. Multiple sclerosis (MS) subjects demonstrated weaker connectivity strength, decreased network density, reduced global changes, but increased changes in interhemispheric connectivity compared to controls. The MCCA model determined that executive functions and processing speed ability measured by Wechsler Adult Intelligence Scale IV (WAIS‐IV) Working Memory Index, WAIS‐IV Processing Speed Index, and the Verbal Fluency Test were positively correlated with education, dynamic connectivity, and static connectivity strength; while poor task switching was correlated with disease severity, psychiatric comorbidities such as depression, anxiety, and fatigue, and static network density. Taken together, our results suggest that better executive functioning in MS requires maintenance of a continued coordination between stationary and dynamic functional connectivity as well as the support of education, and dynamic functional connectivity may provide an additional cognitive biomarker of disease severity in the MS population.

We examined the influence of dysfunctional, non-lesional white matter on cognitive performance in multiple sclerosis (MS). Forty-six MS subjects were assessed using MRI-based myelin water imaging (MWI), and average myelin water fraction (MWF) values across 20 white matter regions of interest (ROIs) were determined. A data-fusion method, multiset canonical correlation analysis (MCCA), was used to investigate the multivariate, deterministic joint relations between MWF, executive function, and demographic and clinical characteristics. MCCA revealed one significant component (p = 0.009) which consisted of three linked profiles, with a pairwise correlation between the MWF and cognitive profiles of r = 0.37, a correlation between MWF and demographics profiles of r = 0.31, and between cognitive and demographics profiles r = 0.64. White matter ROIs representing long-range intra-hemispheric tracts and ROIs connecting the two hemispheres were positively related through their individual profiles to overall cognitive performance, education and female gender, while age, EDSS, and disease duration were related negatively. Surprisingly, lesions within the ROIs had a negligible effect on overall relations between imaging, cognitive, and demographic variables. These findings indicate that there is a strong association between a pattern of MWF values and cognitive performance in MS, which is modulated by age, education, and disease severity. Moreover, this consistent relation involves multiple white matter regions and is separate from the influence of lesions.

Parkinson's Disease (PD) is associated with decreased ability to perform habitual tasks, relying instead on goal-directed behaviour subserved by different cortical/subcortical circuits, including parts of the putamen. We explored the functional subunits in the putamen in PD using novel dynamic connectivity features derived from resting state fMRI recorded from thirty PD subjects and twenty-eight age-matched healthy controls (HC). Dynamic functional segmentation of the putamina was obtained by determining the correlation between each voxel in each putamen along a moving window and applying a joint temporal clustering algorithm to establish cluster membership of each voxel at each window. Contiguous voxels that had consistent cluster membership across all windows were then considered to be part of a homogeneous functional subunit. As PD subjects robustly had two homogenous clusters in the putamina, we also segmented the putamina in HC into two dynamic clusters for a fair comparison. We then estimated the dynamic connectivity using sliding windowed correlation between the mean signal from the identified homogenous subunits and 56 other predefined cortical and subcortical ROIs. Specifically, the mean dynamic connectivity strength and connectivity deviation were then compared to evaluate subregional differences.HC subjects had significant differences in mean dynamic connectivity and connectivity deviation between the two putaminal subunits. The posterior subunit connected strongly to sensorimotor areas, the cerebellum, as well as the middle frontal gyrus. The anterior subunit had strong mean dynamic connectivity to the nucleus accumbens, hippocampus, amygdala, caudate and cingulate. In contrast, PD subjects had fewer differences in mean dynamic connectivity between subunits, indicating a degradation of subregional specificity. Overall UPDRS III and MoCA scores could be predicted using mean dynamic connectivity strength and connectivity deviation. Side of onset of the disease was also jointly related with functional connectivity features.Our results suggest a robust loss of specificity of mean dynamic connectivity and connectivity deviation in putaminal subunits in PD that is sensitive to disease severity. In addition, altered mean dynamic connectivity and connectivity deviation features in PD suggest that looking at connectivity dynamics offers an additional dimension for assessment of neurodegenerative disorders.