Keren Rosenberg-Katz

Gray matter atrophy distinguishes between Parkinson disease motor subtypes

Objective: To assess differences in gray matter (GM) atrophy between 2 Parkinson disease (PD) subtypes: the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype. Methods: Patients were classified as belonging to the predominately PIGD (n = 30) or predominately TD (n = 29) subtype. Voxel-based morphometry was used to compare GM in these 2 subtypes and to evaluate correlations between predefined regions of interest and the degree of symptoms. In the regions where GM atrophy was associated with symptoms, the relationship between GM volumes and functional connectivity was examined. Results: GM was reduced in the predominately PIGD group, compared with the predominately TD group, in areas that involve motor, cognitive, limbic, and associative functions (p < 0.05, false discovery rate corrected). Lower GM volumes in the pre–supplementary motor area (SMA) and in the primary motor area were associated with increased severity of PIGD symptoms (r = −0.42, p < 0.001; r = −0.38, p < 0.003, respectively). Higher GM volumes within the pre-SMA were associated with stronger functional connectivity between the pre-SMA and the putamen (r = 0.415, p < 0.025) in the patients with predominately PIGD. Conclusions: In patients with PD, PIGD symptoms are apparently associated with GM atrophy in motor-related regions and decreased functional connectivity. GM degeneration and a related decrease in spontaneous coactivation between cortical and subcortical motor-planning areas may partially account for the unique clinical characteristics of a subset of patients with PD.

White Matter Hyperintensities in Parkinson’s Disease: Do They Explain the Disparity between the Postural Instability Gait Difficulty and Tremor Dominant Subtypes?

Background Brain white matter hyperintensities (WMHs) commonly observed on brain imaging of older adults are associated with balance and gait impairment and have also been linked to cognitive deficits. Parkinson’s disease (PD) is traditionally sub-classified into the postural instability gait difficulty (PIGD) sub-type, and the tremor dominant (TD) sub-type. Considering the known association between WMHs and axial symptoms like gait disturbances and postural instability, one can hypothesize that WMHs might contribute to the disparate clinical sub-types of patients with PD. Methods 110 patients with PD underwent a clinical evaluation and a 3T MRI exam. Based on the Unified Parkinson Disease Rating Scale, the patients were classified into motor sub-types, i.e., TD or PIGD, and scores reflecting PIGD and TD symptoms were computed. We compared white matter burden using three previously validated methods: one using a semi-quantitative visual rating scale in specific brain regions and two automated methods. Results Overall, MRI data were obtained in 104 patients. The mean WMHs scores and the percent of subjects with lesions in specific brain regions were similar in the two subtypes, p = 0.678. The PIGD and the TD scores did not differ even when comparing patients with a relatively high burden of WMHs to patients with a relatively low burden. Across most of the brain regions, mild to moderate correlations between WMHs and age were found (r = 0.23 to 0.41; p<0.021). Conversely, no significant correlations were found between WMHs and the PIGD score or disease duration. In addition, depressive symptoms and cerebro-vascular risk factors were similar among the two subtypes. Conclusions In contrast to what has been reported previously among older adults, the present study could not demonstrate any association between WMHs and the PIGD or TD motor sub-types in patients with PD.

Altered brain activation in complex walking conditions in patients with Parkinson's disease

INTRODUCTION Behavioral studies suggest that deficits in cognitive domains and sensory-motor processes associated with Parkinsons disease (PD) impair the ability to walk in complex environments. However, the neural correlates of locomotion in complex environments are still unclear. METHODS Twenty healthy older adults (mean age 69.7 ± 1.3 yrs) and 20 patients with PD (mean age 72.9 ± 1.6 yrs; disease duration: 6.8 ± 1.3 yrs; UPDRSIII: 29.8 ± 2.4) were asked to imagine themselves walking while in the MRI scanner. Three imagined walking tasks, i.e., usual walking, obstacle negotiation, and navigation were performed. Watching the same virtual scenes without imagining walking served as control tasks. Whole brain analyses were used. RESULTS Compared to usual walking, both groups had increased activation during obstacle negotiation in middle occipital gyrus (MOG) (pFWEcorr<0.001), middle frontal gyrus (MFG) (pFWEcorr<0.005), and cerebellum (pFWEcorr<0.001). Healthy older adults had higher activation in precuneus and MOG (pFWEcorr<0.023) during navigation, while no differences were observed in patients with PD. Between group comparisons revealed that patients with PD had a significantly higher activation in usual walking and obstacle negotiation (pFWEcorr<0.039) while during navigation task, healthy older adults had higher activation (pFWEcorr<0.047). CONCLUSIONS Patients with PD require greater activation during imagined usual walking and obstacle negotiation than healthy older adults. This increased activation may reflect a compensatory attempt to overcome inefficient neural activation in patients with PD. This increased activation may reduce the functional reserve needed during more demanding tasks such as during navigation which may contribute to the high prevalence of falls and dual tasking difficulties among patients with PD.

Disparate effects of training on brain activation in Parkinson disease

Objective: To compare the effects of 2 forms of exercise, i.e., a 6-week trial of treadmill training with virtual reality (TT + VR) that targets motor and cognitive aspects of safe ambulation and a 6-week trial of treadmill training alone (TT), on brain activation in patients with Parkinson disease (PD). Methods: As part of a randomized controlled trial, patients were randomly assigned to 6 weeks of TT (n = 17, mean age 71.5 ± 1.5 years, disease duration 11.6 ± 1.6 years; 70% men) or TT + VR (n = 17, mean age 71.2 ± 1.7 years, disease duration 7.9 ± 1.4 years; 65% men). A previously validated fMRI imagery paradigm assessed changes in neural activation pretraining and post-training. Participants imagined themselves walking in 2 virtual scenes projected in the fMRI: (1) a clear path and (2) a path with virtual obstacles. Whole brain and region of interest analyses were performed. Results: Brain activation patterns were similar between training arms before the interventions. After training, participants in the TT + VR arm had lower activation than the TT arm in Brodmann area 10 and the inferior frontal gyrus (cluster level familywise error–corrected [FWEcorr] p < 0.012), while the TT arm had lower activation than TT + VR in the cerebellum and middle temporal gyrus (cluster level FWEcorr p < 0.001). Changes in fall frequency and brain activation were correlated in the TT + VR arm. Conclusions: Exercise modifies brain activation patterns in patients with PD in a mode-specific manner. Motor-cognitive training decreased the reliance on frontal regions, which apparently resulted in improved function, perhaps reflecting increased brain efficiency.

Dependency Network Analysis (DEPNA) Reveals Context Related Influence of Brain Network Nodes

Communication between and within brain regions is essential for information processing within functional networks. The current methods to determine the influence of one region on another are either based on temporal resolution, or require a predefined model for the connectivity direction. However these requirements are not always achieved, especially in fMRI studies, which have poor temporal resolution. We thus propose a new graph theory approach that focuses on the correlation influence between selected brain regions, entitled Dependency Network Analysis (DEPNA). Partial correlations are used to quantify the level of influence of each node during task performance. As a proof of concept, we conducted the DEPNA on simulated datasets and on two empirical motor and working memory fMRI tasks. The simulations revealed that the DEPNA correctly captures the network’s hierarchy of influence. Applying DEPNA to the functional tasks reveals the dynamics between specific nodes as would be expected from prior knowledge. To conclude, we demonstrate that DEPNA can capture the most influencing nodes in the network, as they emerge during specific cognitive processes. This ability opens a new horizon for example in delineating critical nodes for specific clinical interventions.

Subcortical Volumes Differ in Parkinson’s Disease Motor Subtypes: New Insights into the Pathophysiology of Disparate Symptoms

Objectives: Patients with Parkinson’s disease (PD) can be classified, based on their motor symptoms into the Postural Instability Gait Difficulty (PIGD) subtype or the Tremor Dominant (TD) subtype. Gray matter changes between the subtypes have been reported using whole brain Voxel-Based Morphometry (VBM), however, the evaluation of subcortical gray matter volumetric differences between these subtypes using automated volumetric analysis has only been studied in relatively small sample sizes and needs further study to confirm that the negative findings were not due to the sample size. Therefore, we aimed to evaluate volumetric changes in subcortical regions and their association with PD motor subtypes. Methods: Automated volumetric magnetic resonance imaging (MRI) analysis quantified the subcortical gray matter volumes of patients with PD in the PIGD subtype (n = 30), in the TD subtype (n = 30), and in 28 healthy controls (HCs). Results: Significantly lower amygdala and globus pallidus gray matter volume was detected in the PIGD, as compared to the TD subtype, with a trend for an association between globus pallidus degeneration and higher (worse) PIGD scores. Furthermore, among all the patients with PD, higher hippocampal volumes were correlated with a higher (better) dual tasking gait speed (r = 0.30, p < 0.002) and with a higher global cognitive score (r = 0.36, p < 0.0001). Lower putamen volume was correlated with a higher (worse) freezing of gait score (r = −0.28, p < 0.004), an episodic symptom which is common among the PIGD subtype. As expected, differences detected between HCs and patients in the PD subgroups included regions within the amygdala and the dorsal striatum but not the ventral striatum, a brain region that is generally considered to be more preserved in PD. Conclusions: The disparate patterns of subcortical degeneration can explain some of the differences in symptoms between the PD subtypes such as gait disturbances and cognitive functions. These findings may, in the future, help to inform a personalized therapeutic approach.

Alterations in conflict monitoring are related to functional connectivity in Parkinson's disease

Patients with Parkinsons disease (PD) have difficulties in executive functions including conflict monitoring. The neural mechanisms underlying these difficulties are not yet fully understood. In order to examine the neural mechanisms related to conflict monitoring in PD, we evaluated 35 patients with PD and 20 healthy older adults while they performed a word-color Stroop paradigm in the MRI. Specifically, we focused on changes between the groups in task-related functional connectivity using psycho-physiological interaction (PPI) analysis. The anterior cingulate cortex (ACC), which is a brain node previously associated with the Stroop paradigm, was selected as the seed region for this analysis. Patients with PD, as compared to healthy controls, had reduced task-related functional connectivity between the ACC and parietal regions including the precuneus and inferior parietal lobe. This was seen only in the incongruent Stroop condition. A higher level of connectivity between the ACC and precuneus was correlated with a lower error rate in the conflicting, incongruent Stroop condition in the healthy controls, but not in the patients with PD. Furthermore, the patients also had reduced functional connectivity between the ACC and the superior frontal gyrus which was present in both the incongruent and congruent task condition. The present findings shed light on brain mechanisms that are apparently associated with specific cognitive difficulties in patients with PD. Among patients with PD, impaired conflict monitoring processing within the ACC-based fronto-parietal network may contribute to difficulties under increased executive demands.

Cerebral Imaging Markers of GBA and LRRK2 Related Parkinson’s Disease and Their First-Degree Unaffected Relatives

Cerebral atrophy has been detected in patients with Parkinson’s disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program. All participants were cognitively intact based on a computerized cognitive assessment battery. Fifty-seven idiopathic PD patients, 9 LRRK2-PD, 12 GBA-PD, 49 NMNC, 41 LRRK2-NMC and 14 GBA-NMC participated in this study. Lower volumes among patients with PD compared to unaffected participants were detected in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala and the right pallidum (p = 0.016). PD patients demonstrated lower cortical thickness indexes in a majority of regions assessed compared with non-manifesting participants. No differences in cortical thickness and subcortical volumes were detected within each of the groups of participants based on genetic status. Mutations in the GBA and LRRK2 genes are not important determinants of cortical thickness and subcortical volumes in both patients with PD and non-manifesting participants. PD is associated with a general reduction in cortical thickness and sub-cortical atrophy even in cognitively intact patients.

Differential neural activation in healthy older adults compared to subjects with Parkinson's disease during motor imagery of walking in virtual environments

The neural correlates of locomotion in complex environments are unclear. Twenty healthy older adults and 20 patients with Parkinsons disease (PD) were asked to imagine walking in different virtual environments in MRI scanner. Whole brain analyses were performed. Between group comparisons revealed that patients with PD had a significantly higher activation already during imagined usual walk. However, comparisons between walking tasks showed increased activation during imagined complex walking tasks only in healthy older adults. This increased activation in patients with PD act as a compensatory strategy that limits the ability to recruit additional brain areas during more demanding walking tasks.