Predicting the multi-domain progression of Parkinson's disease: a Bayesian multivariate generalized linear mixed-effect model.

BACKGROUND: It is challenging for current statistical models to predict clinical progression of Parkinson's disease (PD) because of the involvement of multi-domains and longitudinal data. METHODS: Past univariate longitudinal or multivariate analyses from cross-sectional trials have limited power to predict individual outcomes or a single moment. The multivariate generalized linear mixed-effect model (GLMM) under the Bayesian framework was proposed to study multi-domain longitudinal outcomes obtained at baseline, 18-, and 36-month. The outcomes included motor, non-motor, and postural instability scores from the MDS-UPDRS, and demographic and standardized clinical data were utilized as covariates. The dynamic prediction was performed for both internal and external subjects using the samples from the posterior distributions of the parameter estimates and random effects, and also the predictive accuracy was evaluated based on the root of mean square error (RMSE), absolute bias (AB) and the area under the receiver operating characteristic (ROC) curve. RESULTS: First, our prediction model identified clinical data that were differentially associated with motor, non-motor, and postural stability scores. Second, the predictive accuracy of our model for the training data was assessed, and improved prediction was gained in particularly for non-motor (RMSE and AB: 2.89 and 2.20) compared to univariate analysis (RMSE and AB: 3.04 and 2.35). Third, the individual-level predictions of longitudinal trajectories for the testing data were performed, with ~80% observed values falling within the 95% credible intervals. CONCLUSIONS: Multivariate general mixed models hold promise to predict clinical progression of individual outcomes in PD. TRIAL REGISTRATION: The data was obtained from Dr. Xuemei Huang's NIH grant R01 NS060722 , part of NINDS PD Biomarker Program (PDBP). All data was entered within 24 h of collection to the Data Management Repository (DMR), which is publically available ( https://pdbp.ninds.nih.gov/data-management ).

Lexical-semantic search related to side of onset and putamen volume in Parkinson's disease.

Parkinson's disease (PD) is characterized by dopaminergic cell loss and reduced striatal volume. Prior studies have demonstrated striatal involvement in access to lexical-semantic knowledge and damage to this structure may be evident in the lexical properties of responses. Semantic fluency task responses from early stage, non-demented PD participants with right (PD-R) or left (PD-L) lateralizing symptoms were compared to matched controls on lexical properties (word frequency, age of acquisition) and correlated with striatal volumes segmented from T1-weighted brain MR images. PD-R participants produced semantic fluency responses of a lower age of acquisition than PD-L and control participants (p < 0.05). PD-R age of acquisition responses correlated positively with putamen volume (p < 0.05), while age of acquisition of responses correlated negatively with caudate volume in controls (p < 0.05). Findings provide evidence for a role of the striatum in lexical-semantic access and qualitative changes in lexical access in select PD patients.

Cortical Thinning and Cognitive Impairment in Parkinson's Disease without Dementia.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction (bradykinesia, rigidity, tremor, and postural instability), and pathologically by the loss of dopaminergic neurons in the substantia nigra of the basal ganglia. Growing literature supports that cognitive deficits may also be present in PD, even in non-demented patients. Gray matter (GM) atrophy has been reported in PD and may be related to cognitive decline. This study investigated cortical thickness in non-demented PD subjects and elucidated its relationship to cognitive impairment using high-resolution T1-weighted brain MRI and comprehensive cognitive function scores from 71 non-demented PD and 48 control subjects matched for age, gender, and education. Cortical thickness was compared between groups using a flexible hierarchical multivariate Bayesian model, which accounts for correlations between brain regions. Correlation analyses were performed among brain areas and cognitive domains as well, which showed significant group differences in the PD population. Compared to Controls, PD subjects demonstrated significant age-adjusted cortical thinning predominantly in inferior and superior parietal areas and extended to superior frontal, superior temporal, and precuneus areas (posterior probability >0.9). Cortical thinning was also found in the left precentral and lateral occipital, and right postcentral, middle frontal, and fusiform regions (posterior probability >0.9). PD patients showed significantly reduced cognitive performance in executive function, including set shifting (p = 0.005) and spontaneous flexibility (p = 0.02), which were associated with the above cortical thinning regions (p < 0.05).

Association of neurobehavioral performance with R2* in the caudate nucleus of asymptomatic welders.

OBJECTIVES: Welding fumes contain several metals including manganese (Mn) and iron (Fe) that may affect the nervous system. Previous studies of potential welding-related neurotoxicity have focused primarily on Mn exposure. The current study examined neurobehavioral and brain imaging changes in asymptomatic welders and their associations with both Mn and Fe exposure measurements. METHODS: Data were obtained from subjects with (n=46) and without (controls; n=31) a history of welding exposure. Occupational questionnaires estimated recent (HrsW; welding hours and E90; cumulative exposure, past 90days) and lifetime (YrsW; total welding years and ELT; cumulative exposure, lifetime) exposure. Brain MRI pallidal index (PI), R1 (1/T1), and R2* (1/T2*) were measured to estimate Mn and Fe concentrations in the basal ganglia [caudate nucleus (CN), putamen, and globus pallidus], amygdala, and hippocampus. Comprehensive neuropsychological tests were conducted to examine behavioral differences between welders and controls. Correlation analyses were conducted between neuropsychological tests and those exposure measurements that showed significant group differences. RESULTS: Compared to controls, welders had significantly higher R2* in the CN and lower performance on the Phonemic Fluency test. Correlation analyses revealed that welders' Phonemic Fluency scores were inversely associated with R2* in the CN, but not with the PI or R1 in any brain region of interest studied. DISCUSSION: The results showed that neurobehavioral performance for the asymptomatic welders in our study was worse than individuals who had not welded, and suggest the differences may be associated with higher Fe accumulation in the CN.

Decreased leftward 'aiming' motor-intentional spatial cuing in traumatic brain injury.

OBJECTIVE: To characterize the mediation of attention and action in space following traumatic brain injury (TBI). METHOD: Two exploratory analyses were performed to determine the influence of spatial 'Aiming' motor versus spatial 'Where' bias on line bisection in TBI participants. The first experiment compared performance according to severity and location of injury in TBI. The second experiment examined bisection performance in a larger TBI sample against a matched control group. In both experiments, participants bisected lines in near and far space using an apparatus that allowed for the fractionation of spatial Aiming versus Where error components. RESULTS: In the first experiment, participants with severe injuries tended to incur rightward error when starting from the right in far space, compared with participants with mild injuries. In the second experiment, when performance was examined at the individual level, more participants with TBI tended to incur rightward motor error compared to controls. CONCLUSIONS: TBI may cause frontal-subcortical cognitive dysfunction and asymmetric motor perseveration, affecting spatial Aiming bias on line bisection. Potential effects on real-world function need further investigation. (PsycINFO Database Record

The pattern of gray matter atrophy in Parkinson's disease differs in cortical and subcortical regions.

Cortical and subcortical gray matter (GM) atrophy may progress differently during the course of Parkinson's disease (PD). We delineated and compared the longitudinal pattern of these PD-related changes. Structural MRIs and clinical measures were obtained from 76 PD with different disease durations and 70 Controls at baseline, 18-, and 36 months. Both cortical and subcortical (putamen, caudate, and globus pallidus) GM volumes were obtained, compared, and associated with PD clinical measures at baseline. Their volumes and rates of change also were compared among Controls, PDs, and PD subgroups based on duration of illness [≤1 year (PD(E)), 1-5 years (PD(M)), and >5 years (PD(L))]. Compared to Controls, PD subjects displayed smaller cortical GM and striatal(putamen, caudate, ps ≤0.001), volumes at baseline. Cortical GM volumes were negatively associated with disease duration at baseline, whereas striatal volumes were not. PD subjects demonstrated accelerated volume loss in cortical GM (p = 0.006), putamen (p = 0.034), and caudate (p = 0.008) compared to Controls. Subgroup analyses demonstrated that accelerated cortical atrophy reached statistical significance in PD subjects with duration of illness 1-5 years (PD(M), ps<0.001) and the trend of accelerated atrophy seemed to persist until later stages, whereas striatal atrophy occurred in PD subjects with PD(E) (p = 0.021 for putamen, p = 0.005 for caudate) and PD(M) (p = 0.002 for putamen, p = 0.001 for caudate) that significantly slowed down in PD(L) (ps for PD(L) vs PD(E) or PD(M): <0.01). The pattern of GM loss in PD differs in cortical and subcortical regions, with striatal atrophy occurring earlier and extra-striatal cortical atrophy later.

Side of motor onset is associated with hemisphere-specific memory decline and lateralized gray matter loss in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that generally begins with asymmetric motor symptoms that persist over time. This suggests that the dysfunction in the nigrostriatal motor circuit may be lateralized. The present study examined whether the asymmetric motor presentation is associated with hemisphere-specific cognitive decline and lateralized gray matter volume loss. METHODS: Data from comprehensive cognitive tests that measured visuospatial and verbal functions and high-resolution T1-weighted magnetic resonance images of the brain were acquired in 23 PD subjects with left-side motor symptom onset (PDL), 23 PD subjects with right-side onset (PDR), and 23 matched Controls. GM volume differences were assessed using voxel-based morphometry (VBM). Cognitive results and VBM were compared among the three groups, and correlation analyses were performed between those cognitive domains and brain areas that showed significant differences. RESULTS: PDL subjects had lower performance on visuospatial memory tasks compared to PDR. Furthermore, PDL subjects experienced lateralized GM loss, which was localized predominantly in the right hemisphere contralateral to the side of motor symptom onset. Visuospatial memory performance in PDL was correlated with GM loss in the right middle frontal gyrus and precuneus. CONCLUSION: These data suggest that the onset of asymmetric motor symptoms in PD may be associated with hemisphere-specific memory decline and lateralized GM loss, particularly in PDL. This study underscores the importance of classifying PD subgroups based on the side of motor symptom onset for clinical care and research to optimize cognitive outcomes.

Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients.

BACKGROUND: Whereas the motor dysfunction in Parkinson's disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss. METHODS: High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences. RESULTS: PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients. CONCLUSIONS: Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized "frontal lobe" function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.