Cerebro-cerebellar motor networks in clinical subtypes of Parkinson's disease

Abstract

Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instability-and-gait-disorder (PIGD) motor subtypes. PIGD represents a more aggressive form of the disease that TD patients have a potentiality of converting into. This study investigated functional alterations within the cerebro-cerebellar system in PD-TD and PD-PIGD patients using stepwise functional connectivity (SFC) analysis and identified neuroimaging features that predict TD to PIGD conversion. Thirty-two PD-TD, 26 PD-PIGD patients and 60 healthy controls performed clinical/cognitive evaluations and resting-state functional MRI (fMRI). Four-year clinical follow-up data were available for 28 PD-TD patients, who were classified in 10 converters (cTD-PD) and 18 non-converters (ncTD-PD) to PIGD. The cerebellar seed-region was identified using a fMRI motor task. SFC analysis, characterizing regions that connect brain areas to the cerebellar seed at different levels of link-step distances, evaluated similar and divergent alterations in PD-TD and PD-PIGD. The discriminatory power of clinical data and/or SFC in distinguishing cPD-TD from ncPD-TD patients was assessed using ROC curve analysis. Compared to PD-TD, PD-PIGD patients showed decreased SFC in temporal lobe and occipital lobes and increased SFC in cerebellar cortex and ponto-medullary junction. Considering the subtype-conversion analysis, cPD-TD patients were characterized by increased SFC in temporal and occipital lobes and in cerebellum and ponto-medullary junction relative to ncPD-TD group. Combining clinical and SFC data, ROC curves provided the highest classification power to identify conversion to PIGD. These findings provide novel insights into the pathophysiology underlying different PD motor phenotypes and a potential tool for early characterization of PD-TD patients at risk of conversion to PIGD.

Fig. 1. Study framework.

A Mapping motor activation in the cerebellum. B Cortical connectivity diagram of a selected area in the cerebellum using stepwise connectivity analysis. Cortical maps show characterization of direct and indirect functional connectivity from motor cerebellar seed region. Functional connectivity reorganization was then evaluated in different PD subtypes. C ROC analyses for characterization of PD-TD patients at risk of conversion to PIGD. c, converter; fMRI, functional MRI; HC, healthy controls; nc, non-converter; PD-TD, Parkinson’s disease tremor dominant; PD-PIGD, Parkinson’s disease with postural instability and gait disorders.

Fig. 2. Differences between Parkinson’s disease participants and healthy controls in stepwise functional connectivity of the cerebellar seed region.

Cortical maps represent the significant differences in stepwise functional connectivity values between PD subtypes and healthy controls (I, II) and among PD groups (III). Statistical analysis was adjusted for age and gender. Results were corrected for multiple comparisons using a threshold-free cluster enhancement method combined with nonparametric permutation testing at p-value <0.05 FWE-corrected. Color bars show the t-statistic applicable to the image. HC, healthy controls; L, left; R, right; PD-TD, Parkinson’s disease tremor dominant; PD-PIGD, Parkinson’s disease with postural instability and gait disorders.

Fig. 3. Differences in stepwise functional connectivity of the cerebellar seed region between PD-TD converters and non-converters to PD-PIGD subtype in a 4-year follow-up.

I Cortical maps represent the significant differences in stepwise functional connectivity values between PD-TD subtypes. Statistical analysis was adjusted for age and gender. Results were corrected for multiple comparisons using a threshold-free cluster enhancement method combined with nonparametric permutation testing at p-value < 0.05 FWE-corrected. Color bars show the t-statistic applicable to the image. II Functional connectivity of altered network in PD-TD converters to PIGD subtype. Box plot of functional connectivity of altered brain network is shown for patient group. The red horizontal line in each box plot represents the median, the two lines just above and below the median represent the 25th and 75th percentiles, whiskers represent the minimum and maximum values, and all the dots outside the confidence interval are considered as outliers. III ROC analyses for characterization of patient at high risk of conversion to PIGD subtype. The predictive accuracy of direct (one-link-step) and indirect (four link-steps) functional connectivity and/or clinical data for the conversion to PIGD subtype was evaluated by area under the curve of ROC analysis. AUC, area under the curve; c, converters; CI, confidence interval; FC, functional connectivity; HC, healthy controls; L, left; nc, non-converter; R, right; ROC, receiver operating characteristic; PD-TD, Parkinson’s Disease tremor dominant.