Cortical Implications of Advancing Age and Disease Duration in Parkinson's Disease Patients with Postural Instability and Gait Dysfunction

Abstract

Background: Parkinson's Disease patients with predominant gait dysfunction appear to have reduced cortical thickness compared to other motor phenotypes. The extent to which advancing age or disease duration impact the pattern of these distinctions is unclear.

Objective: We examine if PD patients with predominant signs of postural instability and gait dysfunction are distinguished by distinct patterns of cerebral atrophy, and how these differences are influenced by age and disease duration.

Methods: The Unified Parkinson's Disease Rating Score (UPDRS) was administered to 196 PD patients (age = 61.4±8.9yrs) in the Off and On dopamine state. All completed a structural T1-weighted brain MRI. We defined 3 motor phenotypes: tremor dominant, akinetic-rigid, and postural instability with gait disorder. General linear modeling quantified cortical thickness in relation to disease duration, and motor improvement after dopaminergic therapy. Cortical thickness and subcortical volumes were compared between the three motor subtypes, after controlling for disease duration and age.

Results: We identified 177/196 patients who met criteria for a motor subtype. When corrected for disease duration, postural-instability patients had marked cortical thinning of the bilateral frontal-temporal and posterior cortical regions (cuneus/precuneus). After regressing for age, reduced frontal thickness was evident in patients with gait dysfunction. Widespread cortical thinning was associated with increasing disease duration and reduced motor improvement to dopaminergic therapy.

Conclusions: Results emphasize that the profile of motor signs, especially prominent gait manifestations, relate to cortical thinning in distinct regions. Unique patterns of atrophy appear to be driven by advancing pathology related to age and disease duration.

Keywords: MRI; PIGD; Parkinson’s disease; gait disorders; motor phenotypes; tremor dominant.

Fig. 1

Cortical thickness maps emphasizing cortical relationships with increasing disease duration and reduced motor response to dopamine therapy. (a) Areas of significant inverse correlation between disease duration and cortical thickness. (b) Areas of significant correlation between decreased motor response to dopamine therapy (UPDRS On – UPDRS Off) and decreased cortical thickness.

Fig. 2

Cortical thinning distinguishes PIGD from other motor phenotypes in the Off Dopamine state. (a) Corrected for disease duration: When defining motor phenotypes in the Off dopamine state, widespread cortical distinctions separate PIGD (n = 74) from the other phenotypes (AR n = 48 and TD n = 55). Yellow: p < 0.0005, orange: p < 0.005, red: p < 0.05). (b) Corrected for age: Cortical distinctions in the frontal lobe separate PIGD (n = 74) from the TD (p < 0.005). No significant differences were observed between PIGD and AR phenotypes or between AR and TD phenotype.