Changes in Action Tremor in Parkinson's Disease over Time: Clinical and Neuroimaging Correlates

Abstract

Background: The various symptoms of Parkinson's disease (PD) may change differently over time as the disease progresses. Tremor usually manifests early in the disease, but unlike other motor symptoms, its severity may diminish over time. The cerebral mechanisms underlying these symptom-specific longitudinal trajectories are unclear. Previous magnetic resonance imaging (MRI) studies have shown structural changes in brain regions associated with PD tremor, suggesting that structural changes over time may define clinical trajectories.

Objectives: The aims were to investigate the longitudinal trajectory of PD tremor in relation to bradykinesia and rigidity, and assess whether tremor progression is related to structural changes in tremor-related areas.

Methods: We used data from the Personalized Parkinson Project: a two-year longitudinal study involving 520 PD patients and 60 healthy controls, who were measured twice clinically and with MRI. Mixed-effects models were used to compare tremor, bradykinesia, and rigidity progression; investigate gray matter changes in tremor-related regions (cerebello-thalamo-cortical circuit and pallidum); and calculate associations between symptom severity and brain structure. Associations across the whole brain were included to assess anatomical specificity.

Results: Bradykinesia and rigidity worsened over 2 years, whereas tremor behaved differently: resting tremor severity remained stable, whereas postural and kinetic tremor severity decreased. Attenuation of postural and kinetic tremor was associated with, but not restricted to, atrophy in tremor-related areas. Opposite relationships were observed for bradykinesia and rigidity.

Conclusions: Action tremor (postural and kinetic) is an early symptom of PD, which reduces with disease progression. Longitudinal brain atrophy correlates with tremor and other motor symptoms in opposite ways. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson; atrophy; longitudinal; progression; tremor.

FIG. 1

Clinical motor progression. Longitudinal trajectories of (A) bradykinesia, (B) rigidity, and (C) tremor severity in the cohort presenting with at least all three symptoms at baseline (n = 363). Tremor was subdivided into (D) resting, (E) postural, and (F) kinetic tremor. For each tremor subtype, longitudinal trajectories are shown in the cohort presenting with at least any form of resting (n = 247), postural (n = 278), or kinetic (n = 279) tremor at baseline. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Two‐year atrophy in tremor‐related regions and across the whole brain. (A–D) Gray matter atrophy in left (blue) and right (red) tremor‐related regions. (E–G) For whole‐brain analyses, only areas showing significant two‐year atrophy are visualized. 2Y, two‐year. MNI‐coordinate slices (B: z = 7; D: y = −4). [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Atrophy was related to attenuation of postural and kinetic tremor, and inversely to worsening of bradykinesia and rigidity. (A) Example of how within‐subject gray matter values are obtained using person‐mean centering of timepoint‐specific volumes. (B) Atrophy in the globus pallidus was related to attenuation of postural tremor scores. Here, paired person‐mean centered volumes from one patient are shown using red arrows. (C) Thinning of the precentral gyri and (D) atrophy of cerebellar lobules V were related to attenuation of kinetic tremor. (E) Thinning of the precentral gyri and (F) pallidal atrophy were related to worsening of rigidity. The dark‐blue lines show the fitted regression line for person‐mean centered volumes, and the light‐blue shaded areas show the pointwise 95% confidence band for the fitted values. For visualization, person‐mean centered volumes are raw values. Associations between two‐year atrophy across the whole brain and changes in (G) bradykinesia, (H) rigidity, and (I) kinetic tremor severity. Only significant results are presented. Each area is color coded using the strength of the association (β_State). [Color figure can be viewed at wileyonlinelibrary.com]