Objective: This study investigates clinical and neuroimaging predictors of recurrent falls and gait disturbances in PLA2G6-related Parkinsonism.

Background: PLA2G6-related Parkinsonism is characterized by dystonia-parkinsonism, cerebellar ataxia, and rapid progression of axial symptoms. Recurrent falls and gait disturbance are major clinical milestones in Parkinsonian syndromes. It has a detrimental impact on quality of life.

Method: This study included 26 patients with PLA2G6-related Parkinsonism. During the same recruitment period, we also enrolled 211 early-onset Parkinson’s disease patients (onset before age 40) without pathogenic mutations as the control group. Multivariable logistic regression was used to identify factors influencing recurrent falls and freezing of gait. High-resolution MRI and Quantitative Susceptibility Mapping (QSM) were performed on 17 of the PLA2G6 patients, with susceptibility values and volumes measured in deep grey matter regions.

Results: PLA2G6 mutation carriers experienced recurrent falls 6.45 years earlier than non-carriers (p=0.012). Significant predictors for recurrent falls included the presence of PLA2G6 mutations (p<0.001), levodopa equivalent daily dose (LEDD) (p=0.005), and urinary incontinence (p=0.002), but not orthostatic hypotension. Freezing of gait was influenced by age at baseline (p=0.005), LEDD (p<0.001), disease duration (p=0.005), and MMSE (p=0.009), but not the group. Among PLA2G6 carriers, ataxia (p=0.039) and increased QSM susceptibility in the right caudate nucleus (p=0.025) were associated with earlier falls. No significant difference in volume loss of deep grey matter regions was observed.

Conclusion: Unlike PD, where hypotension predicts falls, PLA2G6-related falls are linked to urinary incontinence. This dissociation may arise from the shorter disease duration in PLA2G6 patients, where urinary incontinence manifests as an ​early symptom of autonomic dysfunction. Targeting autonomic restoration may delay falls and improve quality of life. Crucially, in PSP patients with postural instability, decreased regional glucose uptake in the caudate nucleus was correlated with impaired programming of anticipatory postural adjustments (APA). Iron accumulation in right caudate nucleus of PLA2G6-related Parkinsonism may disrupt postural control and eventually accelerate recurrent falling.

Table 1. Factors Affecting Motor Complications

Figure 1. Correlation of falls and right caudate

References: Altmann, C. F., et al. (2023). “Predictors of falls in Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy: a retrospective study.” Neurol Neurochir Pol 57(3): 297-304.
Palmisano, C., et al. (2020). “Gait initiation in progressive supranuclear palsy: brain metabolic correlates.” Neuroimage Clin 28: 102408.
Lan, Y., et al. (2024). “Resting-state functional connectivity of the occipital cortex in different subtypes of Parkinson’s disease.” CNS Neurosci Ther 30(8): e14915.
Magrinelli, F., et al. (2022). “Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.” Mov Disord 37(1): 148-161.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-neuro-imaging-predictors-of-falls-in-pla2g6-related-parkinsonism-a-retrospective-study/