The heterogeneity of Parkinson’s disease (PD) has been recognized since its description by James Parkinson over 200 years ago. The complexity of motor and non-motor PD manifestations has led to many attempts of PD subtyping with different prognostic outcomes; however, the pathophysiological foundations of PD heterogeneity remain elusive. Genetic contributions to PD may be informative in understanding the underpinnings of PD subtypes. As such, recognizing genotype-phenotype associations may be crucial for successful gene therapy. We review the state of knowledge on the genetic architecture underlying PD subtypes, discussing the monogenic forms, as well as oligo- and polygenic risk factors associated with various PD subtypes. Based on our review, we argue for the unification of PD subtyping classifications, the dichotomy of studies on genetic factors and genetic modifiers of PD, and replication of results from previous studies.

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Genetic architecture of Parkinson’s disease subtypes – Review of the literature

Freezing of gait (FOG) is a common symptom in the late stages of Parkinson’s disease and related disorders. Videos are the gold standard method to conduct FOG scoring; however, the measurement accuracy of FOG scoring based on videos has not been formally assessed, despite its use in previous studies. This study aimed to calculate the measurement accuracy of video-based FOG scoring. Three evaluators scored the FOG based on 157 video data points collected from 21 patients using an annotation tool. One evaluator measured the intra-rater reliability of the retest. The total duration of observed FOG, percentage of the time spent with FOG during the walking task (%FOG), and FOG phenotypes (shuffling, trembling, and complete akinesia) were evaluated. Intraclass correlation coefficients were used to determine the intra- and inter-rater reliabilities. The duration of FOG and %FOG showed good measurement accuracy for both intra-rater and inter-rater reliabilities. However, the FOG phenotypes showed poor measurement accuracy in inter-rater reliability. These results indicate that the temporal characteristics of FOG can be scored with a high degree of measurement accuracy, even with different evaluators; conversely, the FOG phenotypes need to be scored by several evaluators.

Measurement Accuracy of Freezing of Gait Scoring Based on Videos

Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily‐ON therapeutic condition.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ene.15558

How resistant are levodopa‐resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease

INTRODUCTION
Elderly individuals with neurodegenerative diseases, such as Parkinson's disease (PD), may experience difficulties when performing functional tasks.


OBJECTIVE
To analyze the handgrip strength, pulling force, and ground reaction forces (GRF) of individuals with and without PD when boarding a bus while performing both simple (ST) and dual tasks (DT).


METHOD
This case-control study addressed 31 individuals with PD (GPD) and 30 healthy individuals (GHI). Assessments were performed in ST and DT situations using a bus model (prototype). Handgrip strength and pulling force were measured in both upper limbs using a dynamometer, and GRF was measured using a force platform. The GPD's and GHI's performances were compared in both ST and DT, and the individuals were classified as fallers according to the Falls Efficacy Scale.


RESULTS
In the inter-group comparison, the GPD presented significantly lower maximum force using their right hand, in handgrip strength (30.43 vs. 36.62, P = .022), and pulling force (10.77 vs 12.81, P = .037). The left hand's pulling force proved to be the most demanding for the GPD, during ST (6.35 vs. 4.76, P = .006) and DT (6.32 vs 4.74, P = .008). The GPD also took longer to perform ST (6.14 vs. 4.67, P < .001) and DT (6.08 vs. 4.81, P = .002). Additionally, the GPD was more afraid of falling compared to the GHI (34.74 vs. 24.77, P < .001).


CONCLUSION
Boarding a bus is a complex task for individuals with PD because they present lower maximum strength in the upper limbs and more significant functional expenditure than their healthy counterparts.

Analysis of handgrip strength, pulling force using the upper limbs, and ground reaction forces in the task of boarding a bus between healthy elderly individuals and those with Parkinson's disease.

One cue does not fit all: A systematic review with meta-analysis of the effectiveness of cueing on freezing of gait in Parkinson’s disease

Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson's disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients.

Cathy K Cui

Papers

Future Therapeutic Strategies for Freezing of Gait in Parkinson's Disease