Impact of motor symptom asymmetry on non-motor outcomes in Parkinson’s disease: a systematic review

Introduction

Motor symptoms in people living with Parkinson’s disease (PwPD) (including resting tremor, bradykinesia, muscle rigidity, postural instability, and gait changes) typically affect one side of the body more than the other, and may eventually affect both sides of the body as the disease advances¹. These asymmetries are generally associated with contralateral neurodegenerative patterns at the level of the basal ganglia (BG), measured through different imaging methods, in particular PET and DAT-SCAN^2,3, but are less obvious using MRI⁴. Current literature lacks consensus regarding the underlying causes of motor symptom asymmetry in Parkinson’s disease (PD), with various hypotheses proposed. These include histopathological mechanisms, genetic predispositions, motor practice, handedness, and the presence of structural lesions⁵. Moreover, the developmental trajectories of motor symptom (a)symmetry seem unclear, with some authors suggesting a persistence of asymmetry of motor symptoms over time, while others suggest a bilateralization of motor symptoms^{6, 7–8}.

While Braak et al. ⁹ model has overlooked motor symptom asymmetry as a potential variable for distinguishing distinct PD phenotypes, the recent α-Synuclein Origin and Connectome Model (SOC Model) proposed by Borghammer¹⁰ suggests the existence of two PD phenotypes based on motor symptom symmetry. Accordingly, the first so-called “Brain-first” phenotype would be characterized by disease development in subcortical regions, in particular in the olfactory bulb or amygdala, associated symptomatically to the presence of fewer autonomic symptoms, less Rapid Eye Movement (REM) sleep disorders, less hyposmia, as well as slower disease progression and cognitive decline; this phenotype is suggested to be more associated with lateralized motor symptoms and asymmetric dopaminergic denervation. The second phenotype, named “Body-first PD”, characterized by pathologic processes in the enteric nervous system, would be symptomatically characterized by greater autonomic symptoms, more rapid disease progression, and cognitive decline. This latter phenotype would be more associated with symmetrical motor symptoms and equally symmetrical dopaminergic denervation^11,12. A recent post-mortem study suggested a revision of the dual-hit SOC model, in particular, the Body-first phenotype (with a symmetrical onset of disease) would be more inclined to develop dementias, especially dementia with Lewy bodies^13,14. Accordingly, and therefore, links are starting to be established between (a-)symmetry of motor symptoms and major cognitive impairments in PD. One of the limitations...