Non-Motor Symptoms in Primary Motor Neurological Disorders: from Molecular Pathways to Clinical and Therapeutic Implications

Neurodegenerative diseases with prominent motor symptoms, such as movement disorders and motor neuron diseases, are among major causes of disability and death worldwide. However, high emotional and economic burden of this neurological disorders is substantially influenced by a variety of non-motor symptoms preceding classical motor signs or appearing during the disease course. In this regard, Parkinson's disease (PD) patients may exhibit many prodromal extra-motor symptoms, such as hyposmia, emotional disorders, autonomic dysfunction, cognitive impairment and sleep disorders, several years to several decades before the onset of motor symptoms. In addition, Amyotrophic Lateral Sclerosis (ALS) patients frequently exhibit at onset one or more features of frontotemporal dysfunction in association with the motor syndrome. Of note, from the neuropathologic point of view, the early involvement in the neurodegenerative process of both motor and extra-motor brain areas in PD was revealed by Braak and his colleagues (2003) who proposed a staging scheme of PD pathology with initiation of alfa-synuclein pathology in the caudal brainstem and the olfactory bulb and spreading to the midbrain and the limbic system and neocortex. On this line, more recently, Brettschneider and his colleagues (2013) identified four neuropathological stages from ALS autopsy cases in agreement with the hypothesis that phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions propagate along axonal pathways from motor towards extra-motor areas via neuronal connections, as also supported in vivo by neuroimaging evidence. From the genetic point of view, although genome-wide association studies (GWAS) and pathway analyses have uncovered genetic variants conferring risk of neurodegenerative diseases and partially overlapped between Alzheimer’s disease (AD), PD and frontotemporal dementia (FTD), their role in determining cognitive and behavioral impairment remains not completely elucidated. Finally, from the prognostic point of view, extra-motor symptoms may have crucial implications on quality of life of patients and their caregivers, significantly impacting patients' ability to engage competently in therapeutic and end-of-life decisions.

In this Research Topic, we aim to address updated insights into clinical, genetic, neuropathological and neuroimaging correlates of non-motor symptoms in primary motor neurodegenerative diseases, derived from clinico-radiological and basic science analyses, focusing on potential prognostic biomarkers and therapeutic perspectives. Neuroscientists from all over the world are invited to submit original research papers, case reports, clinical trials, and review articles.

The use of the cover image was courtesy permitted by Homo Scrivens Ed. [Naples, Italy, 2018; from “Heart's Revenge” (“La rivincita del cuore”), p. 256, by E. Ferrara; image author: Maura Messina].