Cerebral pathological and compensatory mechanisms in the premotor phase of leucine-rich repeat kinase 2 parkinsonism

Abstract

Compensatory cerebral mechanisms can delay motor symptom onset in Parkinson's disease. We aim to characterize these compensatory mechanisms and early disease-related changes by quantifying movement-related cerebral function in subjects at significantly increased risk of developing Parkinson's disease, namely carriers of a leucine-rich repeat kinase 2-G2019S mutation associated with dominantly inherited parkinsonism. Functional magnetic resonance imaging was used to examine cerebral activity evoked during internal selection of motor representations, a core motor deficit in clinically overt Parkinson's disease. Thirty-nine healthy first-degree relatives of Ashkenazi Jewish patients with Parkinson's disease, who carry the leucinerich repeat kinase 2-G2019S mutation, participated in this study. Twenty-one carriers of the leucine-rich repeat kinase 2-G2019S mutation and 18 non-carriers of this mutation were engaged in a motor imagery task (laterality judgements of left or right hands) known to be sensitive to motor control parameters. Behavioural performance of both groups was matched. Mutation carriers and non-carriers were equally sensitive to the extent and biomechanical constraints of the imagined movements in relation to the current posture of the participants' hands. Cerebral activity differed between groups, such that leucine-rich repeat kinase 2-G2019S carriers had reduced imagery-related activity in the right caudate nucleus and increased activity in the right dorsal premotor cortex. More severe striatal impairment was associated with stronger effective connectivity between the right dorsal premotor cortex and the right extrastriate body area. These findings suggest that altered movement-related activity in the caudate nuclei of leucine-rich repeat kinase 2-G2019S carriers might remain behaviourally latent by virtue of cortical

Experience-dependent modulation of alpha and beta during action observation and motor imagery

“…The presently demonstrated state/task-related increases in iAPF during KMI of everyday movements provides encouraging evidence for low-impact KMI training programmes that can yield improvements in iAPF functioning that can translate to resting state iAPF improvements. Previous work from our lab reveals dance-induced plasticity in the extrastriate body area during movement among expert dancers [11], which has been shown to serve as an alternate motor pathway for people with PD [63, 64]. Further research on how dance-induced neuroplasticity manifests in healthy experts will provide greater insights to effective interventions for this and other clinical populations.…”

Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease

“…FMRI studies of LRRK2 G2019S carriers without PD demonstrate altered connectivity during motor and cognitive tasks despite normal performance. 25, 26 These findings suggest underlying compensatory mechanisms that precede overt clinical signs. It is possible that these compensatory mechanisms protect mutation carriers from executive and attention dysfunction, which is often present in PD.…”

Neuroimaging in pre-motor Parkinson's disease

“…Two task-based fMRI studies have demonstrated increases in effective connectivity between basal ganglia and cortical regions including the premotor cortex (van Nuenen et al, 2012, Thaler et al, 2013), perhaps suggestive of mechanisms compensating for early neurodegeneration. Increased task-related premotor cortex activity has also been reported in heterozygous carriers of the PINK1 and parkin mutations (van Nuenen et al, 2009).…”