Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers

Abstract

Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. Results:The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by nigrostriatal dopamine depletion. The motor symptoms of PD appear only when dopaminergic cell death reaches a critical threshold of 50% to 80%.1 This suggests that the nervous system has a marked potential to compensate for these changes.2 However, human studies of cerebral compensation in premotor PD are lacking, given the difficulty of predicting who will develop PD in the future.Previous work has shown that compensatory mechanisms in idiopathic PD depend on brain regions relatively unaffected by dopamine depletion, such as the anterior striatum.3,4 Using fMRI in early-stage PD, we recently showed a shift in corticostriatal connectivity from severely affected striatal regions (posterior putamen) to less affected striatal regions (anterior putamen). 5If these changes reflect compensation, they should also occur in the premotor phase of PD, when functional reorganization of cerebral circuits prevents overt clinical symptoms. 2 *These authors contributed equally to this work.

Early synaptic dysfunction in Parkinson's disease: Insights from animal models

“…Interesting evidence also comes from neuroimaging studies of nonmanifesting subjects carrying the LRRK2 G2019S mutation, a peculiar population with an age‐dependent risk of developing PD. Functional magnetic resonance imaging investigation revealed an age‐dependent reorganization of corticostriatal connectivity with a pattern resembling that found in idiopathic PD patients . Such a connectivity shift, from more affected striatal regions to less affected ones, is believed to reflect the underlying dopaminergic dysfunction and parallel the abnormalities of corticostriatal plasticity …”

Imaging Markers of Progression in Parkinson's Disease

“…Moreover, a region of interest analysis of the SMN functional connectivity within the basal ganglia revealed that l ‐dopa significantly increased the participation of these subcortical regions to SMN activity and may selectively induce low‐frequency rhythm changes . Interestingly, SMN connectivity abnormalities were also detected in asymptomatic LRRK2 (G2019S) mutation carriers, suggesting that functional changes may also occur earlier during the preclinical phase of the disease …”

Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers

“…6,7 A recent fMRI study demonstrated that asymptomatic G2019S mutation carriers may have abnormalities in corticostriatal circuitry. 8 However, there are currently no known ways to predict which G2019S carriers will develop PD.…”