PT  - JOURNAL ARTICLE
AU  - Helmich, Rick C.
AU  - Thaler, Avner
AU  - van Nuenen, Bart F.L.
AU  - Gurevich, Tanya
AU  - Mirelman, Anat
AU  - Marder, Karen S.
AU  - Bressman, Susan
AU  - Orr-Urtreger, Avi
AU  - Giladi, Nir
AU  - Bloem, Bastiaan R.
AU  - Toni, Ivan
TI  - Reorganization of corticostriatal circuits in healthy G2019S <em>LRRK2</em> carriers
AID  - 10.1212/WNL.0000000000001189
DP  - 2015 Jan 27
TA  - Neurology
PG  - 399--406
VI  - 84
IP  - 4
4099  - http://n.neurology.org/content/84/4/399.short
4100  - http://n.neurology.org/content/84/4/399.full
SO  - Neurology2015 Jan 27; 84
AB  - 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.DAT=dopamine transporter; FWE=family-wise error; GBA=β-glucocerebrosidase; LRRK2=leucine-rich repeat kinase 2; MNI=Montreal Neurological Institute; PD=Parkinson disease; ROI=region of interest; SMA=supplementary motor area; SPM=Statistical Parametric Mapping