Background The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking. Objective To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. Methods We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. Results LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status. Conclusion PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Background Reduced arm swing is a well-known clinical feature of Parkinson’s disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing and axial rotation may also be detectable in the prodromal phase. Objective The purpose of this study was to evaluate the relationship between the LRRK2-G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD. Methods A total of 380 participants (186 healthy nonmanifesting controls and 194 PD patients) from 6 clinical sites underwent gait analysis while wearing synchronized 3-axis body-fixed sensors on the lower back and bilateral wrists. Participants walked for 1 minute under the following 2 conditions: (1) usual walking and (2) dual-task walking. Arm swing amplitudes, asymmetry, variability, and smoothness were calculated for both arms along with measures of axial rotation. Results A total of 122 nonmanifesting participants and 67 PD patients were carriers of the G2019S mutation. Nonmanifesting mutation carriers walked with greater arm swing asymmetry and variability and lower axial rotation smoothness under the dual task condition when compared with noncarriers (P < .04). In the nonmanifesting mutation carriers, arm swing asymmetry was associated with gait variability under dual task (P = .003). PD carriers showed greater asymmetry and variability of movement than PD noncarriers, even after controlling for disease severity (P < .009). Conclusions The G2019S mutation is associated with increased asymmetry and variability among nonmanifesting participants and patients with PD. Prospective studies should determine if arm swing asymmetry and axial rotation smoothness may be used as motor markers of prodromal PD.

; for the LRRK2 Ashkenazi Jewish Consortium IMPORTANCE Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. OBJECTIVE To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

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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.

Carrying the LRRK2 G2019S mutation was associated with lower executive performance in a population at risk for PD.

Healthy walking is characterized by pronounced arm swing and axial rotation. Aging effects on gait speed, stride length and stride time variability have been previously reported, however, less is known about aging effects on arm swing and axial rotation and their relationship to age-associated gait changes during usual walking and during more challenging conditions like dual tasking. Sixty healthy adults between the ages of 30–77 were included in this study designed to address this gap. Lightweight body fixed sensors were placed on each wrist and lower back. Participants walked under 3 walking conditions each of 1 minute: 1) comfortable speed, 2) walking while serially subtracting 3’s (Dual Task), 3) walking at fast speed. Aging effects on arm swing amplitude, range, symmetry, jerk and axial rotation amplitude and jerk were compared between decades of age (30–40; 41–50; 51–60; 61–77 years). As expected, older adults walked slower (p = 0.03) and with increased stride variability (p = 0.02). Arm swing amplitude decreased with age under all conditions (p = 0.04). In the oldest group, arm swing decreased during dual task and increased during the fast walking condition (p<0.0001). Similarly, arm swing asymmetry increased during the dual task in the older groups (p<0.004), but not in the younger groups (p = 0.67). Significant differences between groups and within conditions were observed in arm swing jerk (p<0.02), axial rotation amplitude (p<0.02) and axial jerk (p<0.001). Gait speed, arm swing amplitude of the dominant arm, arm swing asymmetry and axial rotation jerk were all independent predictors of age in a multivariate model. These findings suggest that the effects of gait speed and dual tasking on arm swing and axial rotation during walking are altered among healthy older adults. Follow-up work is needed to examine if these effects contribute to reduced stability in aging.