Faculty Bibliography

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

OBJECTIVE: To assess the frequency and clinical characteristics of carriers of previously identified mutations in 6 genes associated with early-onset Parkinson disease (PD) and provide empirical data that can be used to inform genetic counseling. DESIGN: Cross-sectional observational study. SETTING: Thirteen movement disorders centers. PATIENTS: Nine hundred fifty-three individuals with early-onset PD defined as age at onset (AAO) younger than 51 years. Participants included 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Intervention Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2, and GBA were assessed. A validated family history interview and the Unified Parkinson Disease Rating Scale were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status. Main Outcome Measure Mutation carrier frequency stratified by AAO and ethnic background. RESULTS: One hundred fifty-eight (16.6%) participants had mutations, including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA, and 1 (0.2%) DJ1. Mutation carriers were more frequent in those with an AAO of 30 years or younger compared with those with AAO between 31 and 50 years (40.6% vs 14.6%, P < .001), in individuals who reported Jewish ancestry (32.4% vs 13.7%, P < .001), and in those reporting a first-degree family history of PD (23.9% vs 15.1%, P = .01). Hispanic individuals were more likely to be PRKN carriers than non-Hispanic individuals (15.6% vs 5.9%, P = .003). The GBA L444P mutation was associated with a higher mean Unified Parkinson Disease Rating Scale III score after adjustment for covariates. CONCLUSION: Individuals of Jewish or Hispanic ancestry with early-onset PD, those with AAO of 30 years or younger, and those with a history of PD in a first-degree relative may benefit from genetic counseling.

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

OBJECTIVE: We studied the potential efficacy and tolerance of memantine for essential tremor in an open-treatment trial. METHODS: Participants with upper-limb tremor were titrated to no more than 40 mg/d memantine, as monotherapy or as adjunct to stable antitremor medication, followed by a 12-week extension phase. Tremor was assessed in study 1 with accelerometry and in study 2 by blinded ratings of videotaped Washington Heights Inwood Genetic Essential Tremor (WHIGET) rating scale items. Subjects also rated their tremor treatment response and tremor-associated impairment on the Functional Disabilities scale. RESULTS: In study 1, average accelerometry-measured tremor at last titration visit (average dose, 30.3 mg/d) did not change from baseline, but 2 of 9 subjects, taking 40 mg/d, had greater than 70% accelerometry tremor reduction. In study 2, 13 of 16 provided evaluable data. Average blinded rater-evaluated WHIGET scores were significantly different from baseline scores among those taking 20 mg/d (-12.7%; P < 0.05), but not at last titration visit (-8.4%; average dose, 30.4 mg/d), 40 mg/d (-14.1%), or at end-of-extension visit (-18.2%). Raters judged WHIGET scores as greater than 30% improved in 2 subjects. Unblinded subjects rated Functional Disabilities significantly improved at 30 to 40 but not at 10 to 20 mg/d, and tremor treatment response was positive at all doses. Adverse events were more common at higher doses and included dizziness, somnolence, and poor energy. CONCLUSIONS: These pilot results with small samples indicate that the average effect of memantine on tremor is mild or not significant. However, in a small subset of patients, memantine may confer meaningful tremor benefit.