Olfactory dysfunction in sporadic Parkinson's Disease and LRRK2 carriers.

OBJECTIVE: The aim of the study was to examine the sense of smell in LRRK2 mutation carriers and in patients with sporadic PD (sPD). MATERIALS AND METHODS: A total of 343 individuals were included: 275 sPD of whom 90 were de novo patients with sPD, 17 LRRK2 PD, 36 healthy LRRK2 mutation carriers, and 15 healthy family members without mutation. All subjects underwent neurologic examination and olfactory sense testing with B-SIT (a 12-item test). Linear regression analysis was applied to build different models with B-SIT as dependent variable. RESULTS: Sporadic PD had significantly lower scores in olfaction compared with LRRK2 PD (P < 0.001). B-SIT scores were lowest in medicated sPD, and higher scores were found in de novo patients. LRRK2 PD had similar sense of smell to healthy LRRK2 mutation carriers and to healthy family members without mutation when adjusting for age. CONCLUSION: Hyposmia was pronounced already at time of diagnosis in the sPD cases but was not present in healthy LRRK2 mutation carriers and less pronounced in LRRK2 PD compared with sporadic cases. Smell testing may be a preclinical marker in sporadic PD but does not seem applicable in LRRK2 cases.

Cerebrospinal fluid amyloid ß and tau in LRRK2 mutation carriers.

OBJECTIVE: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid ß (Aß) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aß and tau as markers of early or presymptomatic PD. METHODS: CSF Aß42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement. RESULTS: Reduced CSF Aß42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aß42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau. CONCLUSIONS: The disposition of Aß and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers.

OBJECTIVES: Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls. METHODS: Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories. RESULTS: Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status. CONCLUSIONS: Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.

Parkinson-related genetics in patients treated with deep brain stimulation.

OBJECTIVES: To analyze the frequency of mutations associated with Parkinson's disease (PD) in a general PD population compared to patients with PD selected for deep brain stimulation (DBS) and evaluate the outcome of surgery. MATERIAL AND METHODS: A total of 630 consecutive patients with PD were genetically screened, and 60 had DBS surgery, 37 subthalamic nucleus (STN), 21 ventrointermediate nucleus of thalamus (VIM), and two globus pallidus internus (GPi). RESULTS: Mutations in LRRK2, PRKN, and PINK1 were found: the first two of these being overrepresented in STN-operated patients, but none being found in VIM-operated patients. Clinical outcome of the surgery was similar in patients with mutations compared to those without. CONCLUSIONS: In a consecutive PD population, patients treated with STN-DBS are overrepresented for PD-related mutations and they seem to benefit from DBS as well as patients without mutations.