Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.

A range of behaviors presumed to be related to dopaminergic medications have been recently recognized in Parkinson's disease (PD). We evaluated 50 consecutive cognitively intact PD patients on stable dopamine agonist and levodopa therapy and 100 healthy controls for compulsive sexual behavior, compulsive buying, or intermittent explosive disorders assessed by the Minnesota Impulsive Disorders Interview (MIDI), pathological gambling (South Oaks Gambling Screen, SOGS), impulsivity (Barratt Impulsiveness Scale), compulsivity (Maudsley obsessional-compulsive inventory), and depression scores (Geriatric Depression Scale). Overall 28% PD (14/50) and 20% healthy controls (20/100) reported at least one abnormal behavior at MIDI or pathological SOGS score. PD patients had higher scores than controls for impulsivity (P = 0.006), compulsivity (P < 0.001), and depression (P < 0.001). There was no correlation between impulsivity, compulsivity, and depression scores in PD. Male gender and higher impulsivity score, but not dose and kind of dopaminergic medications, were associated in PD with increased probability of impulsive disorders at MIDI. Impulse control disorders are also common in the control population. Individual susceptibility factors, such as high impulsivity and depression, underline abnormal behaviors in PD patients treated with stable dopaminergic therapy.

Background Penetrance estimates of the LRRK2 p.G2019S mutation for Parkinson’s disease (PD) vary widely (24%–100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. Methods The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at eight sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included, when available. Results Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% CI: 26.3 – 65.8%) to age 80 which is not significantly higher than the previously estimated 25% (95% CI: 16.7 – 34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the non-carrier relatives, as seen in Ashkenazi Jewish relatives. Conclusions The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25–42.5% at age 80 in all populations analyzed.

Background:The clinical condition of advanced Parkinson's disease (PD) patients is often complicated by motor fluctuations and dyskinesias which are difficult to control with available oral medications. Objective: To compare clinical and neuropsychological 12 month outcome following subcutaneous apomorphine infusion (APO) and chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) in advanced PD patients. Methods: Patients with advanced PD and medically untreatable fluctuations underwent either APO (13 patients) or STN-DBS (12 patients). All patients were clinically (UPDRS-III, AIMS, 12 h on-off daily) and neuropsychologically (MMSE, Hamilton-17 depression, NPI) evaluated at baseline and at 12 months. APO was discontinued at night. Results: At 12 months APO treatment (74.78¡24.42 mg/day) resulted in significant reduction in off time (251%) and no change in AIMS. Levodopa equivalent medication doses were reduced from 665.98¡215 mg/day at baseline to 470¡229 mg/day. MMSE, NPI, and Hamilton depression scores were unchanged. At 12 months STN-DBS resulted in significant clinical improvement in terms of reduction in daily off time (276%) and AIMS (281%) as well as levodopa equivalent medication doses (980¡835 to 374¡284 mg/day). Four out of 12 patients had stopped oral medications. MMSE was unchanged (from 28.6¡0.3 to 28.4¡0.6). Hamilton depression was also unchanged, but NPI showed significant worsening (from 6.58¡9.8 to 18.16¡10.2; p,0.02). Category fluency also declined. Conclusions: Both APO and STN-DBS resulted in significant clinical improvement in complicated PD. STN-DBS resulted in greater reduction in dopaminergic medications and provided 24 h motor benefit. However, STN-DBS, unlike APO, appears to be associated with significant worsening on NPI resulting from long term behavioral problems in some patients.

Similar to our healthy control population, we found a significant proportion of early PD patients positive for ICDs before starting treatment. We also found a relationship between impulsivity and depression. A detailed behavioral assessment before starting dopaminergic therapy is recommended.

Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.

Background: Pathological gambling (PG) may develop in patients with Parkinson disease (PD) during dopamine replacement therapy, but the underlying neural correlates are still unclear.Objective: To investigate resting state brain perfusion in PD patients with active PG compared with matched PD controls and healthy controls.

Prospective comparative long-term data on the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and continuous subcutaneous infusion of apomorphine (CSAI) in patients with advanced Parkinson disease (PD) are lacking. We report 5-year follow-up of 25 PD patients treated with either STN-DBS (n = 13) or CSAI (n = 12) who fulfilled CAPSIT-PD criteria. Cohorts were matched for disease duration and severity of motor complications. Baseline clinical and neuropsychological status did not differ among cohorts. Patients were assessed with the UPDRS, MMSE, HAMD-17 and Neuropsychiatric Inventory (NPI).Twelve subjects reached the 5-year follow-up with STN-DBS (one was lost at follow-up) versus two in the CSAI cohort. Drop-outs with CSAI were due to subcutaneous nodules (n = 2), insufficient control of motor fluctuations and dyskinesia (n = 4), death for unrelated reasons (n = 3) and one was lost at follow-up. Average apomorphine dose at last visit was 83.4 ± 19.2 mg/day and average treatment duration was 30 months. At 1-year as well as at last follow-up (intention-to-treat analysis), both therapies decreased daily off-time but only STN-DBS reduced dyskinesia duration and severity. Decrement of medications was greater with STN-DBS. There was a significant worsening of NPI after STN-DBS, primarily because four subjects developed apathy.