Anna Zecchinelli

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.

Tolerability of paroxetine in Parkinson's disease: A prospective study

Depression is a common finding in patients with Parkinsons disease (PD). Traditionally, depression has been treated with tricyclic antidepressants, which are often associated with undesirable side effects that may limit their use in PD. Few studies have been performed with selective serotonin reuptake inhibitors (SSRIs) in these patients. We assessed the tolerability of the SSRI antidepressant paroxetine (10–20 mg once per day) in 65 outpatients with PD and depression for a period of at least 3 months. Treatment was continued for 125.3 ± 89.6 days (mean ± standard deviation) in 52 patients. In these subjects the Hamilton Disease Rating Scale improved from 21.7 ± 6.4 to 13.8 ± 5.8 (p <0.001). Overall, 13 patients stopped paroxetine after 9.6 ± 10.6 days because of adverse reactions. Two patients reported increased “off” time and tremor that reversed after treatment was stopped. No risk factors for intolerance were identified. Paroxetine is a safe and effective drug to treat depression in PD.

Randomized study of sertraline and low‐dose amitriptyline in patients with Parkinson's disease and depression: Effect on quality of life

We assessed the effect of 3‐month treatment of sertraline (50 mg) or low‐dose amitriptyline (25 mg) on depression and quality of life in 31 patients with Parkinsons disease in a prospective single‐blind randomized study. Both drugs significantly reduced the Hamilton Depression Rating Scale (HDRS‐17) score. Completion rate was 75% for sertraline (12 of 16) and 73% for amitriptyline (11 of 15). Responder rate (HDRS‐17 score reduction ≥ 50%) was 83.3% for sertraline and 72.7% for amitriptyline. Sertraline but not amitriptyline treatment determined a significant benefit on quality of life (PDQ‐39 scale). We found no change in Unified Parkinsons Disease Rating Scale scores. However, the improvement in specific PDQ‐39 subscores (mobility, activities of daily living, and stigma) suggests that depression affects patient self‐perception of motor function and further emphasizes the need for its treatment.

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinsons disease in both DRD pedigrees and in patients with Parkinsons disease but without a family history of DRD.

Hydrocarbon exposure and Parkinson’s disease

Background: Single cases of parkinsonism have been associated with hydrocarbon solvents. Objective: To determine whether exposure to hydrocarbon solvents is related to PD. Methods: Cohort study of 990 patients with PD according to Core Assessment Program for Intracerebral Transplantations (CAPIT) criteria, selected from 1455 consecutive subjects presenting at a referral center; case–control study assessing Unified PD Rating Scale scores (motor score as primary endpoint) in all subjects with positive history of hydrocarbon solvent exposure (n = 188), matched for duration of disease and gender to 188 subjects selected from the remaining 802 with a negative history. Two subgroups in the case–control study included the following: 1) response to apomorphine (n = 26); 2) brain MRI (n = 15). PET imaging (n = 9) was compared with that of historic controls. Results: Exposed patients were younger (61.0 ± 9.4 versus 64.7 ± 9.4 years, p = 0.002), predominantly male (76.4% versus 45.2%, p = 0.0001), less educated (8.4 ± 4.2 versus 10.1 ± 4.4 years, p = 0.0001), and younger at onset of disease (55.2 ± 9.8 versus 58.6 ± 10 years, p = 0.014). Exposure to hydrocarbon solvents directly correlated to disease severity (r = 0.311) and inversely correlated to latency period (r = −0.252). Nine blue-collar occupations accounted for 91.1% of exposures. Conclusions: Occupations involving the use of hydrocarbon solvents are a risk factor for earlier onset of symptoms of PD and more severe disease throughout its course. Hydrocarbon solvents may be involved in the etiopathogenesis of PD, which does not have a major genetic component.

PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum†‡

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild‐type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta‐analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinsons disease (PD) with and without mutations on the glucocerebrosidase gene (GBA).

Parkin analysis in early onset Parkinson's disease

We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinsons disease (onset ?40 years of age) patients. Twelve cases (8.2%) had homozygous or compound heterozygous point mutations and/or exon rearrangements, while a single mutation was found in four subjects (2.7%). We identified eight exon rearrangements and nine point mutations, two of which were novel: c.735delT (p.C212/X224) and c.815C>G (p.C238W). Genotype-phenotype correlation revealed that parkin carriers had features similar to those of non-carrier early onset Parkinson disease patients.

Dopamine dysregulation syndrome in Parkinson's disease: from clinical and neuropsychological characterisation to management and long-term outcome

Objective Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinsons disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome. Methods In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005–2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded. Results Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between ‘Off’ versus ‘On’ motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment. Conclusions Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.

Parkinson's disease beyond 20 years

Background A very limited number of studies report data on the clinical features of Parkinsons disease (PD) 20 years after onset and beyond. Objective To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. Methods We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20–22, 23–25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20–22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23–89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. Results Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. Conclusions Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes.