Quality of life in young‐ compared with late‐onset Parkinson's disease

The impact of Parkinson's disease on quality of life may vary depending on age at onset. We investigated the effect of age at onset on quality of life in a large Parkinson's disease population (n = 426) using a disease‐specific rating scale (PDQ‐39) and with careful adjustment for confounding and intermediary factors. We also explored the relationship between depression and excessive daytime sleepiness by age at onset and compared this with the general population. We found that a younger age at onset was significantly associated with worse overall quality of life scores (odds ratio, 2.66; 95% confidence interval, 1.39–5.09; P = .003), but this was attenuated by adjustment for depression as an intermediary factor (odds ratio, 1.86; 95% confidence interval, 0.84–4.11; P = .13). Younger onset was also a risk factor for poor emotional well‐being independent of depression status. Risk of depression and excessive daytime sleepiness were elevated in patients with Parkinson's disease compared with controls (odds ratio, 2.99; 95% confidence interval, 1.93–4.65; P < .001; and odds ratio, 3.84; 95% confidence interval, 2.56–5.75; P < .001, respectively), with similar findings seen in both early‐ and late‐onset groups. Our study highlights the need for accurate diagnosis and treatment of depression in younger‐onset patients in order to improve quality of life. © 2011 Movement Disorder Society     

Clinical profiles of late‐onset semantic dementia,compared with early‐onset semantic dementia and late‐onset Alzheimer's disease

Background: Semantic dementia (SD) has been recognized as a representative of dementia with presenile onset; however, recent epidemiological studies have shown that SD also occurs in the elderly. There have been few studies about the differences of clinical profiles between early‐onset SD (EO‐SD) and late‐onset SD (LO‐SD). Age‐associated changes in the brain might cause some additional cognitive and behavioural profiles of LO‐SD in contrast to the typical EO‐SD cases. The aim of the present study was to clarify the characteristics of neuropsychological, and behavioural and psychological symptoms of dementia (BPSD) profiles of LO‐SD patients observed in screening tests in comparison with EO‐SD patients and late‐onset Alzheimer's disease (LO‐AD) patients as controls. Methods: Study participants were LO‐SD (n = 10), EO‐SD (n = 15) and LO‐AD (n = 47). We examined the Mini‐Mental State Examination (MMSE), the Raven's Coloured Progressive Matrices (RCPM), the Short‐Memory Questionnaire (SMQ), the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Results: Both SD groups scored significantly lower than the LO‐AD patients in ‘naming’ of the MMSE. In the ‘construction’ score of the MMSE and the RCPM score, however, the LO‐SD patients as well as the LO‐AD patients were significantly lower than the EO‐SD patients. In the SMQ score, ‘euphoria’ and ‘disinhibition’ scores of the NPI, the SRI total and subscale scores, both SD groups were significantly higher, whereas in the ‘delusion’ score of the NPI, both SD groups were significantly lower than the LO‐AD patients. Conclusions: Visuospatial and constructive skills of LO‐SD patients might be mildly deteriorated compared with EO‐SD patients, whereas other cognitive and behavioural profiles of LO‐SD are similar to EO‐SD. Age‐associated changes in the brain should be considered when we diagnose SD in elderly patients.     

PINK1 mutations in a Brazilian cohort of early‐onset Parkinson's disease patients

Data on the frequency of PINK1 mutations in Brazilian patients with early‐onset Parkinson's disease (EOPD) are lacking. The aim of this report was to investigate mutations of the PINK1 gene in a cohort of Brazilian patients with EOPD. Sixty consecutive familial or sporadic EOPD patients were included. All eight PINK1 exons and exon‐intron boundaries were analyzed. We did not find any pathogenic mutation of PINK1 in our cohort. Single Nucleotide Polymorphisms (SNP) were identified in 46.7% of the patients and in 45.9% of controls (P = 0.9). The SNPs identified in our patients had already been described in previous reports. The results of our study support the hypothesis that mutations in PINK1 may not be a relevant cause of EOPD. In Brazil, if we consider only EOPD patients, it seems that parkin and LRRK2 mutations are more common. © 2009 Movement Disorder Society     

Dopa‐responsive dystonia and early‐onset Parkinson's disease in a patient with GTP cyclohydrolase I deficiency?

We describe a patient with a combination of dystonic and parkinsonian signs. Paraclinical studies revealed a mutation in the GTP cyclohydrolase I gene (GCH1) and a decrease in [123I]-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) binding ratios indicative of Parkinson's disease. We conclude that the patient probably suffers from a variant of dopa-responsive dystonia (DRD) or two separate movement disorders, normally considered to be differential diagnoses, DRD and early-onset Parkinson's disease with resulting difficulties concerning treatment and prognosis.     

Genomewide linkage study of modifiers of LRRK2‐related Parkinson's disease

Mutations in the leucine‐rich repeat kinase 2 gene, located at 12q12, are the most common known genetic causes of Parkinson's disease. Studies of leucine‐rich repeat kinase 2 mutation carriers have shown incomplete and age‐dependent penetrance, and previous studies have suggested that inherited susceptibility factors may modify the penetrance of leucine‐rich repeat kinase 2 mutations. Genomewide linkage to age of onset of leucine‐rich repeat kinase 2–related Parkinson's disease was evaluated in a sample of 113 leucine‐rich repeat kinase 2 mutation carriers from 64 families using single‐nucleotide polymorphism data from the Illumina HumanCNV370 genotyping array. Association between onset age and single‐nucleotide polymorphisms under suggestive linkage peaks was also evaluated. The top logarithmic odds score for onset age (logarithmic odds score = 2.43) was in the chromosome 1q32.1 region. Moderate linkage to onset was also identified at 16q12.1 (logarithmic odds score = 1.58). Examination of single‐nucleotide polymorphism association to Parkinson's disease onset under the linkage peaks revealed no statistically significant single‐nucleotide polymorphism associations. The 2 novel genomic regions identified may harbor modifiers of leucine‐rich repeat kinase 2–related Parkinson's disease onset age or penetrance, and further study of these regions may provide important insight into leucine‐rich repeat kinase 2–related Parkinson's disease. © 2011 Movement Disorder Society     

Higher nigrostriatal dopamine neuron loss in early than late onset Parkinson's disease?—A [99mTc]‐TRODAT‐1 SPECT study

Early-onset Parkinson's disease (EOPD) is distinct from the classic late-onset PD (LOPD) because of its slower disease progression. The aim of this study was to compare dopamine neuronal loss in EOPD with that of LOPD with the same disease duration, through dopamine transporter (DAT) estimation. Fourteen patients, seven EOPD (<50 years) and seven LOPD, matched for disease duration were scanned with [(99m)Tc]-TRODAT-1-SPECT (INER-Taiwan), and were assessed with standard PD scales. EOPD patients had 34% lower striatal DAT binding potential (BP) compared with that of LOPD patients (BP = 0.29 +/- 0.12, BP = 0.44 +/- 0.12, P < 0.02) with similar PD severity. These results suggest that EOPD patients have greater dopamine density loss than LOPD patients without motor-symptom worsening.     

Plasma α‐synuclein in patients with Parkinson's disease with and without treatment

Alpha‐synuclein (α‐syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). α‐Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma α‐syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma α‐syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, α‐syn was elevated early in the development of PD and specific PD treatment did not change plasma α‐syn levels. © 2010 Movement Disorder Society     

Genetic association study of the P‐type ATPase ATP13A2 in late‐onset Parkinson's disease

A role of ATP13A2 in early‐onset Parkinsonism (EOP) has been proposed. Conversely, the contribution of this ATPase to late‐onset Parkinson's disease (PD) remains unexplored. We therefore conducted a case–control association study in this age‐of‐onset group with PD. The initial sample was of German origin and consisted of 220 patients with late‐onset PD (mean age of onset 60.1 years) and 232 age‐matched unrelated controls. Five single nucleotide polymorphisms (SNPs) covering ATP13A2 and its common haplotypes were genotyped. The overall association results in this sample were negative. Interestingly, gender stratification gave a positive result for SNP rs11203280 (P_UNC = 0.016) in men. This result could not be reproduced in a replication sample of German and Serbian origin composed of 161 patients with late‐onset PD (mean age of onset 51.7 years) and 150 age‐ and ethnic‐matched controls. In conclusion, we found no consistent evidence for an association between ATP13A2 and late‐onset PD. © 2008 Movement Disorder Society     

Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease

BackgroundMutations in the F-box protein 7 (FBXO7) gene result in autosomal recessive parkinsonism. This usually manifests as early-onset parkinsonian-pyramidal syndrome but patients exhibit high phenotypic variability. Here we describe the findings of a Yemeni family with two novel FBXO7 mutations.MethodsClinical data and DNA were available for three siblings with early-onset parkinsonism together with their parents and three unaffected siblings. A targeted next generation sequencing panel was used to screen the proband for mutations in 14 genes known to cause a parkinsonian disorder. In addition, SNCA, PARK2, PINK1, and PARK7 were screened for copy number variants.ResultsThe proband carried two novel compound heterozygous FBXO7 mutations: a missense mutation in exon 1 (p.G39R; c.115G > A) and a frameshift mutation in exon 5 (p.L280fs; c.838del). The mutations segregated with disease in the family with the exception of a potentially pre-symptomatic individual whose age was below the age of onset in two of their three affected siblings. P.G39R occurred at a highly conserved amino acid residue and both mutations were predicted to be deleterious in silico. In contrast to most reported families, the phenotype in this pedigree was consistent with clinically typical Parkinson's disease (PD) with a lack of pyramidal signs and good response to dopaminergic therapy.ConclusionsOur study expands the phenotype associated with FBXO7 to include early-onset PD and broadens the list of causative mutations. These data suggest that FBXO7 should be included in clinical genetic testing panels for PD, particularly in patients with early onset or a recessive inheritance pattern.     

Depression and quality of life in monogenic compared to idiopathic,early‐onset Parkinson's disease

Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early‐onset PD cases, 21% of late‐onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson‐associated depression reported fewer feelings of guilt or self‐doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early‐onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized. © 2012 Movement Disorder Society     

Higher serum uric acid associated with decreased Parkinson's disease prevalence in a large community‐based survey

A large community‐based cross‐sectional survey provided an opportunity to evaluate a previously reported association between Parkinson's disease (PD) and low serum uric acid (UA) levels in this population. The association between a self‐reported PD diagnosis with treatment (n = 59) and serum UA level was examined using logistic and linear regression models, controlling for key covariates. In adjusted models, participants with UA levels at or above the median had a significantly lower odds of reporting PD with treatment compared with those with lower UA levels (OR 0.33, 95% CI 0.19–0.60, P = 0.0002). This association was observed for both men and women. The mean UA level among participants reporting PD with treatment was 0.78 mg/dl lower than the mean UA level among those not reporting PD (P ≤ 0.0001). These findings concur with several previous longitudinal studies that found an association between higher UA levels and decreased PD risk. © 2010 Movement Disorder Society     

Structural connectivity differences in motor network between tremor‐dominant and nontremor Parkinson's disease

Motor phenotypes of Parkinson's disease (PD) are recognized to have different prognosis and therapeutic response, but the neural basis for this clinical heterogeneity remains largely unknown. The main aim of this study was to compare differences in structural connectivity metrics of the main motor network between tremor‐dominant and nontremor PD phenotypes (TD‐PD and NT‐PD, respectively) using probabilistic tractography‐based network analysis. A total of 63 PD patients (35 TD‐PD patients and 28 NT‐PD patients) and 30 healthy controls underwent a 3 T MRI. Next, probabilistic tractography‐based network analysis was performed to assess structural connectivity in cerebello‐thalamo‐basal ganglia‐cortical circuits, by measuring the connectivity indices of each tract and the efficiency of each node. Furthermore, dopamine transporter single‐photon emission computed tomography (DAT‐SPECT) with ¹²³I‐ioflupane was used to assess dopaminergic striatal depletion in all PD patients. Both PD phenotypes showed nodal abnormalities in the substantia nigra, in agreement with DAT‐SPECT evaluation. In addition, NT‐PD patients displayed connectivity alterations in nigro‐pallidal and fronto‐striatal pathways, compared with both controls and TD‐PD patients, in which the same motor connections seemed to be relatively spared. Of note, in NT‐PD group, rigidity‐bradykinesia score correlated with fronto‐striatal connectivity abnormalities. These findings demonstrate that structural connectivity alterations occur in the cortico‐basal ganglia circuit of NT‐PD patients, but not in TD‐PD patients, suggesting that these anatomical differences may underlie different motor phenotypes of PD. Hum Brain Mapp 38:4716–4729, 2017. © 2017 Wiley Periodicals, Inc.     

Compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene segregating in a family with early onset Parkinson's disease

BackgroundKnowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study.MethodsInformative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest.ResultsTwo compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants.ConclusionWASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations.