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.     

Transcranial imaging of substantia nigra hyperechogenicity in a Taiwanese cohort of Parkinson's disease.

Transcranial Doppler imaging (TCDI) has been used as a noninvasive diagnostic tool to differentiate Parkinson's disease (PD) from atypical parkinsonism by detecting hyperechogenicity in the substantia nigra (SN). To our knowledge, no TCDI data are available for Asian populations, and TCDI sensitivity is uncertain across populations. Early-onset PD (EOPD) represents a specific PD subtype based on clinical features and pathogenic mechanisms. It is not known if EOPD patients have abnormal echogenicity in SN comparable to late-onset PD (LOPD) patients. We assessed the area of SN hyperechogenicity (hyper-SN) and a ratio of hyper-SN over ipsilateral midbrain (S/M ratio) with TCDI in 164 healthy Taiwanese, 40 EOPD patients, and 40 LOPD patients. The upper 95th percentile values for hyper-SN and S/M ratio were 0.20 cm(2) and 0.07. Our results indicate that S/M ratio is a more sensitive measure than hyper-SN in diagnosing PD. Approximately 92.5% of the LOPD patients and 57.5% of the EOPD patients had S/M ratios >/= 0.07. Enlarged hyperechogenicity of SN is a common finding in LOPD, but not in EOPD. Iron-independent mechanisms of SN cell degeneration in EOPD distinct from that in LOPD might contribute to the sonographic findings.     

Mutation analysis of the PINK1 gene in Southern Italian patients with early- and late-onset parkinsonism

Mutations in the PINK1 gene represent the second most frequent cause of early-onset Parkinson's disease (EOPD). One or two mutated alleles were also reported in some sporadic or familial patients suffering from late-onset Parkinson's disease (LOPD). We aimed at assessing the frequency of mutations in this gene in our population. We performed a sequence analysis of PINK1 in 115 patients diagnosed with Parkinson's disease (PD) from southern Italy, including 93 sporadic cases with EOPD, 9 familial cases with EOPD, and 13 familial cases with LOPD. Three known homozygous mutations (Q456X, W437X, Q126P), corresponding to a 2.6% of all cases, were found. In particular, one mutation was detected among the sporadic cases (1.0%), one mutation among the familial early-onset patients (11.1%) and one mutation among the familial late-onset patients (7.7%). In addition, we found two heterozygous mutations (E476K, R207Q) among the sporadic patients. Only one mutation (R207Q) had not been previously described. Our results assess the role played by PINK1 in EOPD in southern Italy and illustrate the existence of mutations in this gene also in the late-onset form of the disease.     

Effect of deep brain stimulation on autonomic dysfunction in patients with Parkinson’s disease

Increasing attention is being paid to the non-motor symptoms of Parkinson’s disease (PD). While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to clearly improve motor symptoms of PD, the effects of STN DBS on autonomic symptoms have not been well studied. We examined 11 patients undergoing STN DBS for PD. Patients were administered a questionnaire by phone to evaluate pre-operative and post-operative function. Three out of the 11 patients reported marked improvement post-DBS in one or more symptoms of autonomic dysfunction (sweating, bladder, or bowel function). All three patients had early-onset PD (EOPD), whereas the eight patients reporting no significant improvement were those with late-onset PD. Thus, we found that some patients experienced marked improvement in sweating and/or bowel and bladder function after STN DBS, with a trend towards a response in patients with EOPD. Our results suggest the utility of a larger prospective study.     

The motor phenotype of Parkinson's disease in relation to age at onset

Background: Parkinson's disease (PD) is heterogeneous and age at onset may define variation in clinical phenotype. Most previous studies have used various age cut‐offs and have been based on clinical case series. Methods: We have studied the association between clinical features and age of onset in 358 community‐based and regional patients with PD. Results: Tremor at presentation is twice as common in those with onset over 64 years as compared to those with onset under 45 (early onset PD ‐ EOPD) and becomes more common with increasing age at onset (p values for trend ≤ 0.004). Dystonia affects 60% of those with EOPD, shows a curvilinear relationship with age at onset (cubic versus linear p=0.01) with highest risk in patients whose disease began before 48 years. In this study age at onset was a strong predictor of the development of dyskinesias, with younger age associated with a higher risk of dyskinesias. Following multivariable analysis, allowing for possibly confounding factors (disease duration, L‐DOPA dosage, L‐DOPA treatment duration) younger age at onset, (less than 55 years) predicted the development of L‐DOPA induced dyskinesia (odds ratio <45 years 2.1, 95% CI 1.0, 4.8; odds ratio < 55 years 3.8, 95% CI 1.8, 8.0). Only 2/70 (2.9%) EOPD patients carried pathogenic parkin or PINK1 mutations and the clinical differences between early and late onset disease were not explained by the presence of mutations in these genes. Discussion: This study highlights the clinical differences between early and late onset PD, which have important implications for diagnosis and management. © 2011 Movement Disorder Society     

Gender and onset age-related features of non-motor symptoms of patients with Parkinson's disease – A study from Southwest China

BackgroundNon-motor symptom (NMS) differences between male Parkinson's disease (PD) and female PD, and between early-onset PD (EOPD) and late-onset PD (LOPD) in Chinese populations remain largely unknown.MethodsA total of 522 PD patients from Southwest China were included. Patients were assessed using the Non-Motor Symptom Scale (NMSS) and Unified PD Rating Scale (UPDRS).ResultsMore NMS and significantly higher NMSS score were found in LOPD patients than in EOPD patients (9.3 ± 5.9 vs. 7.7 ± 5.6, P = 0.005; 37.4 ± 32.2 vs. 30.5 ± 28.9, P = 0.018), while no such differences were found between male and female patients. The NMS of gastrointestinal and urinary domains were more common in LOPD patients than in EOPD patients, whereas sexual dysfunction was more common in EOPD than in LOPD. The sleep/fatigue domain, the mood/apathy domain and “pain” symptoms were more prevalent and severe in female patients than in male patients while urinary symptoms were more common and severe in male patients. Significant positive correlations were observed between disease duration, Hoehn & Yahr stage, UPDRS Ⅲ, and NMSS score in the total sample, subgroups of both male and female patients as well as both EOPD and LOPD patients.ConclusionsNMS are common in the Chinese PD population. LOPD patients are likely to present with more and severe NMS than EOPD patients. Males are subjected to urinary symptoms and females are subjected to mood/apathy, sleep and pain symptoms.     

Suicidal ideation in early-onset Parkinson’s disease

Journal of Neurology - Patients with early-onset Parkinson’s disease (EOPD) often suffer from more frequent depression than those with late-onset Parkinson’s disease (LOPD). However,...     

单胺氧化酶B基因多态与早发帕金森病的相关性

目的 探讨单胺氧化酶B(MAO-B)基因型和等位基因与早发帕金森病(early-onset Parkinson's disease,EOPD)的关系.方法 采取聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,研究65例EOPD患者(<50岁)、60例晚发PD(late-onset Parkinson's disease,LOPD)患者(≥60岁)和66名健康对照者(<50岁)的基因型频率和等位基因频率的分布差异.结果 EOPD组的AA基因型频率(49/65,75.4%)高于健康对照组(34/66,51.5%),差异有统计学意义(x2=8.075,P=0.018);LOPD组分别与EOPD组、健康对照组的从基因型频率比较,差异无统计学意义;男性EOPD组分别与男性健康对照组、男性LOPD组,女性EOPD组分别与女性健康对照组、女性LOPD组的AA基因型频率比较,差异无统计学意义;男性LOPD组与男性健康对照组、女性LOPD组与女性健康对照组的AA基因型频率比较,差异无统计学意义.EOPD组的A等位基因频率(107/130,82.3%)高于健康对照组(87/132,65.9%),差异有统计学意义(X2=9.165,P=0.002);LOPD组分别与EOPD组、健康对照组的A等位基因频率比较,差异无统计学意义;男性EOPD组的A等位基因频率(60/70,85.7%)高于男性健康对照组(51/72,70.8%),差异有统计学意义(x2=4.606,P=0.032);女性EOPD组的A等位基因频率(47/60,78.3%)高于女性健康对照组(36/60,60.0%),差异有统计学意义(x2=4.728,P=0.030);男性LOPD组分别与男性EOPD组、男性健康对照组,女性LOPD组分别与女性EOPD组、女性健康对照组的A等位基因频率比较,差异均无统计学意义.结论 MAO-B的从基因型频率增高是EOPD组发病的危险因素;MAO-B的A等位基因频率增高是EOPD组、男性EOPD组及女性EOPD组发病的危险因素.     

Depression in patients with early versus late onset of Parkinson's disease

We examined correlates of depression in patients whose onset of Parkinson's disease (PD) began before age 55 (early-onset group) compared with patients whose onset was after age 55 (late-onset group). The early-onset group showed a significantly higher frequency of depression than the late-onset group. When both groups were matched for duration of the disease, the early-onset group still showed a significantly higher frequency of depression, whereas tremor, akinesia, and rigidity were significantly more severe in the late-onset group. A stepwise regression analysis showed that in the early-onset group, depression scores were significantly correlated with scores of cognitive impairment and duration of the disease, while in the late-onset group, depression scores were significantly correlated with impairments in activities of daily living. These data suggest that depression in patients with early-onset PD may have a different etiology than in patients with late-onset PD.     

A prospective study in one year cumulative incidence of depression after ischemic stroke and Parkinson's disease: a preliminary study

BACKGROUND AND AIMS: 1) To measure the one year cumulative incidence of depression after ischemic stroke event and 2) to compare its incidence with that of Parkinson's disease (PD) in an outpatient neurology department. MATERIALS AND METHODS: Stroke patients were recruited after their first diagnosis and PD patients were recruited during the same recruitment period. Main measures included: 1) disability (Barthel Index and Modified Rankin Scale), 2) cognitive function (Thai Mental State Examination and 3) depression (Clinical Interview Schedule-Revised). The patients were assessed at 1, 2, 3, 6 and 12 months. RESULTS: Seventy-seven stroke patients with hemispheric infarction and 59 PD patients were recruited. The baseline characteristics of the two groups were comparable except that stroke patients were 4 years younger. The cumulative one year incidence of depression was 12% after stroke and 5.1% in PD with no significant difference. Cox regression analysis showed that the risk for depression among stroke cohort was almost three times higher, although not statistically significant, than that among PD cohort (hazard ratio 2.92). In stroke, depression mainly occurred within 3 months after the event but in PD, depression developed randomly throughout the follow up period. CONCLUSION: The one year cumulative incidence of post-stroke depression in the Thai population is much lower than in the Caucasian population. However, its adjusted cumulative incidence was much higher to that of PD. The findings are in line with previous studies that stroke significantly contributes to the pathogenesis of depression.     

Different iron deposition patterns in early- and middle-late-onset Parkinson's disease

BackgroundIron deposition may contribute to the clinical symptoms in Parkinson's disease (PD). With partial different clinical manifestations, the iron deposition patterns between patients with early-onset Parkinson's disease (EOPD) and middle-late-onset Parkinson's disease (M-LOPD) are still unclear. This study was designed to investigate the patterns of iron deposition and their clinical relevance in EOPD and M-LOPD patients, using quantitative susceptibility mapping technique.Materials and methodsThirty-five EOPD patients and 24 matched young controls, 33 M-LOPD patients and 22 matched older controls were recruited in the study. The iron content in the deep grey matter nuclei in the basal ganglia and midbrain were measured, and compared between patients and their corresponding controls. The correlations of regional iron content and clinical features were explored in patient groups.ResultsBoth M-LOPD and EOPD patients showed increased iron content in the substantia nigra (SN) pars compacta and SN pars reticulata. Increased iron content in the putamen was only observed in M-LOPD patients. The relationship between the increased iron content and disease severity (H&Y stages, UPDRS II scores and UPDRS III scores) was observed in M-LOPD patients, but not in EOPD patients.ConclusionOur study suggested that the iron deposition pattern was greatly influenced by the age of PD onset, which increases our understanding of the different pathological underpinnings of EOPD and M-LOPD patients.     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

早发帕金森病临床特征、多巴转运体PET显像及基因突变分析

目的探讨早发帕金森病的临床特征、多巴胺功能改变和基因突变。方法选取作者医院收治的10例早发帕金森病患者(男、女各5例),发病年龄平均(31.4±8.0)岁,平均病程(3.0±0.8)年,无家族史,对所有患者的临床资料、多巴转运体PET显像及基因检测结果进行回顾性分析。结果 10例患者均有受累肢体运动迟缓及肌张力增高,6例出现静止性震颤,5例有足部肌张力障碍,4例腱反射活跃,2例腱反射亢进,4例存在日间症状波动。3例伴抑郁。9例患者对多巴丝肼反应良好。8例进行脑多巴胺转运体PET显像(11 C-CFT DATPET)检查,1例起病对侧壳核后部DAT降低,7例显示双侧壳核后部DAT降低,其中4例起病对侧DAT降低更为明显。1例parkin基因3、4外显子缺失,PINK1基因外显子1还发生重复突变。1例parkin基因外显子4出现了纯合突变。3例parkin基因外显子3或4发生杂合突变。结论早发帕金森病具有独特的临床特征,纹状体多巴胺功能发生改变,parkin基因和PINK1基因与其发病相关。     

Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinson's disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (less than or equal to 40 years, N = 33) reached the same level of disability as the late-onset PD (greater than or equal to 70 years, N = 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression ("malignant PD"; duration of symptoms less than 1 year and Hoehn/Yahr stage of 2.5, N = 11) as compared with those with a relatively slow rate of progression ("benign PD"; duration of symptoms greater than 4 years, N = 65). Comparisons of tremor-dominant PD (mean tremor score/mean PIGD score less than or equal to 1.5, N = 441) with the PIGD-dominant type (mean tremor score/mean PIGD score greater than or equal to 1.0, N = 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.     

PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.     

Genetic analysis of the alpha2-macroglobulin gene in early- and late-onset Parkinson's disease

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD). The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of A2M in PD. We performed association studies in a large sample of 328 German PD patients and 322 closely matched healthy controls. Analyzing the Val1000Ile polymorphism and a pentanucleotide deletion in the 5' splice site of exon 18 of the A2M gene we found an excess of homozygosity for the A2M deletion in early-onset PD (EOPD) patients (age at onset < 50 years) compared to late-onset PD (LOPD) patients (age at onset > 50 years; p = 0.008, p(p)c = 0.064, chi2 = 7.017). Therefore our data might indicate an age at onset modulating effect of the homozygous A2M deletion in PD.     

Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: Phenotypic characterization and frequency of SNCA,PRKN, PINK1, and LRRK2 mutations

The aim of the study was to evaluate the frequency and to perform phenotypic and genotypic characterization of familial Parkinsonism and early onset Parkinson's disease (EOPD) in a Brazilian movement disorder unit. We performed a standardized clinical assessment of patients followed by sequencing of PRKN, PINK1 in EOPD cases and SNCA, LRRK2 in familial Parkinsonism individuals. During the period of study (January through December, 2006), we examined 575 consecutive patients of whom 226 (39.3%) met the diagnosis of Parkinsonism and idiopathic Parkinson's disease (IPD) was diagnosed in 202 of the latter. Of the IPD cases, 45 (22.3%) had EOPD. The age at onset in the EOPD cases (n = 45) was 34.8 ± 5.4 years (mean ± standard deviation). The age at onset in the familial late‐onset PD patients (n = 8) was 52.3 ± 12.2 years. In the early onset cases, we identified five known mutations in PRKN, two single heterozygous and three compound heterozygous (P153R, T240M, 255Adel, W54R, V3I); in addition, we identified one novel mutation in PINK1 (homozygous deletion of exon 7). In the familial cases (late onset), 1 patient had a novel LRRK2 variant, Q923H, but no SNCA mutations were identified. We have demonstrated that EOPD accounts for a high frequency of IPD cases in our tertiary referral center. PRKN was the most commonly mutated gene, but we also identified a novel mutation in PINK1 and a novel variant in LRRK2. © 2009 Movement Disorder Society     

Association between PLA2G6 gene polymorphisms and Parkinson's disease in the Chinese Han population

The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A(2), and has been suggested as the causative gene for autosomal recessive dystonia-parkinsonism. We conducted a case-control study using 531 mainland Chinese Parkinson's disease (PD) patients and 561 healthy controls, and genotyped 4 tag single nucleotide polymorphisms (SNPs) of the PLA2G6 gene: rs4375, rs2267369, rs132985, and rs2284063. Logistic regression analysis revealed no difference in genotype or allele frequencies for any of the SNPs between the sporadic PD group and control group. Similarly, comparison of SNPs in patients with either early-onset (EOPD, ≤ 50 years) or late-onset (>50 years) PD revealed no statistical differences from controls. We detected no significant association of the 4 SNPs with PD at the genotypic level, after adjustment for age. The rs132985 genotype frequency showed a difference in male patients but not in female patients, but the P value did not survive Bonferroni correction (Pcorr = 0.068). We found that the rs132985 A-rs2284063 C haplotype is marginally associated with increased risk of developing PD (P = 0.048) after 10,000 permutations. These findings suggest that PLA2G6 is not a susceptibility gene for PD in our population. However, a broader examination and a replication of this study in other populations are needed.     

Phenotype analysis in patients with early onset Parkinson’s disease with and without <Emphasis Type="Italic">parkin</Emphasis> mutations

The data regarding whether parkin genotype attributes phenotypic variation are conflicting. Since the incidence of parkin mutations is very low in patients with an age at onset (AAO) of >40 years, previous studies have unfairly compared phenotypes of two early onset Parkinson’s disease (EOPD) groups with different AAOs. Thus, we compared the clinical features between patients with and without parkin mutations in EOPD with an AAO of ≤40 years. Of the 124 patients with EOPD with an AAO of ≤40 years who were recruited and screened for parkin mutations, 84 completed assessments for comparison of the phenotype according to parkin genotype. Fourteen of the 84 subjects carried two parkin mutations; 6, a single mutation; and 64, no mutations. Patients with two mutations had significantly younger AAOs, longer duration of PD, and more common family history than patients without parkin mutations. Otherwise, motor and nonmotor symptoms did not differ between them. Subgroup analysis of EOPD with an AAO of ≤35 years revealed similar results. Phenotype of EOPD may depend on early AAOs rather than presence of parkin mutations.     

Variable <Emphasis Type="Italic">PARK2</Emphasis> Mutations Cause Early-Onset Parkinson’s Disease in a Small Restricted Population

Early-onset Parkinson’s disease (EOPD) is less common than the typical adult-onset PD and may be associated with a genetic etiology. Mutations in several genes are known to cause autosomal recessive (AR) PD. This study aimed to detect the etiology of EOPD in consanguineous families or families living in a specific small geographic region in Israel. Six families with EOPD affecting more than a single individual were recruited. Homozygous mapping analysis using a single-nucleotide polymorphism-based array was performed in all families, followed by Sanger sequencing of related genes based on the mapping results. In addition, all families underwent PARK2 sequencing and testing for large deletions and duplications in PD-associated genes. Different truncating mutations were detected in the PARK2 gene among affected individuals of three families: c.996C>A (p.Cys332X) and c.101delA in either homozygous or compound heterozygous fashion. Exon 4 deletion was detected in a heterozygous manner in a late-onset PD and in homozygous state in early-onset disease in the same family. No disease-causing mutations were detected in any other tested genes. In total, mutations in the PARK2 gene were detected in four of the six tested families with a history of EOPD. These results further demonstrate the role of PARK2 in AR PD. We recommend genetic analysis for the PARK2 gene when AR PD is suspected.