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.     

SORL1基因多态性与中国东北地区帕金森病的相关性分析

目的探究SORL1基因rs2070045位点的单核苷酸多态性与帕金森病(Parkinson disease,PD)的相关性。方法本研究纳入215名中国东北地区汉族健康人和377例PD患者。根据其发病年龄,将PD组患者再分为早发PD组(发病年龄≤50岁)和晚发PD组(发病年龄50岁),收集一般临床资料,提取外周血基因组DNA,利用MALDI-TOF-PEX技术检测SORL1基因rs2070045多态性分布情况,分析其与帕金森病的相关性。结果在PD组与对照组以及晚发PD组与对照组的比较中,SORL1基因rs2070045位点单核苷酸多态性的基因型及等位基因频率分布无统计学差异。早发PD组与对照组比较,rs2070045基因型分布有显著差异(P=0.036),而等位基因频率无显著差异。在晚发PD中G等位基因携带者的起病年龄明显低于非携带者(P=0.001),其他临床特征如性别、Hoehn-Yahr分期以及病程在携带者和非携带者间无统计学差异。结论 SORL1基因rs2070045位点的单核苷酸多态性与中国东北地区汉族早发帕金森病相关,G等位基因可能是早发PD的保护性因素。     

Parkin 基因多态性与散发性帕金森病关系的研究

目的探讨Parkin基因S/N 167多态性与散发性帕金森病(PD)的遗传易感性之间的关系.方法以120例散发性PD患者为研究对象,分为早发性PD组和晚发性PD组,120名正常人作为对照.采用聚合酶链式反应(PCR)扩增所需DNA片段,用限制性内切酶酶切技术测定所研究对象的基因型和等位基因.比较各组间基因型及等位基因频率的差异.结果 PD组与对照组S/N 167多态性等位基因频率无显著性差异(P>0.05);早发性PD组S/N 167多态性等位基因频率显著高于对照组和晚发性PD组(均P<0.05).结论Parkin基因S/N 167多态性可能是早发性PD的危险因素,其患PD的危险性较对照组增高1.69倍.     

Age-induced cognitive disturbances in Parkinson's disease

We investigated the influence of age on the occurrence of cognitive disturbances in Parkinson's disease (PD), by evaluating neuropsychological performances in early- and late-onset groups of patients (less than 45 and greater than 65 years, respectively), individually paired for all the variables of parkinsonism and compared with age-matched controls. Cognitive disorders were limited in the early-onset PD group compared with their age-matched controls. Conversely, we found global cognitive changes, including marked frontal lobe dysfunction, in the late-onset group. This specific cognitive impairment in older patients related to a significant interaction between the aging and disease processes. Late onset seemed to compound the subtle cognitive changes associated with the disease for which the early-onset group compensated. This compounding effect of aging may explain, at least partially, the high frequency of dementia in older PD patients.     

Parkinson's disease, CYP2D6 polymorphism, and age

OBJECTIVE: PD may be caused by genetic susceptibility to neurotoxins. CYP2D6 is a candidate gene for PD because it regulates drug and toxin metabolism, but association studies have been inconsistent. The aim of this study was to test if the CYP2D6*4 allele (poor metabolizer phenotype) is associated with earlier age at onset. METHODS: Five hundred seventy-six patients with PD and 247 subjects without PD were studied using standard diagnostic, genotyping, and statistical techniques. RESULTS: Surprisingly, mean onset age was significantly later in *4-positive patients. Frequency of *4 was significantly higher in late-onset PD than early-onset PD. When early- and late-onset PD were analyzed separately, *4 had no effect on onset age; hence, the association with delayed onset was likely an artifact of an elevated *4 frequency in late-onset PD. Contrary to a common assumption that CYP2D6 frequencies do not change with age, *4 frequency rose significantly with advancing age, both in patients with PD (from 0.16 at mean age of 56.5 years to 0.21 at mean age of 72) and subjects without PD (from 0.09 at mean age of 45.5 years to 0.21 at mean age of 72). *4 Frequencies in patients with early- and late-onset PD, although different from each other, were in agreement with similarly aged subjects without PD, suggesting the elevated *4 frequency in late-onset PD was likely an age effect, unrelated to PD. CONCLUSION: The CYP2D6*4 allele is not associated with earlier PD onset. *4 May be associated with survival. Inconsistent results from allelic association studies may have been due to an unrecognized age effect.     

Personality disorder comorbidity in early-onset versus late-onset major depression in Japan

This study explored the comorbidity of DSM-III-R personality disorders in early-onset versus late-onset major depression in Japan. The subjects were 117 consecutive outpatients with major depression, with 26 classified as having an early onset (first depressive episode at age 22 or earlier) and 91 classified as having a late onset (first depressive episode at age 23 or later). Personality disorders were assessed using the Structured Clinical Interview for DSM-III-R Personality Disorders after a 2-month antidepressant treatment. The results indicated that early-onset major depression was characterized by greater personality disorder comorbidity than late-onset major depression in Japan. Subjects with any one cluster A or B personality disorder were more prevalent in the early-onset group. In terms of each personality disorder, histrionic, narcissistic, and borderline patients were more prevalent, and the number of criteria met for schizotypal and cluster B personality disorders was significantly larger in early-onset major depression after corrections for age and gender. The results suggested that the higher prevalence of personality pathologies in early-onset major depression may reflect a higher likelihood to convert into bipolar disorders or a stronger impact of having experienced depressive episodes in young individuals. The possibility that the predisposing personality pathology may be different in early-onset and late-onset major depression is also discussed.     

帕金森病与疲劳

目的探讨异质性帕金森病(Parkinson’s disease,PD)患者出现疲劳的临床特征及疲劳与运动及非运动症状的关联,明确症状的归属,以期寻找缓解症状的治疗方法。方法连续收集2014-04-2016-06就诊于广州市第一人民医院神经科运动障碍疾病门诊及住院的144例PD患者的病历资料,按帕金森病异质分组原则分组,全部患者采用疲劳严重程度(fatigue severity scale,FSS)和疲劳量表(fatigue scale,FS-14)评价疲劳,同时完成PD运动症状(motor symptoms,MS)、非运动症状(nomotor symptoms,NMS)、日常生活能力及质量相关的量表分析。结果 144例PD患者中,有疲劳症状60例(41.47%),疲劳组中早期PD且无其他NMS症状10例。异质性帕金森病不同组别比较显示强直为主型、女性及中晚期PD患者发生疲劳机会增加。单因素分析示,PD患者年龄、病程、H-Y分级、运动症状评分(UPDRS评分Ⅲ(R)、UPDRS评分Ⅲ总分)及UPDRSⅣ部分得分疲劳组得分均高于非疲劳组;非运动症状评分(NMSS)提示,疲劳组患者的NMS出现程度及频率均较非疲劳组严重,差异有统计学意义(P0.05);疲劳组精神情绪总体状况(UPDRSⅠ)、抑郁(HAMD)、焦虑(HAMA)、白天嗜睡(ESS)均明显高于非疲劳组;MMSE评分证实2组患者智能正常,差异无统计学意义(P0.05),但疲劳组较非疲劳组MMSE得分有下降趋势;疲劳组日常生活动能力(UPDRSⅡ)和生活质量PDQ39评分均显著高于非疲劳组,英格兰日常生活能力量表Schwab显著低于非疲劳组,差异均有统计学意义(P0.05)。多重线性回归分析,NMSS程度、焦虑、抑郁评分与疲劳显著相关。结论 PD患者疲劳的发生率高;异质性帕金森病发生疲劳几率不同;单因素分析疲劳组PD患者病程更长,运动症状及病情更严重,NMS更多、更重,生活质量更差;NMSS的程度、焦虑、抑郁是导致疲劳的主要原因;部分疲劳组患者的疲劳发生与MS及NMS无关,提示疲劳可能是PD病程中的独立的非运动症状之一。     

Abnormal nocturnal blood pressure fall in senile-onset depression with subcortical silent cerebral infarction

Recent studies have shown that the complication rate of silent cerebral infarction (SCI) in patients with geriatric depression increases with the age at the onset of depression. This study investigated the cardiovascular factors involved in the development of SCI in geriatric depression. Thirty-six patients with geriatric depression were classified according to the age at onset into 16 who developed depression at the age of <50 years (early-onset group) and 20 who developed depression at the age of > or =50 years (late-onset group). The incidence of SCI assessed by subcortical hyperintensity on MRI images, office blood pressure (BP), nocturnal systolic BP fall pattern examined by 24-hour ambulatory BP monitoring, and the severity of carotid atherosclerosis examined by B-mode ultrasonography were compared between the two groups. Furthermore, the association between the presence or absence of SCI and the nocturnal systolic BP fall pattern or the severity of carotid atherosclerosis was evaluated. The SCI complication rate was higher in the late-onset group (55.0%) than in the early-onset group (18.7%). The office BP and mean 24-hour BP did not differ significantly between the two groups. Abnormal nocturnal systolic BP fall patterns were observed in 85.0% (nondipper type showing a fall of <10% in 60.0%, extreme-dipper type showing a fall of > or =20% in 25.0%) in the late-onset group, which was significantly higher than the incidence in the early-onset group (18.7%). No significant difference was observed in any parameter of carotid atherosclerosis between the two groups. In addition, the patients with SCI more frequently showed abnormal nocturnal systolic BP fall patterns than those without SCI. These results suggest that abnormal nocturnal BP fall patterns appear to be involved in the development of SCI in senile-onset depression.     

The neuropsychology of de novo patients with idiopathic Parkinson's disease: the effects of age of onset

One hundred de novo patients with Parkinson's disease (PD) were classified into two groups according to age of onset of symptoms. Seventy two patients were under 70 years and 28 were 70 years and over. All patients were given neurological and neuropsychological assessments, and the severity of the signs was rated on a modified Columbia scale. The neuropsychological assessment was also administered to 50 age-and-education-matched controls. The neuropsychological test battery included tests of verbal learning, visual memory, verbal fluency, visuospatial skill, simple and choice reaction time, language and maze learning. The late-onset patients had significant impairment in nonverbal reasoning, auditory verbal learning, visual memory and choice reaction time in contrast to early-onset patients and controls. A relationship was found between bradykinesia and widespread cognitive impairment. Severity of tremor was found to be significantly correlated with impairment in auditory verbal learning, visual memory and increased choice reaction time, while rigidity was found to be associated with cognitive impairment in verbal fluency and visuospatial skill. Using DSM II criteria, 39% of the late-onset and 8% of the early-onset group were classified as demented. Dementia was more common in patients with bilateral symmetrical disease and in those patients with marked tremor and bradykinesia. The pattern of cognitive impairment in PD was consistent with that associated with a subcortical dementia. This study confirms that the expression of PD is markedly influenced by the age of onset.     

Frequency and clinical characteristics of early-onset dementia in consecutive patients in a memory clinic

AIMS: To investigate the frequency, rate of causes of dementia, and clinical characteristics of early-onset dementia in consecutive patients of a memory clinic. METHODS: A total of 668 consecutive demented patients were involved in this study. We examined the distribution of patients' diagnosis, differences in sex, education, dementia severity and cognitive function at the first visit, and the duration from onset to consultation. We also examined the changes in the proportion of subjects during the research period. RESULTS: There were 185 early-onset patients, 28% of all demented patients. No significant differences were observed between the early-onset and late-onset dementia groups in Clinical Dementia Rating and Mini-Mental State Examination score at the first consultation, but the duration from onset to consultation was significantly longer in the early-onset group. In the early-onset group, the rates of patients with Alzheimer's disease and dementia with Lewy bodies were relatively low and the rate of patients with frontotemporal lobar degeneration was relatively high. There were no significant differences in the proportion between either demented subjects and nondemented subjects or early-onset dementia patients and late-onset dementia patients during the research period. CONCLUSION: We conclude that early-onset dementia is not rare and its clinical characteristics and causes are different from late-onset dementia.     

A family study of Alzheimer disease and early- and late-onset depression in elderly patients

BACKGROUND: The substantial symptomatic overlap between depression and dementia in old age may be explained by common genetic vulnerability factors. METHODS: We investigated this idea by comparing the occurrence of both disorders in first-degree relatives of 78 patients with Alzheimer disease (AD), of 74 with late-onset depression (onset age of > or = 60 years), of 78 with early-onset depression, of 53 with comorbid lifetime diagnoses of AD/depression, and of 162 population control subjects. Diagnostic information on their 3002 relatives was obtained from structured direct assessments and from family history interviews. RESULTS: The 90-year lifetime incidence of primary progressive dementia was significantly higher in relatives of patients with AD (30%) and comorbid AD/depression (27%) than in relatives of patients with early-onset (21%) or late-onset (26%) depression, or of controls (22%) (P =.01). Lifetime incidence of depression was significantly higher in relatives of patients with early-onset depression (13%) than in relatives of patients with AD (10%) or controls (9.0%) (P =.006). Lifetime incidence of depression was similar in control relatives and in relatives of those patients with comorbid AD/depression (8.6%). Relatives of patients with late-onset depression also showed similar occurrence of depression until the age of 80 years, but the figure increased sharply thereafter to 19.1% by the age of 90 years. CONCLUSIONS: Primary progressive dementia and early-onset depression represent clinical entities with distinct inheritance. Late-onset depression does not share substantial inheritance in common with dementia or with early-onset depression, but does show modest familial clustering.     

Early-onset depression and the emotional and behavioral characteristics of offspring

We compared the emotional and behavioral characteristics of offspring of parents with early-onset depression and the offspring of parents with late-onset depression. Forty-three parents who met criteria for major depressive disorder (MDD) completed the Achenbach Child Behavior Checklist-Parent Report Version (CBCL) for a birth child (n=43, age range 6-17 years). Parents were classified as having either early SD onset (<19 years) or late-onset (> or = 19 years) MDD based on responses gathered during the SCID-P interview. Unpaired t-tests were used to compare the two offspring groups on CBCL clinical and competency scales. Chi-square analyses and unpaired t-tests were used to compare the two parent groups on demographic and clinical features. Offspring of parents with early-onset depression scored significantly higher on the majority of the CBCL clinical scale scores when compared with offspring of parents with late-onset depression, rated as exhibiting higher levels of the characteristics measured: withdrawn, anxious/depressed, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior. Additionally, this group had a significantly higher total T score (a global measure of psychopathology) and significantly lower social functioning. Children of parents with early-onset depression may be at higher risk for behavioral and emotional problems than offspring of parents with late-onset depression. This finding may be significant in uncovering sources of vulnerability and formulating intervention strategies for offspring of depressed parents.     

Mitochondrial neurogastrointestinal encephalopathy in an Indian family with possible manifesting carriers of heterozygous TYMP mutation

Depression and anxiety have both been associated with relative left frontal hypoactivation and the motor symptoms of Parkinson's disease typically begin in a lateral or asymmetrical fashion. Hence, PD patients with right hemibody onset may experience heightened depression and anxiety. However, research is mixed regarding whether right or left hemibody onset PD is associated with elevated levels of depression and anxiety. This literature, though, has not considered the potential moderating variable of disease duration. We hypothesized that disease duration would be positively correlated with measures of depression and anxiety in right but not left hemibody onset PD patients. The results indicated that scores on the Geriatric Depression Scale, Beck Depression Inventory-II, and the State Trait Anxiety Scale - State correlated positively with disease duration, but only in the right hemibody onset group of PD patients. Thus, right hemibody onset PD is associated with more severe depressive and anxiety symptoms, but only when disease duration is considered.     

GLIS1 rs797906: An Increased Risk Factor for Late-Onset Parkinson's Disease in the Han Chinese Population

Background: Single nucleotide polymorphism (SNP) rs797906 of the GLIS family zinc finger 1 (GLIS1) gene has been linked to a risk of Parkinson's disease (PD) in genome-wide association studies of Caucasian populations. Methods: A total of 380 unrelated Han patients with PD from the Department of Neurology, West China Hospital of Sichuan University, and 275 unrelated Han Chinese healthy controls (HC) from the same region were included. rs797906 SNP was genotyped using Sequenom iPLEX Assay technology. Results: No significant differences were found in the genotype and allele frequencies for rs797906 between the PD and HC groups. There were no significant differences in genotype frequencies between early-onset PD and HC groups and between late-onset PD and HC groups. The frequency of allele 'A' for rs797906 in the late-onset PD group was significantly higher than that in the HC group (p = 0.046, OR 1.2726, 95% CI 1.0039-1.6132). Moreover, the frequency of allele 'A' in the late-onset PD group was significantly higher than that in the early-onset PD group (p = 0.001). Conclusion: We have found that allele 'A' of rs797906 SNP increases the risk for late-onset PD in the Han Chinese population. More associated studies with larger numbers of participants are needed to confirm the present findings.     

Age at onset influences neurodegenerative processes underlying PD with levodopa-induced dyskinesias

PurposeRecently, we demonstrated that PD patients with levodopa-induced dyskinesias are characterized by neuroanatomical and functional changes involving the prefrontal cortex. When compared with non-dyskinetic PD patients, dyskinetic PD patients showed increased volume of the inferior frontal cortex and a dysfunctional imbalance between this region and the supplementary motor area during motor task. In the current study, we investigated the impact of age at onset of the disease on the neuroanatomical characteristics of dyskinetic patients, because it is well known that early-onset PD patients usually develop dyskinesias sooner with respect to late-onset PD.MethodsWhole-brain voxel-wise investigations of gray matter volume and cortical thickness were carried out in dyskinetic (n = 33), non-dyskinetic PD patients (n = 33) and in age-sex-matched healthy controls (n = 40). Neuroimaging analyses were performed separately according to the age at onset (early < 50 y > late).ResultsIndependent of age at onset, dyskinetic PD patients showed altered morphology in the inferior frontal cortex when compared with non-dyskinetic patients. Moreover, additional significant abnormalities emerged in the early- and late-onset PD patients when compared to controls. In fact, early-onset dyskinetic patients showed increased volume in a large cluster of the midbrain encompassing substantia nigra and red nucleus, whereas late-onset dyskinetic patients were characterized by abnormal gray matter increase in the supplementary motor area.DiscussionOur findings demonstrate different patterns of brain abnormalities in patients with LID according to age at onset, highlighting the role of the nigral pathology in early-onset and of the cortical pathology in late-onset patients with PD.     

Nonthymoma early-onset- and late-onset-generalized myasthenia gravis--a retrospective hospital-based study

OBJECTIVE: Acquired myasthenia gravis (MG) is predominantly due to nicotinic acetylcholine receptor (AChR) autoantibodies (Ab). Differences between nonthymoma early-onset and late-onset MG were reported. We studied the clinical and serological characteristics of nonthymoma AChR Ab-positive-generalized MG patients. PATIENTS AND METHODS: Chinese AChR Ab-positive-generalized MG patients who had generalized disease for 3 years or longer were studied. RESULTS: Among 41 such patients, 25 (61%) were female. The mean onset age was 43.5 years (range 9-78 years) and the mean follow-up duration was 7.8 years (range 3-20 years). Sixteen (39%) patients had late-onset disease (onset age >or=50 years). Compared to early-onset patients (onset age <50 years), late-onset patients were characterized by male predominance (p=0.002), absence of thymic lymphofollicular hyperplasia (p=0.036), and a higher striated muscle Ab seropositivity rate (94% versus 4%, p<0.001). Although there was no statistically significant difference in clinical severity and outcome or response to treatment between late-onset and early-onset patients, 50% and 75% of late-onset patients had moderate or severe disease at onset and worst status, respectively, compared to 28% and 52% for early-onset patients at onset and worst status, respectively. Also 63% of late-onset patients had disease progressed within first 3 years compared to only 40% of early-onset patients did. CONCLUSION: Nonthymoma late-onset-generalized MG patients were common among Hong Kong Chinese, with a statistically non-significant trend that it was clinically more severe than early-onset MG but with similar clinical outcome or response to treatment; >90% of these patients were seropositive for striated muscle Ab.     

Major depressive disorder in the elderly: The relationship between age of onset and cognitive impairment

In order to determine if later age of onset of depression in the elderly is associated with increased cognitive impairment, the scores on the Mini-Mental State Examinations of 41 elderly depressed patients were correlated with the ages of onset of depression. All subjects, average age 74.7, were referred to a psychiatric day hospital for treatment of a major depressive disorder, and all scored at least 14 on the 17-item Hamilton Depression Rating Scale. The ages of first mental health contact and symptom onset were significantly negatively correlated with Mini-Mental State scores (p =0.021 and 0.035 respectively) after the confounding effect of age was adjusted for using partial correlations. The relation between late-onset depression and cognitive impairment lends support to the hypothesis that late-onset depressive disorders in the elderly may be associated with occult brain disease.     

Adults with early-onset obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a clinically heterogeneous disorder with a bimodal age at onset and range of treatment outcomes. This study attempted to ascertain the importance of the age at OCD symptom onset for a better phenotypic precision. Therefore, the authors compared adult OCD patients with an early symptom onset to OCD patients with a later symptom onset. METHOD: Forty-two adult outpatients with OCD were evaluated with semistructured interviews: 21 with symptom onset before the age of 10 (early-onset group) and 21 with symptom onset after the age of 17 (late-onset group). RESULTS: Early onset was associated with higher scores on the Yale-Brown Obsessive Compulsive Scale, higher frequencies of tic-like compulsions, higher frequency of sensory phenomena, and a higher rate of comorbid tic disorders. The early-onset group also responded less well to treatment with clomipramine and selective serotonin reuptake inhibitors. CONCLUSIONS: The results indicate that age at onset may be an important factor in subtyping OCD and that the phenotypic differences found were not restricted to childhood.     

67例晚发性和早发性抑郁症的病例对照研究

为了检验是否存在有所谓的早发性及晚发性抑郁症，并比较其临床特点和与发病有关的因素，本文回顾性研究了３７例晚发抑郁（平均年龄６７．７岁）和３０例（平均年龄２４．１岁）早发抑郁病人。结果显示，与早发抑郁相比，晚发抑郁病人一般抑郁症状较轻、较少内源性忧郁的特征，而焦虑、躯体症状、以及疑病症状相对较重，另外，在发病前所遇生活事件也较重、较多。     

Brain computed tomography findings in geriatric depression and primary degenerative dementia.

Brain computed tomography (CT) scans were performed in hospitalized geriatric patients with major depression (n = 45) or primary degenerative dementia (n = 21). Depressed patients with onset of illness at age 60 years or older (n = 32) had greater ventricular size than geriatric depressives with earlier age of illness onset (n = 13). CT parameters of late-onset depressives were comparable to those of patients with primary degenerative dementia. However, early-onset geriatric depressives had significantly smaller ventricles and less sulcal widening than demented patients. The findings suggest that late-onset depression may have a stronger association with neurological dementing disorders than early-onset depression.