The Study Of Nonmotor Complications And Gene Mutation In Patients With Parkinson's Disease

IntroductionParkinson's disease (PD) is the second most common progressive neurodegenerative disorders, with a prevalence of approximately 1% at the age of 65, increasing to 4-5% by the age of 85. In China,the prevalence of PD increases sharply and we already have 1700,000 PD patients now. Zhang Zhenxin reported that the prevalence figures are similar to some of the highest prevalence figures in the west. It is crucial for the neurologists in China to do more work on PD study.PD patients suffer from bradykinesia, tremor, cogwheel rigidity, and postural instability. The progressive neurologic disorder is due to the relatively selective loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to a profound reduction in striatal dopamine (DA). Despite the environment risks, scientists have long suspected genetics play a role in the onset of the disease.Over the past decade, the treatment of Parkinson disease (PD) has undergone tremendous changes. Levo-dopa (L-dopa) therapy is still the cornerstone of treatment for PD in the elderly. After 5-8 years of treatment, motor complications such as fluctuations and dyskinesia usually occur and adjunct therapy may be required. Many new drugs have been introduced to manage the cardinal motorsymptoms of PD. However, the adverse drug effects of adjunct therapy in the elderly are more common than with L-dopa alone. There are many secondary symptoms of Parkinson's disease. Recently, doctors and patients noticed that non-motor symptoms also impact the life of a person with Parkinson's. A survey published in October 2003, "The Impact of Parkinson's Disease on Quality of Life" revealed that two of the top three most disabling symptoms for people with Parkinson's are non-motor symptoms, including loss of energy and pain. These symptoms need to be treated in order to improve life qualities of PD patients. Others non-motor complications, such as drooling, dementia or confusion, sleep disturbances, constipation, depression, fear or anxiety, memory difficulties and slowed thinking, sexual dysfunction, urinary problems have been reported occurred in PD patients. In China, both doctors and patients pay more attention to motor syndroms. Non-motor complications are so common and require our special attention.Depression has been shown to occur more often (approximately 45%) in patients with Parkinson's disease than in age matched samples, reduces quality of life independent of motor symptoms but its mechanism is poorly understood. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms and available rating scales for major depression may not be adequate to correctly measure severity of depression in PD, it is not easy to make a accurate diagnosis of Parkinson's Disease Depression (PDD). Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergi noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD.Sleep disorders are common in Parkinson's disease with both impairment of nighttime sleep and excessive daytime sleepiness. It has been estimated that over 75% of PD patients have sleep problems. Insomnia, sleep fragmentation, periodic limb movements (PLM) with and without restless legs syndrome (RLS), REM behavior disorder (RBD), and sleep apnea have been reported to occur more often in PD than in normal controls. Despite the frequent occurrence of sleepdisturbances, both physician and patient identification of such problems in PD in clinical practice is poor. Therefore the Parkinson's disease sleep scale (PDSS), a visual analogue scale of 15 questions regarding sleep difficulties, had been developed. However, the utility of this scale in identifying sleep disorders in PD in the clinical practice setting has not been tested. Also, the Epworth Sleepiness Scale (ESS) is not fit Chinese culture. Therefore we evaluated PDSS in a clinic and compared it to other assessments of sleep disorders. This study attempt to address the validity, sensitivity or specificity of the PDSS scale for Chinese PD population.Constipation is common in PD patients and can appear earlier than motor disorders. Constipation not only impairs the quality of life of the patients, but also affects dopaminergic drug absorption, or may lead to an emergency colon pseudo-obstruction. As both nigrostriatal dopaminergic pathways and the locus coeruleus are lesioned in PD, these lesions may result in the decreased colonic contraction in the patients. The peripheral abnormality in PD has been recognised as a decrease of dopaminergic neurons with Lewy bodies in the intrinsic myenteric nerve plexus (Auerbach's plexus) of postmortem PD.Psychosis is a disabling nonmotor complication of Parkinson's disease (PD). Visual hallucinations are the most common clinical manifestation and have been observed in up to 40% of patients with advanced disease in hospital-based series. Age, cognitive dysfunction, depression, as well as severity and duration of disease have all been identified as risk factors in multiple studies. All major antiparkinsonian drugs can induce psychosis in at-risk patients. Early drug-induced psychosis has been observed in up to 16% of patients treated with dopamine agonists and has been associated with increased risk for the development of dementia later on.Pain is reported by nearly 50% of patients with Parkinson's disease. It can be caused by low DOPA, high DOPA.Many patients report pain that has no obvious relation to dopaminergic medications or may even be caused by other conditions.The vast majority of cases of PD are thought to be due to the potentialinteractions of genes and the environment. Two new studies strongly suggest that a mutation in a recently discovered gene is the most common genetic cause of Parkinson's disease identified to date. Parkin gene is involved in the ubiquitination and elimination and the mutation of Parkin was found both in patient with/without positive family history. In addition to other well-confirmed PD gene, mutation in the PTEN induced Kinase (PINK1) gene have been identified in families with recessive early onset PD.The discovery by an international research team provides fresh evidence that genetics may contribute to the development of some cases of Parkinson's disease. The findings could lead to the development of a genetic test to detect the mutation in individuals at risk.Objective1. To investigate and confirm the most common non-motor complications in Chinese population and compared with west population.2. To evaluate the clinical usefulness of the Questionnarie of non-motor complications in patients with PD and to evaluate the usefulness of Parkinson's Disease Sleep Scale.3. To investigate the causes, the manifestations of depression and sleep disorders in PD patients.4. To explore the correlation between non-motor complications and mutation of the gene(Parkin ,PINK1) in PD patientsMethods 1.122 consecutive idiopathic PD patients were recruited in this study.62 patients were seen in the Movement Disorders Center at Mount Sinai Medical Center in New York. This study was approved by Mount Sinai Medical Center institutional review board(IRB). And 60 patients were from Qilu Hospital. The diagnosis of PD was made according to the UK PD Brain Bank criteria. Individuals with atypical parkinsonism or taking sedatives were excluded. Patients were interviewed in the clinic by a movement disorders physician regarding demographics, disease characteristics,medications and whether they had a sleep problem.2. 122 IPD patients were assessed with the following battery of tests: Hoehn & Yahr stage (H/Y); Questionnaire of Non-motor Complications in Patients with Parkinson's Disease; Parkinson's Disease Sleep Scale; Epworth Sleepiness Scale (for 62 west PD patients); Unified Parkinson's Disease Rating Scale and Hamilton Rating Scale for Depression (for 60 Chinese PD patients). Patients who were suspected having restless leg syndrome(RLS) should be examed with International RLS Study Group criteria for the diagnosis of RLS.3. 30 Chinese PD patients and 30 normal controls had genetic test. Exons 2-7,10 of parkin gene and exons5, 8 of PINK1 gene were amplified by PCR. PCR products were observed using Agarose Gel Electrophoresis. For exon4 of parkin and exon8 of PINK1, PCR products were digested by restriction enzyme and observed using PAGE. All 30 PD patients were assessed by Hamilton Depression Rating Scale (HAMD), Unified parkinson's Disease Rating Scale (UPDRS).4. Statistic Manual: The data were analyzed using SPSS 12.0 for Windows (Chicago, IL.) and SAS. Chi-square test, Fisher's exact test, t-test, univariate logistic regression and Pearson correlations. A level of significance of p<0.05 was used.Results1. The most common non-motor complications are: frequency of urine(68.8%), constipation(54.9%), difficulty getting to sleep at night or staying asleep at night(54.1%),urgency of urine(52.4%), unpleasant sensations in limbs at night or while resting(51.6%), sexual dysfunction(50.8%), depression(44.2%), anxiety(40.1%), excessive daytime sleepiness(38.5%), unexplained pains (37.7%), dribbling saliva(36.8%), memory loss(34.4%), sweating(31.9%). Some difference of the nonmotor complications were found between 60 Chinese patients and 62 patients from Mount Sinai hospital.2. The mean total PDSS was correlated with Hoehn and Yahr score (p<0.05). For 62 patients from Mount Sinai, the mean total ESS score was 9.7 ± 4.7. Univariate analysis showed significant correlation between the ESS and items 1 (p=0.041), 3 (p=0.011), and 15 (p=0.001) of the PDSS scale, as well as the total PDSS score(104.7 ± 21.5,p=0.004), and the Hoehn and Yahr score (p=0.017). Only items 3 (p=0.045) and 15 (p<0.001) remained as significant independent predictors of the total ESS score after a subsequent multivariate analysis adjusting for each of the subscores of the PDSS Scale.3. 12 patients from Mount Sinai hospital who got ESS score over 8 had polysomnographic testing. Two patients had possible sleep apnea based on clinical history and the remaining ten patients had the following polysomnographic findings: Sleep apnea(8), Sleep maintenance insomnia(5), Periodic limb movements of sleep(4), Sleep onset insomnia(2) and REM behavior disorder(2). Multiple diagnoses in individual patients occurred. The mean PDSS score in 8 patients with sleep apnea was 89.6 ± 20.9 which differed from the score in patients without sleep apnea (107.5 ± 20.1, p=0.03).4. We found one PD patient has the mutation of exon 5 in parkin gene, and three with mutation of exon 8 in PINKl.Four patients with gene mutation have obvious non-motor complications. However, the number of the study group was too small to allow for statistical analysis. This association did not reach significant differences in patients without gene mutation.Conclusions1. Non-motor complications frequently co-occur with the core motor impairments of PD patients and contribute to the disability. Screening for non-motor symptoms is necessary in clinic practice.2. The PDSS is a useful tool to identify sleep problems related to PD in the clinic and increases recognition and awareness of sleep disorders. We proved the PDSS is also good tool to evaluate the sleep conditions for Chinesepopulations.3. The genetic test suggested that patients with gene mutation in parkin and PINK1 have more non-motor complications. Detecting the gene mutation in the sporadic patients is helpful for early diagnosis and treatments.Significance1. In the present project, we used the latest questionairre for non-motor complications both in Chinese and American PD patients. We proved the most common non-motor symptoms and explained the main causes of the co-occuring. This is the first study of all non-motor complications in China.2. This is the first Chinese version of PDSS.Our assessment of PDSS suggested this scale is very helpful to diagnose sleep disorders. In China, we have no sleep scales better than PDSS.It is easy to use PDSS in the clinic and very convenient for neurologists.3. Discovery the mutation in exon 8 of PINKl brought hope for future study of the degeneration disease. It is necessary to detect the gene mutation in the sporadic PD patients.