Recent Progress in Non-motor Features of Parkinson’s Disease with a Focus on Circadian Rhythm Dysregulation

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.     

Survival in Parkinson's disease. Relation with motor and non-motor features

BackgroundSurvival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease.MethodsA broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease.ResultsAfter a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms.ConclusionsHigher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features.     

Motor and non-motor features of Parkinson's disease that predict persistent drug-induced Parkinsonism

BackgroundDrug-induced Parkinsonism is common, causes significant morbidity, and can be clinically indistinguishable from idiopathic Parkinson's disease. Additionally, drug-induced Parkinsonism may, in some cases, represent “unmasking” of incipient Parkinson's disease. Clinical features or tests that distinguish degenerative from pharmacologic Parkinsonism are needed.MethodsWe performed a retrospective case-control study of 97 drug-induced Parkinsonism subjects and 97 age-matched patients with Parkinson's disease. We compared the frequency of subjective motor and non-motor complaints, objective motor findings (Unified Parkinson's Disease Rating Scale Part III) and, where available, objective olfactory tests. We also performed a nested case-control study wherein we compared these same features between drug-induced Parkinsonism patients based on whether or not they recovered after changing the offending agent.ResultsNon-motor symptoms including constipation and sexual dysfunction were more common in Parkinson's disease than in drug-induced Parkinsonism. While total motor scores were similar between groups, Postural Instability-Gait Difficulty scores were also higher in Parkinson's disease. Features that were significantly different or showed a trend towards significance in both comparisons included subjective loss of facial expression, dream-enactment behavior, autonomic complaints and Postural Instability-Gait Difficulty scores. Hyposmia was more common in Parkinson's disease and was strongly predictive of persistent drug-induced Parkinsonism after therapy change (odds ratio 30.3, 95% confidence interval: 1.5–500, p = 0.03).ConclusionsA constellation of motor and non-motor features may differentiate unmasked Parkinson's disease from drug-induced Parkinsonism. In particular, olfactory testing may offer a simple and inexpensive method to help predict outcomes in drug-induced Parkinsonism and, potentially, identify a cohort of pre-motor Parkinson's disease.     

The effects of transdermal rotigotine on non-motor symptoms of Parkinson's disease: a multicentre,observational, retrospective,post-marketing study

Aim: This study evaluated the effect of ≥6 months of transdermal rotigotine on non-motor and motor symptoms of patients with advanced Parkinson's disease. Materials and methods: The study was conducted in Spain between September 2011 and December 2012 (ClinicalTrials.gov: NCT01504529). The primary efficacy variable was the change from baseline in non-motor symptoms, as assessed by changes in Parkinson's Disease Non-Motor Symptoms Questionnaire total scores at 6 months. Secondary endpoints included the assessment of motor symptoms by Unified Parkinson's Disease Rating Scale III scores. Results: Data from 378 patients (mean age: 70.2 years; 56.9% male) with Parkinson's disease receiving rotigotine from were collected. Mean disease duration was 6.1 years, and mean rotigotine treatment duration was 45.6 months. Rotigotine reduced non-motor symptoms by 14.6% (mean change from baseline in Parkinson's Disease Non-Motor Symptoms Questionnaire: ?1.5 ± 3.4; p < 0.0001). The majority of patients (58.2%) had improved non-motor symptoms at 6 months. Comparing the baseline versus study end, fewer patients experienced events in the urinary (78.6% vs. 73.3%; p = 0.0066), sleep (82.8% vs. 72.8%; p < 0.0001) and mood/cognition (77.3% vs. 66.4%; p < 0.0001) domains of the Parkinson's Disease Non-Motor Symptoms Questionnaire. Mean motor symptoms were reduced from baseline by 8.0% (mean change from baseline in Unified Parkinson's Disease Rating Scale III: ?2.6 ± 8.0; p < 0.0001). Conclusions: In clinical practice in Spain, rotigotine may be an effective treatment to reduce the non-motor and motor symptoms in patients with advanced Parkinson's disease.     

Sleep benefit in Parkinson's disease is associated with short sleep times

Sleep benefit in Parkinson's disease is characterized by restoration of mobility upon awakening from sleep and prior to drug intake. With this study, we aimed at assessing clinical and nocturnal sleep correlates of this phenomenon. We recorded motor and non-motor symptoms in 131 Parkinson patients with and without sleep benefit, as assessed by questionnaires. Polysomnography recordings were performed in 60 of these patients. Thirty-nine Parkinson patients (30%) reported sleep benefit. Motor symptoms, measures of sleepiness, fatigue, depression, anxiety, sleep-wake disorders, and dopaminergic treatment were not associated with sleep benefit, and most polysomnography measures were similar between both groups. However, Parkinson patients with sleep benefit had shorter total sleep times and longer sleep latencies at nocturnal polysomnography. The link between the occurrence of sleep benefit and shorter nocturnal sleep in Parkinson's disease remains unclear.     

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.     

Differentiating drug-induced parkinsonism from Parkinson's disease: An update on non-motor symptoms and investigations

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions.Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with “pure” drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease.Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.     

Reduced plasma taurine level in Parkinson's disease: association with motor severity and levodopa treatment

Purpose: This study aimed to evaluate the level of taurine in plasma, and its association with the severity of motor and non-motor symptoms (NMS) and chronic levodopa treatment in Parkinson's disease (PD). Patients and methods: Plasma taurine level was measured in treated PD (tPD), untreated PD (ntPD) and control groups. Motor symptoms and NMS were assessed using the Unified Parkinson's Disease Rating Scale, the short form of the McGill Pain Questionnaire, the Hamilton Depression Scale, the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms and the Pittsburgh Sleep Quality Index. Longtime exposure to levodopa was indicated by its approximate cumulative dosage. Results: The plasma taurine levels of PD patients were decreased when compared with controls and negatively associated with motor severity but not NMS. Moreover, tPD patients exhibited lower levels of plasma taurine than ntPD patients. Interestingly, plasma taurine levels negatively correlated with cumulative levodopa dosage in tPD. After controlling for potential confounders, the association between taurine and levodopa remained significant. Conclusion: Our study supports that taurine may play important roles in the pathophysiology of PD and the disturbances caused by chronic levodopa administration.     

Cognitive and functional changes in prediagnostic phase of Parkinson disease: A population-based study

IntroductionProdromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease.MethodsThis study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models.ResultsNo significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2–3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis.ConclusionIn late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase.     

Incorporating oral health into interprofessional care teams for patients with Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the motor system. However, non-motor symptoms such as cognitive, autonomic, sleep-related and sensory dysfunctions are often reported. A subgroup of non-motor symptoms, oropharyngeal problems, also affects these patients in ways that greatly deteriorate quality of life. Each patient may develop a different set of non-motor symptoms, making interprofessional collaboration among health care providers a must to treat patients with PD. In this review, we argue that dental health professionals must be included in this interprofessional health care team. Patients with PD are at a higher risk for developing oral health problems that can exacerbate or be exacerbated by other non-motor symptoms, such as mental health and dysphagia This accelerates decline in quality of life and even increases the risk of death by aspiration pneumonia. Dentists can create preventive oral health plans as soon as a diagnosis is made and promptly treat a patient's dental problems, preventing them from affecting other health areas. We describe major oral health concerns and how health professionals and dentists can participate and collaborate to improve the health of patients with PD.     

Progressive loss of raphe nuclei serotonin transporter in early Parkinson's disease: A longitudinal 123I-FP-CIT SPECT study

BackgroundSerotonergic raphe nuclei dysfunction has been documented in Parkinson's disease, both in pathological and neuroimaging studies, and has been associated with scores of tremor and non-motor symptoms. However, no in vivo longitudinal investigations have been conducted to assess the rate of decline of raphe serotonin transporter availability in the early stages of the disease.ObjectiveTo measure the rate of decline of raphe serotonin transporter availability over a two-year interval in patients with recently diagnosed disease and its association with non-motor symptoms over time.MethodsBaseline and two-year follow-up ¹²³ioflupane-fluoropropyl-carbomethoxy-3-beta-4-iodo-phenyltropane (¹²³I-FP-CIT) SPECT scans of 173 early Parkinson's disease patients enrolled in the Parkinson's Progressive Markers Initiative were analysed and non-motor symptoms scores recorded.ResultsA 16.6 ± 20.9% (mean ± SD) reduction in raphe serotonin transporter availability was found from baseline to two-year follow-up in the entire cohort. No differences in progression were found between tremor dominant and postural instability/gait difficulty phenotypes. At follow-up 34.1% of patients showed a moderate-to-severe reduction of raphe serotonin transporter availability with respect to the controls’ mean. We did not find any significant correlation between raphe serotonin transporter availability and scores of depression, excessive daytime sleepiness and REM sleep behaviour disorder.Conclusion¹²³I-FP-CIT SPECT was able to measure longitudinal reductions in raphe serotonin transporter availability in the early phases of Parkinson's disease. About four years after diagnosis, raphe serotonin transporter availability was significantly reduced in more than one third of the population, but does not appear to be correlated to non-motor symptoms at this stage.     

MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease

Objective: To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). Methods: Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. Results: One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. Conclusions: This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.     

Prevalence of non-motor dysfunction among Parkinson's disease patients from a tertiary referral center in Mexico City

Data on the frequency of non-motor symptoms among patients with Parkinson's disease (PD) in Mexico has not been reported.     

Motor,behavioural, and cognitive correlates of fatigue in early,de novo Parkinson disease patients

IntroductionFatigue is one of the most common and disabling non-motor symptoms in Parkinson's disease (PD). The objective of this study was to determine prevalence and motor, behavioural, and cognitive correlates of distressing fatigue in early, de novo PD patients.MethodsEighty-one consecutive de novo PD patients (64% men; mean age 65.73 ± 8.26 years) underwent a comprehensive examination, including Parkinson's disease Fatigue Scale (PFS), Epworth Sleepiness Scale (ESS), Parkinson's Disease Sleep Scale (PDSS), Beck Depression Inventory (BDI), Parkinson's Anxiety Scale (PAS), and Apathy Evaluation Scale (AES). Moreover, all patients underwent a detailed neuropsychological evaluation exploring attention and working memory, executive functions, memory, visuospatial abilities and language. Score of patients with or without distressing fatigue (defined as a PFS score ≥ 8) were compared by Student's t-test or Pearson's chi-square test. Logistic regression analyses were performed to search for motor and non-motor features independently associated with presence of distressing fatigue.ResultsTwelve (15%) patients presented distressing fatigue. Logistic regression identified sleepiness (p = 0.04), “episodic anxiety” subscale of PAS (p = 0.005), and “cognitive apathy” subscale of AES (p = 0.017) as the main factors associated with distressing fatigue. No significant association was found between diagnosis of Mild Cognitive Impairment and distressing fatigue (p = 0.745).ConclusionIn a sample of consecutive de novo PD patients, distressing fatigue is associated with episodic anxiety, cognitive apathy and sleepiness, but not with cognitive impairment. Our findings suggest possible shared pathogenic mechanisms underlying these non-motor symptoms and foster development of early combined therapeutic approaches.     

Neural networks associated with quality of life in patients with Parkinson's disease

IntroductionThe neural underpinnings of health-related quality of life in Parkinson's disease remain unclear. This study was conducted to unravel which motor and non-motor symptoms in Parkinson's disease influence health-related quality of life and reveal neural networks most likely linked to it.MethodsComprehensive clinical assessments were conducted for 247 Parkinson's disease patients and image analyses were performed for 181 patients. Clinical scores commonly used to assess various symptoms related to health-related quality of life were investigated. Factor and resting-state functional magnetic resonance imaging analyses were reviewed to reveal health-related quality of life-associated brain networks.ResultsThe Spearman's rank correlation coefficient for the Parkinson's disease Questionnaire-39 summary index was high in the Activities-specific Balance Confidence Scale, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part 2, Freezing of Gait Questionnaire, and Self-reported Autonomic Symptoms in Parkinson's disease. Multiple regression and Random Forest regression analyses indicated that health-related quality of life-associated factors were Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part 1, Depression Rating Scales, and the above-mentioned scales. The resting-state functional magnetic resonance imaging analysis revealed decreased functional connectivity between the anterior cingulate cortex and right temporo-parietal junction as health-related quality of life worsened.ConclusionFear of falling, daily living activities, gait freezing, and autonomic dysfunction have notable effects on health-related quality of life in Parkinson's disease. Brain networks consisting of the anterior cingulate cortex and temporo-parietal junction may be associated with the emotion-related and social factors of health-related quality of life in Parkinson's disease.     

Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease

BackgroundThe relative impact of motor- and non-motor symptoms on health-related quality of life in early Parkinson's disease is poorly documented.Methods188 patients with incident Parkinson's disease from a population-based study were examined at the time of diagnosis, before initiation of dopaminergic treatment, with follow-up of 166 patients three years later. Health-related quality of life was assessed by the 36-item Short-form Health Survey (SF-36). Motor and non-motor variables were derived from the Unified Parkinson's disease rating scale and other established scales.ResultsMultiple regression analyses showed that the non-motor symptoms strongest associated with reduced SF-36 scores at diagnosis and three years later were depression, fatigue and sensory complaints. The motor symptoms most related to impaired SF-36 scores were problems with gait and activities of daily living that cover personal needs. The variance of SF-36 mental summary scores was much better explained by non-motor vs. motor symptoms, both at baseline (R² = 0.384 vs. 0.095) and 3 years later (R² = 0.441 vs. 0.195). Also SF-36 physical summary scores were better explained by non-motor vs. motor symptoms with R² = 0.372 vs. 0.322 at baseline and R² = 0.468 vs. 0.315 after 3 years.ConclusionIn early PD, including the phase before dopaminergic treatment is initiated, non-motor symptoms are more important for reduced health-related quality of life than motor symptoms. Fatigue, depression, sensory complaints and gait disturbances emerge as the most relevant symptoms and should be given corresponding attention in the management of patients with early PD.     

How specific are non-motor symptoms in the prodrome of Parkinson's disease compared to other movement disorders?

The clinical diagnosis of Parkinson's disease (PD) based on motor signs is often preceded by several non-motor symptoms that can indicate early prodromal neurodegenerative processes. Such prodromal symptoms can aid the early detection of PD, but their specificity for prodromal PD in comparison to prodromes of other movement disorders is still largely unclear. We here aim to give a first insight into the published evidence of prodromal non-motor symptoms in PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease (HD), progressive supranuclear palsy (PSP) and spinocerebellar ataxia (SCA). REM-sleep behavior disorder (RBD) and autonomic dysfunction have been observed in the prodromes of PD, MSA, DLB and SCA. Depression and cognitive decline have been reported for prodromal PD, DLB, HD, SCA, and PSP. Olfactory loss has only been described in prodromal PD/DLB. However, estimating the specificity of prodromal non-motor symptoms in PD is so far complicated by scarce prospective evidence and study limitations. Information on marker specificity is a prerequisite for an accurate early (differential) diagnosis of prodromal diseases, as well as specific recruitment for targeted neuroprotective interventions. We here would like to raise awareness of these issues and encourage further prospective research of prodromal non-motor symptoms in neurodegenerative movement disorders and other diseases.     

Determinants and impact of alexithymia on quality of life in Parkinson's disease

IntroductionAlexithymia is a neuropsychiatric symptom conceptualized as difficulty identifying and describing feelings. Although associated with other non-motor symptoms, mainly neuropsychiatric, alexithymia may present as an isolated symptom in persons with Parkinson's Disease (PwP). The objective of the study is to identify determinants of alexithymia and its association with quality of life (QoL) in Parkinson's disease.MethodsSubjects with Parkinson's disease were recruited. The following instruments were applied: Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Non-Motor Symptoms Scale (NMSS), Montreal Cognitive Assessment (MoCA), Toronto alexithymia scale (TAS-20) and Parkinson's Disease Questionnaire (PDQ-8). Matched healthy controls were screened using TAS-20. Clinical and demographical variables were compared between alexithymic and non-alexithymic. Regression models were used to find determinants of alexithymia. Impact of alexithymia on QoL was estimated with a linear regression model.Results98 patients were included. 56.1% PwP and 28.8% controls were alexithymic (p < 0.001). Education level (OR 0.86) and NMSS urinary score (OR 1.09) determined alexithymia as well as TAS-20 score. Alexithymia was an independent determinant of QoL.ConclusionsAlexithymia is a prevalent independent non-motor symptom in PwP with impact on QoL. Low education level and urinary symptoms are important determinants of alexithymia.     

Fatigue in Parkinson's disease: Motor or non-motor symptom?

Fatigue is one of the most disabling symptoms in patients with Parkinson's disease (PD), with a significant impact on patients' quality of life. Clinical studies using ad hoc questionnaires showed that in PD fatigue is associated with non-motor as well motor symptoms. Neurophysiological observations suggest that motor mechanisms play a role in the pathophysiology of fatigue but there is no clear correlation between fatigue measured with clinical instruments and fatigue assessed with neurophysiological tests. Neuroimaging studies show that fatigue is associated with an involvement of non-dopaminergic or extrastriatal dopaminergic pathways. It is conceivable that both motor and non-motor mechanisms underlie the pathophysiology of fatigue.     

Intrinsic and extrinsic psychosis in Parkinson's disease

Direct and indirect signs and symptoms of Parkinson's disease are a major cause of disability in the elderly. Intrinsic symptoms comprise not only the well-known clinical hallmarks of this disease with motor behavioral abnormalities, such as bradykinesia, hypokinesia, rigidity and tremor, but also autonomic failure with orthostatic hypotension, urinal incontinence and impotence as well as non-motor behavioral abnormalities: mental dysfunction characterized by mood disorders, cognitive dysfunction and, sporadically, delusions and hallucinations. These symptoms are caused by a progressive abnormal degeneration of the dopamine (DA) producing cells in the substantia nigra (SN) and ventral tegmentum area (VTA) in combination with an interindividual fluctuating degree of decay in the noradrenergic (locus coeruleus), cholinergic forebrain (nucleus basalis of Meynert) and serotoninergic (dorsal raphe nuclei) systems. Extrinsic symptoms, induced by pharmacotherapy, mainly manifest with (un)predictable motor response fluctuations and dopaminomimetic psychosis. Psychological and psychiatric symptoms in Parkinson's disease (PD) are important predictors of the patient's quality of life. As these symptoms are potentially treatable, identification is of major clinical importance both for the patients and their caregivers and may enable to maintain Parkinson's disease patients at home for a longer period.