Psychosis, apathy, depression and anxiety in Parkinson's disease.

Psychiatric symptoms are important non-motor features in PD, which occur at high frequency and have significant impact on health related quality of life. This review concentrates on the prevalence, pathophysiology, diagnosis and treatment of depression, anxiety, apathy and psychosis. The pathophysiology of these disorders is complex, reflecting the widespread brainstem and cortical pathology in PD, with involvement of several neurotransmitters, including dopaminergic, serotonergic, noradrenergic and cholinergic systems. The diagnosis of psychiatric conditions, in particular affective disorders, is challenging because of the overlap of somatic features of psychiatric disorders and underlying movement disorder. The pathogenesis is likely to differ considerably from non-PD patients, and treatments used in general psychiatry services may not be as effective in PD and will require clearer clarification in well-designed clinical studies. Management strategies include adjustment of dopaminergic medication, use of psychotropic treatments and behavioural and psychological approaches. However, the future challenge will be to develop treatments developed specifically for the pathogenesis of these disorders in PD.

Validation of the MDS-UPDRS Part I for nonmotor symptoms in Parkinson's disease.

The UPDRS has been the main outcome measure in studies of PD. Modifications have been made to improve scale properties and represent the breadth of manifestations of PD, particularly nonmotor symptoms (NMS), resulting in the Movement Disorder Society's revision of the UPDRS (MDS-UPDRS). This study was undertaken to determine the validity of MDS-UPDRS Part I (nonmotor experiences of daily living). The MDS-UPDRS and a number of validated scales for the NMS in PD were used in 94 patients with PD from Hoehn and Yahr stage I to V. We assessed reliability, floor and ceiling effects, and correlations with validated scales for the nonmotor symptoms of PD. MDS-UPDRS Part I showed high internal consistency (Cronbach's alpha: 0.85), small floor and ceiling effects (2% floor and 0% ceiling effect), and good concurrent validity (correlation with the original UPDRS Part I: r = 0.81, P < 0.001). The standardized z-score of the MDS-UPDRS Part I score demonstrated high convergent validity with the composite z-score of nonmotor scales (r = 0.89, P < 0.0001), and the two subscores based on the original factor analysis of Part I also had high correlations with the composite z-scores of corresponding nonmotor scales (depression, anxiety, apathy factor score: r = 0.72, P < 0.0001; other nonmotor features factor score: r = 0.87, P < 0.0001). Our data demonstrate that the MDS-UPDRS Part I total score has a strong relationship with a composite score of validated scales for the nonmotor aspects of PD.

Testing an aetiological model of visual hallucinations in Parkinson's disease.

The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.

Developing and assessing a new web-based tapping test for measuring distal movement in Parkinson's disease: a Distal Finger Tapping test.

Disability in Parkinson's disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III finger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor fluctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% specificity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS finger-tapping sub-score (Pearson's r = - 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor fluctuation states which were not reflected clearly by the MDS-UPDRS-III finger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.

Dysautonomia Causing Severe Orthostatic Hypotension: An Important, Early Finding in Neurodegenerative Disorders.

Orthostatic hypotension is common and dangerous; it has neurogenic and nonneurogenic causes. We present the case of a 40-year-old man with severe neurogenic hypotension, caused by young-onset multiple system atrophy. In patients presenting with neurogenic orthostatic hypotension, underlying neurodegenerative diseases should always be considered. (Level of Difficulty: Advanced.).

What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them?

Nonmotor symptoms (NMS) are increasingly recognized as important and neglected aspects of Parkinson's disease (PD). We evaluated their relative frequency and comparative impact on health-related quality of life (Hr-QoL) using validated questionnaires. In addition, we assessed the rate of reporting of NMS in neurology clinics compared with their subjective impact on patients. We used a range of validated clinimetric scales of motor and nonmotor symptoms and Hr-QoL to assess consecutive patients with PD. Reporting of NMS was assessed by comparison with case note documentation. A mean of 11 of 30 NMS per patient were elicited on the NMS questionnaire of which on average 4.8 were reported in the clinical notes (44%). The most common NMS were autonomic (particularly urinary). The Hr-QoL scores correlated most strongly with autonomic dysfunction (r = 0.84; particularly urinary and gastrointestinal symptoms), mood (r = 0.74), fatigue (r = 0.74), sleep problems (nocturnal r = 0.55; daytime somnolence r = 0.65), pain (r = 0.56), and psychosis (r = 0.55, all p < 0.0001) followed by UPDRS motor score (r = 0.48, p < 0.0001). Greater motor fluctuations (r = 0.57) and dyskinesia (r = 0.43, both p < 0.0001) were also associated with worse Hr-QoL. In multivariate analysis, depression had the strongest association with Hr-QoL (adjusted R(2) = 0.53, p = 0.005) followed by fatigue, thermoregulatory, gastrointestinal, and cardiovascular autonomic function (especially orthostatic hypotension), daytime somnolence, and urinary problems. This study demonstrates that a autonomic dysfunction, psychiatric complications, pain, fatigue, and sleep problems are major correlates of poor Hr-QoL. However, whilst psychiatric problems are increasingly documented, many symptoms (particularly those possibly perceived as embarrassing or unrelated) remain under-reported.

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease.

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinson's disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study.

Nonmotor symptoms (NMS) are increasingly recognized as a significant cause of morbidity in later stages of Parkinson's disease (PD). Prodromal NMS are also a well recognized component of the clinical picture in some patients but the prevalence of NMS as presenting complaints, and their impact on clinical management, in pathologically-proven cases of PD is unknown. The presenting complaints of 433 cases of pathologically-proven PD archived at the Queen Square Brain Bank for Neurological Diseases were identified from the clinical case notes. 91/433 (21%) of patients with PD presented with NMS of which the most frequent were pain (15%), urinary dysfunction (3.9%), anxiety, or depression (2.5%). Presenting with NMS is associated with a delayed diagnosis of PD (Mann-Whitney U, P = 0.001). These patients were more likely to be misdiagnosed initially and were more likely to have been referred to orthopedic surgeons or rheumatologists than neurologists (nonmotor group 5.5% vs. motor group 44.2%, chi(2) P < 0.0001). NMS are commonly seen as presenting complaints in pathologically confirmed PD, and initial misdiagnosis may be associated with potentially inappropriate medical interventions. Presenting with NMS does not affect the motor response to medication, but is associated with shorter disease duration (chi(2) P = 0.016).

Impact of newer pharmacological treatments on quality of life in patients with Parkinson's disease.

Parkinson's disease is a common progressive neurodegenerative condition with multiple motor and nonmotor features contributing to impairment of health-related quality of life (HR-QOL). Pharmacological treatments have been directed primarily at dopamine replacement with levodopa and agents to improve its bioavailability, including DOPA decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors, as well as synthetic dopamine agonists. These treatments to restore motor function are often very successful in early Parkinson's disease, with objective improvement and concomitant improvement in subjective HR-QOL scores. However, as the disease progresses, motor complications and nonmotor symptoms predominate and are often refractory to therapeutic interventions. Antiparkinsonian medications have been shown to improve motor severity and motor complications of advancing disease, and there is increasing evidence that this can be translated into subjective improvement of HR-QOL from a patient's point of view. However, the degree of improvement is less marked on HR-QOL scores than on motor scores, and some studies do not show improvement of HR-QOL in parallel to motor improvements. A number of explanations are possible, including limitations of the scales used, trial designs and lack of clinical improvement from the patients' point of view. This review concentrates on clinical trials with an index of HR-QOL as an outcome measure, with particular emphasis on well designed, randomized, double-blind, placebo-controlled or active comparator-controlled methodology. Drugs that have been more recently added to the armamentarium of Parkinson's disease, including the oral (pramipexole, ropinirole and piribedil) and transdermal (rotigotine) non-ergotamine-derived dopamine agonists, the novel MAO-B inhibitor rasagiline and the COMT inhibitors tolcapone and entacapone, were included. The effect of each of these agents on overall HR-QOL and depression, a factor that has been shown to significantly contribute to HR-QOL in several multivariate analyses, is discussed.Overall, the literature search revealed 14 double-blind, placebo- or active comparator-controlled trials with an index of HR-QOL as an outcome measure. Entacapone resulted in HR-QOL improvement in nonfluctuating patients (one study) but not clearly in those with motor fluctuations (two studies). Tolcapone was only tested in patients with motor fluctuations and resulted in significant improvement in two of four studies using HR-QOL as an outcome measure. Rasagiline improved HR-QOL as monotherapy in early Parkinson's disease (one study), but not clearly in more advanced disease (one study). Rotigotine improved HR-QOL in both early Parkinson's disease (one study) and more advanced disease with motor fluctuations (one study). The impact of ropinirole and pramipexole on HR-QOL as monotherapy in early Parkinson's disease versus placebo has not been assessed, but both agents have resulted in improved HR-QOL in patients with motor fluctuations (ropinirole one study, pramipexole one study). The evidence for antidepressant efficacy of antiparkinsonian medications is limited.

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

BACKGROUND: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. METHODS: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. RESULTS: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. CONCLUSIONS: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.

Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS-UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross-sectional study, demographic data and MDS-UPDRS scores were collected, including HY stage. Subscores on MDS-UPDRS Parts I through IV were analyzed using 1-way analyses of variance for each HY stage and in 5-year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0-5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS-UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5-year increments of disease duration, MDS-UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS-UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5-year increments of disease duration in the first 15 years of the disease.

Why do patients with Parkinson's disease fall? A cross-sectional analysis of possible causes of falls.

BACKGROUND: Falls in Parkinson's disease (PD) are associated with significant injury, disability, hospitalization, and reduced quality of life. AIMS: To identify modifiable medical causes of falls in a cohort of PD patients. METHODS: Eighty seven PD patients were interviewed and examined using validated scales assessing motor and nonmotor aspects of PD, comorbidities and medication use. The frequency of falls in the last month was the primary outcome measure. Falls were hypothesized to be associated with increasing age, advanced motor severity, particularly axial features (e.g., freezing and postural instability), and dyskinesia. Nonmotor features hypothesized to be associated with falls included; cognitive impairment, psychosis, sleep disorders, cardiovascular dysfunction, and ophthalmological and medical comorbidities. RESULTS: Fallers had longer disease duration, higher Levodopa-equivalent doses, greater 'On' time with dyskinesia (all P < 0.005), and higher scores on some Movement Disorder Society-Unified Parkinson's Disease Rating Scale items, particularly axial scores. However, patients with falls did not differ from non-fallers in age or overall motor UPDRS scores. Severity of psychosis, executive cognitive impairment, autonomic (particularly cardiovascular) dysfunction and sleep disturbances (particularly REM sleep behavioral disorder) were significantly associated with falls (all P < 0.005). Fallers more frequently reported use of antidepressants (both tricyclics and SSRIs) and neuroleptics (P < 0.001), but not hypnotics. There was no difference in medical comorbidities, ophthalmological assessments, fatigue, and apathy scores between the groups. In logistic regression analysis, cardiovascular dysfunction, antidepressant use, and REM sleep behavioral disorder were significantly associated with falls. CONCLUSIONS: The causes of falls in PD are multifactorial and extend beyond motor impairment and dyskinesia; addressing these in patients already treated with dopaminergic medications has the potential to improve this important complication of PD.

Etiopathogenesis and treatment of Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-apoptotic agents. Evidence has also been gained from cell culture and animal models for the potential disease modifying action of currently available dopaminergic therapies. These drugs have undergone clinical evaluation using studies with novel designs including "delayed start" methodology and studies using neuroimaging as a surrogate marker of dopaminergic cell loss. It is estimated from clinical, pathological and imaging studies that at least 50% of dopaminergic neurons are lost before the development of significant motor symptoms with a pre-motor phase of approximately 6-8 years. A number of pre- and post-synaptic neuroplastic homeostatic mechanisms occur during this period to maintain motor function. However these changes have been implicated in the development of motor complications (wearing "off" and dyskinesias). The evidence for treatments of motor complications in PD is discussed as are potential non-dopaminergic therapeutic targets to delay or improve motor complications.

Pathological gambling in Parkinson's disease: risk factors and differences from dopamine dysregulation. An analysis of published case series.

Pathological gambling (PG) has been reported as a complication of the treatment of Parkinson's disease (PD). We examined all published cases of PG for prevalence and risk factors of this complication, the relationship of PG and use of dopamine agonists (DA), and the relationship of PG to the dopamine dysregulation syndrome (DDS). The prevalence of PG in prospective studies of PD patients using DA has been reported between 2.3 and 8%, compared to approximately 1% in the general population. As in the general population, PD patients with this complication are often young, male and have psychiatric co-morbidity. The vast majority are on DA, often at maximum dose or above. Differences between oral DA failed to reach significance. PG associated with levodopa monotherapy is uncommon, but in the majority of cases levodopa is co-prescribed, suggesting possible cross-sensitization of brain systems mediating reward. PG can occur with DDS but often occurs in isolation. In contrast to DDS, escalation and self regulation of anti-parkinsonian medication are not usually seen. PG in patients with PD using DA is higher than PG reported in the general population, but shares similar characteristics and risk factors. PG is predominantly associated with oral DA. It often occurs in isolation and may not be associated with DDS, which typically occurs on treatment with levodopa or subcutaneous apomorphine.