Parkinson's disease: The quintessential neuropsychiatric disorder
TL;DR: The emergent focus on nonmotor aspects of Parkinson's disease over the past quarter of a century is highlighted by a nonlinear increase in the number of articles published devoted to this topic.
Abstract: Although diagnosed by characteristic motor features, Parkinson's disease may be preceded, and is frequently accompanied by, a wide range of cognitive and neuropsychiatric features. In addition to the most commonly studied disorders of dementia, depression, and psychosis, other relatively common and clinically significant psychiatric complications include impulse control disorders, anxiety symptoms, disorders of sleep and wakefulness, and apathy. These problems may be underrecognized and are frequently undertreated. The emergent focus on nonmotor aspects of Parkinson's disease over the past quarter of a century is highlighted by a nonlinear increase in the number of articles published devoted to this topic. Although the development of newer antidepressants, atypical antipsychotics, and cholinesterase inhibitors in recent years has had a positive benefit on the management of these troublesome and distressing symptoms, responses are frequently suboptimal, and this remains an area of major unmet therapeutic need.
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CEU San Pablo University1, University of Marburg2, National and Kapodistrian University of Athens3, Rush University Medical Center4, Toronto Western Hospital5, University of Toronto6, University of Pennsylvania7, Newcastle University8, University of New South Wales9, University of Sydney10, Centre national de la recherche scientifique11, Peking Union Medical College12, Columbia University13, University of Paris14, Aarhus University15, UCL Institute of Neurology16, National Institutes of Health17, Emory University18, San Francisco VA Medical Center19, University of California, San Francisco20, Veterans Health Administration21, Erasmus University Medical Center22, Baylor College of Medicine23, University of Kiel24, Hebrew University of Jerusalem25, University of Barcelona26, Columbia University Medical Center27, McGill University28, University of Alabama at Birmingham29, Northwestern University30, Icahn School of Medicine at Mount Sinai31, University of Perugia32, University of British Columbia33, Vancouver Coastal Health34
TL;DR: This multiple‐author article provides a historical state‐of‐the‐art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease.
Abstract: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.
523 citations
Cites background from "Parkinson's disease: The quintessen..."
...The high prevalence of cognitive impairment and protean psychiatric complications has changed how we conceptualize PD.(47,48) This has manifested itself in the recently proposed revised clinical diagnostic criteria,(17,49) which allows for dementia to be a comorbid condition at the time of diagnosis....
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TL;DR: An overall improvement in neuropsychiatric symptomatology is shown and it is proposed that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation.
Abstract: Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation.
266 citations
Cites background from "Parkinson's disease: The quintessen..."
...Non-motor fluctuations, corresponding to rapid oscillations between hypo- and hyperdopaminergic states, constitute a frequent and disabling complication of dopaminergic treatment (Witjas et al., 2002; Stacy et al., 2005; Ardouin et al., 2009; Thobois et al., 2010; Weintraub and Burn, 2011)....
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...BRAIN A JOURNAL OF NEUROLOGY...
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TL;DR: Clinical studies demonstrate the efficacy of medications and psychotherapies for PD depression, underscoring the importance of their timely detection and concerted management.
Abstract: Depressive disturbances are common in patients with Parkinson’s disease (PD) and influence many other clinical aspects of the disease. In addition to causing inherent emotional distress, depressive disorders negatively impact quality of life, motor and cognitive deficits, functional disability, and other psychiatric comorbidities in patients with PD. Knowledge of the pathophysiology of PD depression remains limited. However, clinical studies demonstrate the efficacy of medications and psychotherapies for PD depression, underscoring the importance of their timely detection and concerted management.
245 citations
Additional excerpts
...Reported risk factors for PD depression include motor disability [64], female gender [15], past psychiatric history [65, 66], neuropsychiatric comorbidities [67], predominance of right-sided motor symptoms [68], and greater imbalance and rigidity [69], but others have not confirmed these results [70, 71]....
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TL;DR: This study was undertaken to determine the prevalence and correlates of cognitive impairment and neuropsychiatric symptoms in early, untreated patients with Parkinson's disease.
Abstract: This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson’s disease (PD).
Background
Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS.
231 citations
Cites background from "Parkinson's disease: The quintessen..."
...Cognitive impairment and neuropsychiatric symptoms (NPS) are frequent in patients with Parkinson disease (PD), negatively impacting patients’ quality of life and increasing caregiver burden.(1) Approximately 25% of non-demented PD patients have mild cognitive impairment (MCI),(2) and up to 80% of all PD patients will eventually develop dementia....
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...Future analyses of this cohort will examine biological predictors and the course of CI and NPS. VC 2015 International Parkinson and Movement Disorder Society Key Words: anxiety; apathy; cognition; depression; impulse control disorder; Parkinson’s disease; psychosis Cognitive impairment and neuropsychiatric symptoms (NPS) are frequent in patients with Parkinson disease (PD), negatively impacting patients’ quality of life and increasing caregiver burden.1 Approximately 25% of non-demented PD patients have mild cognitive impairment (MCI),2 and up to 80% of all PD patients will eventually develop dementia.3 Psychosis, depression, anxiety, apathy, and impulse control disorders (ICDs) are the most frequent and problematic NPS.1 To what extent cognitive impairment and NPS are attributable to the neurodegenerative process, psychosocial, demographic or clinical factors, or a complication of dopamine replacement therapy (DRT) is unclear....
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...Psychosis, depression, anxiety, apathy, and impulse control disorders (ICDs) are the most frequent and problematic NPS.(1) To what extent cognitive impairment and NPS are attributable to the neurodegenerative process, psychosocial, demographic or clinical factors, or a complication of dopamine replacement therapy (DRT) is unclear....
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TL;DR: Gender-related patterns of NMS involvement may be relevant for clinical trials in PD and significant differences between men and women in prevalence and severity of fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness were found.
Abstract: Differences in the expression of non-motor symptoms (NMS) by Parkinson's disease (PD) patients may have important implications for their management and prognosis. Gender is a basic epidemiological variable that could influence such expression. The present study evaluated the prevalence and severity of NMS by gender in an international sample of 951 PD patients, 62.63% males, using the non-motor symptoms scale (NMSS). Assessments for motor impairment and complications, global severity, and health state were also applied. All disease stages were included. No significant gender differences were found for demographic and clinical characteristics. For the entire sample, the most prevalent symptoms were Nocturia (64.88%) and Fatigue (62.78%) and the most prevalent affected domains were Sleep/Fatigue (84.02%) and Miscellaneous (82.44%). Fatigue, feelings of nervousness, feelings of sadness, constipation, restless legs, and pain were more common and severe in women. On the contrary, daytime sleepiness, dribbling saliva, interest in sex, and problems having sex were more prevalent and severe in men. Regarding the NMSS domains, Mood/Apathy and Miscellaneous problems (pain, loss of taste or smell, weight change, and excessive sweating) were predominantly affected in women and Sexual dysfunction in men. No other significant differences by gender were observed. To conclude, in this study significant differences between men and women in prevalence and severity of fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness were found. Gender-related patterns of NMS involvement may be relevant for clinical trials in PD.
207 citations
Cites background from "Parkinson's disease: The quintessen..."
...The prevalence of depression has been reported to vary from 4 to 75%, with higher predominance in female gender [3, 4, 38, 44, 45]....
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References
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TL;DR: The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
Abstract: We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
6,662 citations
TL;DR: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone.
Abstract: BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).
2,497 citations
Istanbul University1, University of Bergen2, Stavanger University Hospital3, King's College London4, Newcastle University5, Pierre-and-Marie-Curie University6, Juntendo University7, University of New South Wales8, University of California, Los Angeles9, Mayo Clinic10, McGill University11, Rush University Medical Center12, Tel Aviv University13, French Institute of Health and Medical Research14, University of Louisville15, Icahn School of Medicine at Mount Sinai16, Innsbruck Medical University17, University of Lisbon18, University of Barcelona19
TL;DR: Clinical diagnostic criteria for probable and possible PD‐D are proposed, characterized by impairment in attention, memory, executive and visuo‐spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent.
Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.
2,454 citations
TL;DR: Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia, and more than three quarters of this representative PD cohort developed dementia during the 8-year study period.
Abstract: Background Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown. Objective To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD. Methods Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years. Results We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5). Conclusions More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.
1,310 citations
TL;DR: Dopamine agonist treatment in PD is associated with 2- to 3.5-fold increased odds of having an ICD, which represents a drug class relationship across ICDs.
Abstract: Context An association between dopamine-replacement therapies and impulse control disorders (ICDs) in Parkinson disease (PD) has been suggested in preliminary studies. Objectives To ascertain point prevalence estimates of 4 ICDs in PD and examine their associations with dopamine-replacement therapies and other clinical characteristics. Design Cross-sectional study using an a priori established sampling procedure for subject recruitment and raters blinded to PD medication status. Patients Three thousand ninety patients with treated idiopathic PD receiving routine clinical care at 46 movement disorder centers in the United States and Canada. Main Outcome Measures The Massachusetts Gambling Screen score for current problem/pathological gambling, the Minnesota Impulsive Disorders Interview score for compulsive sexual behavior and buying, and Diagnostic and Statistical Manual of Mental Disorders research criteria for binge-eating disorder. Results An ICD was identified in 13.6% of patients (gambling in 5.0%, compulsive sexual behavior in 3.5%, compulsive buying in 5.7%, and binge-eating disorder in 4.3%), and 3.9% had 2 or more ICDs. Impulse control disorders were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08-3.54; P P = .14). Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems. Conclusions Dopamine agonist treatment in PD is associated with 2- to 3.5-fold increased odds of having an ICD. This association represents a drug class relationship across ICDs. The association of other demographic and clinical variables with ICDs suggests a complex relationship that requires additional investigation to optimize prevention and treatment strategies. Trial Registration clinicaltrials.gov Identifier:NCT00617019
1,220 citations
"Parkinson's disease: The quintessen..." refers background in this paper
...Impulse control disorders (ICDs; ie, compulsive gambling, buying, sexual behavior, and eating) are now known to occur relatively commonly in PD.118 As patients may not report such behaviors to a treating physician, either because of embarrassment and not sus- pecting an association with PD treatment or ambivalence regarding ceasing the behavior or treatment, ICDs remain generally underrecognized in clinical practice.119 In a recent large multisite observational study, an ICD was identified in 14% of PD patients, and 4% had comorbid ICDs.120 ICDs were more common in patients taking a DA....
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...In a recent large multisite observational study, an ICD was identified in 14% of PD patients, and 4% had comorbid ICDs.(120) ICDs were more common in patients taking a DA....
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