A.J.H. Moonen

The spectrum of cognitive disorders in Parkinson's disease: A data-driven approach

The objective of this study was to identify different cognitive phenotypes in Parkinsons disease (PD) using a data‐driven approach. A model‐based cluster analysis was conducted on the neuropsychological test results of 558 PD patients from 2 European movement disorder centers (Lille, n = 403; Maastricht, n = 155). The number of clusters was determined according to their clinical relevance as well as on the basis of 3 statistical criteria: the cubic cluster criterion, the pseudo F statistic, and the total squared correlation ratio (R2). A factorial discriminant analysis was performed to assess the quality of the clusters separation. Descriptive variables were used to further characterize the clusters. A 5‐cluster model was considered the clinically most relevant. The 5 clusters comprised: (1) cognitively intact patients (19.39%); (2) patients without cognitive deficits but with slight mental slowing (41.29%); (3) patients with slightly impaired overall cognitive efficiency and deficits in all cognitive domains except recognition memory (12.93%); (4) patients with severe mental slowing, impaired overall cognitive efficiency, and severe cognitive impairment in all domains, including memory (23.88%); and (5) patients with very severe impairment in all cognitive domains (2.51%). Cognitively intact patients were significantly younger and had received more years of formal education. Patients in the last 3 clusters had more severe motor symptoms, longer disease duration, and more axial signs. In the last cluster, most patients were demented. Our results confirm the heterogeneity of cognitive presentations in PD, ranging from cognitively intact patients with rather high levels of performance in each cognitive domain to very severely impaired patients.

Modeling depression in Parkinson disease Disease-specific and nonspecific risk factors

Objective: To construct a model for depression in Parkinson disease (PD) and to study the relative contribution of PD-specific and nonspecific risk factors to this model. Methods: Structural equation modeling of direct and indirect associations of risk factors with the latent depression outcome using a cross-sectional dataset of 342 patients with PD. Results: A model with acceptable fit was generated that explained 41% of the variance in depression. In the final model, 3 PD-specific variables (increased disease duration, more severe motor symptoms, the use of levodopa) and 6 nonspecific variables (female sex, history of anxiety and/or depression, family history of depression, worse functioning on activities of daily living, and worse cognitive status) were maintained and significantly associated with depression. Nonspecific risk factors had a 3-times-higher influence in the model than PD-specific risk factors. Conclusion: In this cross-sectional study, we showed that nonspecific factors may be more prominent markers of depression than PD-specific factors. Accordingly, research on depression in PD should focus not only on factors associated with or specific for PD, but should also examine a wider scope of factors including general risk factors for depression, not specific for PD.

Cognitive Phenotypes in Parkinson's Disease Differ in Terms of Brain-Network Organization and Connectivity

Cognitive deficits are common in Parkinsons disease and we suspect that dysfunctions of connected brain regions can be the source of these deficits. The aim of the present study was to investigate changes in whole‐brain intrinsic functional connectivity according to differences in cognitive profiles in Parkinsons disease. 119 participants were enrolled and divided into four groups according to their cognitive phenotypes (determined by a cluster analysis): (i) 31 cognitively intact patients (G1), (ii) 31 patients with only slight mental slowing (G2), (iii) 43 patients with mild to moderate deficits mainly in executive functions (G3), (iv) 14 patients with severe deficits in all cognitive domains (G4–5). Rs‐fMRI whole‐brain connectivity was examined by two complementary approaches: graph theory for studying network functional organization and network‐based statistics (NBS) for exploring functional connectivity amongst brain regions. After adjustment for age, duration of formal education and center of acquisition, there were significant group differences for all functional organization indexes: functional organization decreased (G1 > G2 > G3 > G4‐5) as cognitive impairment worsened. Between‐group differences in functional connectivity (NBS corrected, P < 0.01) mainly concerned the ventral prefrontal, parietal, temporal and occipital cortices as well as the basal ganglia. In Parkinsons disease, brain network organization is progressively disrupted as cognitive impairment worsens, with an increasing number of altered connections between brain regions. We observed reduced connectivity in highly associative areas, even in patients with only slight mental slowing. The association of slowed mental processing with loss of connectivity between highly associative areas could be an early marker of cognitive impairment in Parkinsons disease and may contribute to the detection of prodromal forms of Parkinsons disease dementia. Hum Brain Mapp 38:1604–1621, 2017.

Factor analysis of the Hamilton Depression Rating Scale in Parkinson's disease

INTRODUCTION Several studies have validated the Hamilton Depression Rating Scale (HAMD) in patients with Parkinsons disease (PD), and reported adequate reliability and construct validity. However, the factorial validity of the HAMD has not yet been investigated. The aim of our analysis was to explore the factor structure of the HAMD in a large sample of PD patients. METHODS A principal component analysis of the 17-item HAMD was performed on data of 341 PD patients, available from a previous cross sectional study on anxiety. An eigenvalue ≥1 was used to determine the number of factors. Factor loadings ≥0.4 in combination with oblique rotations were used to identify which variables made up the factors. Kaiser-Meyer-Olkin measure (KMO), Cronbachs alpha, Bartletts test, communality, percentage of non-redundant residuals and the component correlation matrix were computed to assess factor validity. RESULTS KMO verified the samples adequacy for factor analysis and Cronbachs alpha indicated a good internal consistency of the total scale. Six factors had eigenvalues ≥1 and together explained 59.19% of the variance. The number of items per factor varied from 1 to 6. Inter-item correlations within each component were low. There was a high percentage of non-redundant residuals and low communality. CONCLUSION This analysis demonstrates that the factorial validity of the HAMD in PD is unsatisfactory. This implies that the scale is not appropriate for studying specific symptom domains of depression based on factorial structure in a PD population.

An fMRI study into emotional processing in Parkinson’s disease: Does increased medial prefrontal activation compensate for striatal dysfunction?

Background Apart from a progressive decline of motor functions, Parkinson’s disease (PD) is also characterized by non-motor symptoms, including disturbed processing of emotions. This study aims at assessing emotional processing and its neurobiological correlates in PD with the focus on how medicated Parkinson patients may achieve normal emotional responsiveness despite basal ganglia dysfunction. Methods Nineteen medicated patients with mild to moderate PD (without dementia or depression) and 19 matched healthy controls passively viewed positive, negative, and neutral pictures in an event-related blood oxygen level-dependent functional magnetic resonance imaging study (BOLD-fMRI). Individual subjective ratings of valence and arousal levels for these pictures were obtained right after the scanning. Results Parkinson patients showed similar valence and arousal ratings as controls, denoting intact emotional processing at the behavioral level. Yet, Parkinson patients showed decreased bilateral putaminal activation and increased activation in the right dorsomedial prefrontal cortex (PFC), compared to controls, both most pronounced for highly arousing emotional stimuli. Conclusions Our findings revealed for the first time a possible compensatory neural mechanism in Parkinson patients during emotional processing. The increased medial PFC activity may have modulated emotional responsiveness in patients via top-down cognitive control, therewith restoring emotional processing at the behavioral level, despite striatal dysfunction. These results may impact upon current treatment strategies of affective disorders in PD as patients may benefit from this intact or even compensatory influence of prefrontal areas when therapeutic strategies are applied that rely on cognitive control to modulate disturbed processing of emotions.

Severity of depression and anxiety are predictors of response to antidepressant treatment in Parkinson's disease

BACKGROUND Antidepressants have appeared to be more effective than placebo treatment in treating depressive syndromes in patients with Parkinsons disease (PD). OBJECTIVE To identify factors that predict improvement in depressive symptoms during antidepressant treatment in depressed PD patients. METHODS A secondary analysis was performed on the dataset of the Randomized Placebo-controlled Study of Antidepressants in PD (SAD-PD), in which 76 patients received active treatment with either paroxetine or venlafaxine extended release (XR), and 39 patients received placebo treatment. Backward stepwise regression analyses were conducted with change in 24-item Hamilton Depression Rating Scale (HAMD-24) score between assessments at baseline and week 12 as the main outcome measure, and sex, age, baseline HAMD-24 score, Unified Parkinsons Disease Rating Scale section III (UPDRS-III) score, Mini-Mental State Examination (MMSE), and the Clinical Anxiety Scale (CAS) as independent variables. RESULTS In both the active treatment and placebo groups, higher baseline HAMD-24 score and lower UPDRS-III score were associated with greater reduction in HAMD-24 score. Higher anxiety scores predicted less response in the active treatment group. Higher MMSE scores predicted greater response only in the placebo-treated group. Sex and age were no predictors of response. CONCLUSIONS Higher pre-treatment depression scores and lower pre-treatment anxiety scores are the two most important predictors for improvement during antidepressant treatment in depressed PD patients, which is in line with those found in treatment studies of depressed non-PD patients. Furthermore, our results indicate the requirement for different or more intensive treatment for depressed PD patients with more severe anxiety symptoms.

Modeling anxiety in Parkinson's disease

The aim of this work was to construct a model for anxiety in PD and compare the relative contributions of PD‐specific and ‐nonspecific general population risk factors for anxiety in this model.

Neurobiological correlates of emotional processing in Parkinson's disease: A systematic review of experimental studies

Deficits in emotional processing in patients with Parkinsons disease (PD) have received increasing interest over the past decades. In this systematic review, we present the results of 18 behavioral studies that have examined the neurobiological base of emotional processing in PD. Multiple aspects of emotional processing have been studied, using a variety of research methods. Deficits in PD are mainly related to autonomic and perceptive processing of intense emotional stimuli, which is accompanied by structural and functional neurobiological abnormalities in predominantly ventral regions of affective neurocircuitry. These structures are more strongly dependent on dopaminergic neurotransmission than the dorsal structures of affective neurocircuitry, which are more related to the cognitive and regulatory aspects of emotion and appear to remain largely intact in PD patients. Considering the importance of active dopaminergic neurotransmission, PD can serve as a prolific model for studying the neurobiological correlates of normal human emotional behavior as well as psychiatric disorders such as anxiety, depression, and apathy. Moreover, the fact that PD patients are able to cognitively regulate or modulate their emotional responses despite reduced dopamine supplies, can have important implications for the treatment of affective disorders not only in PD patients but in the general population likewise.

Electroencephalography-based machine learning for cognitive profiling in Parkinson's disease: Preliminary results: Eeg-Based Cognitive Screening Tool For PD

Cognitive symptoms are common in patients with Parkinsons disease. Characterization of a patients cognitive profile is an essential step toward the identification of predictors of cognitive worsening.

Cognitive behavioural therapy for anxiety disorders in Parkinson's disease: Design of a randomised controlled trial to assess clinical effectiveness and changes in cerebral connectivity

BACKGROUND Anxiety disorders occur in up to 35% of patients with Parkinsons disease (PD) and have a negative effect on motor symptoms and quality of life. To date, no clinical trials specifically targeting anxiety in PD patients have been published. OBJECTIVE To describe the rationale and methodology of a randomised controlled trial (RCT) that aims to study the clinical effectiveness, alterations in brain circuitry, and cost-effectiveness of cognitive behavioural therapy (CBT) for anxiety in PD. METHODS This study is a prospective, two-centre RCT in which sixty PD patients with anxiety will be randomised to CBT treatment and clinical monitoring (intervention group) or to clinical monitoring only (control group). The CBT module used in this study was specifically developed to address symptoms of anxiety in PD patients. Participants will undergo standardised clinical, cognitive and behavioural assessment at baseline and at 2 follow-up measurements, as well as resting-state fMRI and DTI scanning before and after the intervention. The primary outcome measure is changes in severity of anxiety symptoms. Secondary outcome measures involve long-term changes in anxiety symptoms, changes in functional and structural connectivity between limbic and frontal cortices, and cost-effectiveness of the treatment. The study is registered at the ClinicalTrials.gov database under registration number NCT02648737. CONCLUSION This study is the first that evaluates both the clinical effectiveness, cost-effectiveness, as well as the biological impact of CBT for anxiety in PD patients that, if proven effective, will hopefully contribute to a better and evidence-based approach for these non-motor symptoms.