Apathy in Patients with Parkinson's Disease Correlates with Alteration of Left Fronto-Polar Electroencephalographic Connectivity.
ABSTRACT: Introduction: Quantitative electroencephalography (QEEG) brain frequency and network analyses are known to differentiate between disease stages in Parkinson's disease (PD) and are possible biomarkers. They correlate with cognitive decline. Little is known about changes in brain networks in relation to apathy. Objective/Aims: To analyze changes in brain network connectivities related to apathy. Methods: 40 PD patients (14 PD with mild cognitive deficits and 26 PD with normal cognition) were included. All patients had extensive neuropsychological testing; apathy was evaluated using the apathy evaluation score (AES, median 24.5, range 18-39). Resting state EEG was recorded with 256 electrodes and analyzed using fully automated Matlab® code (TAPEEG). For estimation of the connectivities between brain regions, PLI (phase lag index) was used, enhanced by a microstates segmentation. Results: After correction for multiple comparisons, significant correlations were found for single alpha2-band connectivities with the AES (p-values < 0.05). Lower connectivities, mainly involving the left fronto-polar region, were related to higher apathy scores. Conclusions: In our sample of patients with PD, apathy correlates with a network alteration mainly involving the left fronto-polar region. This might be due to dysfunction of the cortico-basal loop, modulating motivation.
Project description:Apathy is a common nonmotor symptom in Parkinson's disease (PD) affecting 40% of patients. The aim of the study was to investigate brain changes and correlates of frontal, striatal, and limbic pathways related to subclinical symptoms of apathy in PD patients.Thirty-two PD patients divided into low-subclinical symptoms of apathy (LSA) (n = 18) and high-subclinical symptoms of apathy (HSA) (n = 14) and 25 healthy controls (HC) underwent a T1-weighted, diffusion-weighted, and resting-state functional MRI. Apathy was evaluated with the Lille Apathy Rating Scale. Voxel-based morphometry, tract-based spatial statistics, and resting-state functional connectivity (FC) analyses were performed with a region-of-interest approach.HSA-PD showed increased white matter axial and mean diffusivity compared with HC and increased white matter axial diffusivity compared with LSA-PD. HSA-PD showed decreased fronto-striatal and fronto-limbic FC compared with HC and decreased fronto-striatal FC compared with LSA-PD. LSA-PD showed decreased fronto-limbic but increased fronto-striatal FC (hyperconnectivity) compared with HC. No significant differences in grey matter were found. Fronto-striatal FC and white matter axial and mean diffusivity were associated with symptoms of apathy in HSA-PD. The fronto-striatal hyperconnectivity was associated with lower symptoms of apathy in LSA-PD.Findings suggest distinct brain alterations in PD groups with subclinical symptoms of apathy. The increased pattern of activation in LSA-PD, accompanied with lower apathetic symptomatology, might be the initial manifestation of compensatory mechanisms for dysfunctional limbic pathway. The same pattern of hyperconnectivity has been found in other pathologies and the implication of these abnormalities as a cross-disease model for initial apathy symptomatology is further discussed.
Project description:Parkinson's disease (PD) frequently entails non-motor symptoms, worsening the course of the disease. Apathy is one of the core neuropsychiatric symptoms that has been investigated in recent years; research is however hampered by the limited availability of well-evaluated apathy scales for these patients. We evaluated the psychometric properties of the Apathy Evaluation Scale (AES) in a sample of PD patients. Psychometric properties, convergent and discriminant validity and sensitivity/specificity were evaluated in patients with (n = 582) or without dementia/depression (n = 339). Internal consistency was high in the entire sample as well as in patients without dementia/depression. Correlations were moderate for convergent validity (UPDRS I item 4: motivation). While apathy could be differentiated from cognitive decline, it was related to depression (Geriatric Depression Scale, GDS-15). The overall classification accuracy based on the UPDRS I item 4 was comparable for AES and GDS scores. The AES exhibits good psychometric properties in PD patients with and without dementia and/or depression. Commonly used screenings on the presence of apathy had low detection rates compared to the AES and reflected both apathetic and depressive symptoms. Psychometric evaluation of available instruments will support further research on the clinical relevance of apathy for disease progression and treatment approaches in PD patients.
Project description:BACKGROUND:The relationship between apathy, depression and cognitive impairment in Parkinson's disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD. METHODS:In this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n?=?23) and PD without apathy (PD-NA group, n?=?25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall). FINDINGS:PD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F?=?10.94; p?=?0.002). Depression and apathy had a weak correlation (Pearson index=?0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ. CONCLUSION:Apathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.
Project description:OBJECTIVE:To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS:In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS:At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION:Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION:ClinicalTrials.gov 01914965.
Project description:OBJECTIVE:To conduct a scoping review of the literature on apathy in Parkinson's disease (PD), to better understand how apathy in Parkinson's disease is diagnosed, treated and managed. METHODS:MEDLINE, Embase, PsycINFO, CINAHL, Cochrane Central Register of Control Trials and Cochrane Database of Systematic Reviews were searched to 17 May 2017. An updated review was run from 17 May 2017 to 28 January 2019. The grey literature was searched using the CADTH Grey Matters tool. Original peer-reviewed research was included if it included individuals with PD and apathy. Non-original data was only included if it was in the form of meta-analysis. All information regarding diagnosis, treatment and management of PD was extracted. Citation screening and extraction were performed in duplicate. RESULTS:From 11 375 citations, 362 articles were included in the final review. The majority of included studies focussed on prevalence, with few studies examining treatment. Twenty screening tools for apathy were identified. Fifty per cent of treatment studies were randomised control trials (RCTs). RCTs applied treatment methods including: exercise, mindfulness, rotigotine (Neupro) transdermal patch and rivastigmine (Exelon). CONCLUSIONS:This review identified a large body of literature describing current knowledge on diagnosing, treating and managing apathy in PD. Future research should aim to detect an ideal screening tool for apathy in PD, to identify the best treatment options for apathy and the variety of comorbidities it may present with and finally aim to better understand postoperative apathy in those with deep brain stimulation.
Project description:<h4>Objective</h4>To determine whether ?-amyloidopathy correlates with apathy rating scores independently of mood changes and other neurodegenerative processes in Parkinson disease (PD).<h4>Methods</h4>In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 ± 6.7 years, Hoehn & Yahr stage 2.7 ± 0.5, Montreal Cognitive Assessment score 25.3 ± 3.0) underwent [<sup>11</sup>C]Pittsburgh compound B ?-amyloid, [<sup>11</sup>C]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [<sup>11</sup>C]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version. Patients were recruited on the basis of having at least 1 risk factor for PD dementia, but they were excluded if they had dementia.<h4>Results</h4>Mean apathy rating score was 25.4 ± 6.4, reflecting predominantly subclinical apathy. Apathy rating scale scores correlated with amyloid binding, cognitive, depressive, and anxiety scores but not significantly with age, duration of disease, striatal VMAT2, or cholinergic binding. Multiple regression analysis model (<i>p</i> < 0.0001) showed significant regressor effects for global ?-amyloid burden (<i>p</i> = 0.0038) with significant covariate effects for global cognitive <i>z</i> scores (<i>p</i> = 0.028) and for anxiety (<i>p</i> = 0.038) but not with depressive scores. Voxel-based analysis showed robust correlation between apathy rating scale scores and ?-amyloid binding in bilateral nuclei accumbens, inferior frontal, and cingulate cortices (family-wise error rate-corrected <i>p</i> < 0.005).<h4>Conclusion</h4>Apathy is independently associated with ?-amyloidopathy in patients with PD at risk of dementia. Regional brain findings are most robust for ?-amyloidopathy in the nuclei accumbens, inferior frontal, and cingulate regions. Findings may provide an explanation for the often treatment-refractory nature of apathy in advancing PD despite optimized dopaminergic and antidepressant pharmacotherapy.<h4>Clinicaltrialsgov identifier</h4>NCT01565473.
Project description:BACKGROUND:Apathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and possibly preclinical AD. OBJECTIVE:To compare the three AES sub-scales - subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C) - over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). METHODS:Mixed effects longitudinal models were used to assess predictors of score for each AES sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. RESULTS:Fifty-seven MCI and 18 CN subjects (ages 53-86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. CONCLUSION:In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia.
Project description:Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer's disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy (1H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy.
Project description:Human behaviour can be externally driven, e.g. catching a falling glass, or self-initiated and goal-directed, e.g. drinking a cup of coffee when one deems it is time for a break. Apathy refers to a reduction of self-initiated goal-directed or motivated behaviour, frequently present in neurological and psychiatric disorders. The amount of undertaken goal-directed behaviour varies considerably in clinical as well as healthy populations. In the present study, we investigated behavioural and neural correlates of self-initiated action in a student sample (N?=?39) with minimal to high levels of apathy. We replicated activation of fronto-parieto-striatal regions during self-initiation. The neural correlates of self-initiated action did not explain varying levels of apathy in our sample, neither when mass-univariate analysis was used, nor when multivariate patterns of brain activation were considered. Other hypotheses, e.g. regarding a putative role of deficits in reward anticipation, effort expenditure or executive difficulties, deserve investigation in future studies.
Project description:Background:The Apathy Scale (AS), a popular measure of apathy in Parkinson's disease (PD), has been somewhat limited for failing to characterize dimensions of apathy, such as those involving cognitive, behavioral, and emotional apathy symptoms. This study sought to determine whether factors consistent with these apathy dimensions in PD could be identified on the AS, examine the associations between these factors and disease-related characteristics, and compare PD patients and healthy control (HCs) on identified factors. Methods:Confirmatory (CFA) and exploratory factor analysis (EFA) were conducted on AS scores of 157 nondemented PD patients to identify AS factors. These factors were then correlated with important disease-related characteristics, and PD and HC participants were compared across these factors. Results:Previously proposed AS models failed to achieve an adequate fit in CFA. A subsequent EFA revealed two factors on the AS reflecting joint cognitive-behavioral aspects of apathy (Motivation-Interest-Energy) and emotional apathy symptoms (Indifference). Both factors were associated with anxiety, depression, health-related quality of life, and independent activities of daily living, with Indifference associated more with the latter. In addition, only the Indifference factor was associated with cognitive functioning. PD patients reported higher levels of symptoms than HCs on both factors, with the group difference slightly larger on the Motivation-Interest-Energy factor. Conclusion:The AS can be decomposed into two factors reflecting Motivation-Interest-Energy and Indifference symptoms. These factors are differentially associated with clinical variables, including cognition and independent activities of daily living, indicating the importance of evaluating apathy from a multidimensional perspective.