Apathetic Parkinson's Disease Research Articles

Unawareness of Apathy in Parkinson's Disease: The Role of Executive Dysfunction on Symptom Recognition.

Altered self-awareness or anosognosia may impact patients' everyday life by interfering with their safe and independent functioning. Symptom awareness has been linked to executive dysfunctions caused by damage to frontal regions. Apathy is a frequent neuropsychiatric manifestation of Parkinson's disease (PD) and is considered a consequence of altered functioning of cortico-subcortical circuitries connecting the prefrontal cortex (PFC) with the basal ganglia. Thus, apathetic PD patients may be not be fully aware of their condition due to shared neuropathophysiological mechanisms. The present study aimed to explore the awareness of apathy in PD patients by comparing the self-reported evaluations with their caregivers' ratings. Moreover, we explored the clinical predictors of possible discrepancies and their consequences on patients' self-reported evaluation of quality of life (QoL). We found a fair agreement between patients' self-reports and caregivers' ratings on apathy scores, with patients reporting less severe apathetic symptoms, especially those related to executive and auto-activation processing, compared to their caregivers' reports. Executive functioning was found to mediate the relationship between disease stage and awareness of the apathetic state. Awareness of executive apathy impacted patients' self-reported QoL. Therefore, PD patients might be unaware of their apathetic symptoms, especially those with worse executive functioning, which plays a key role in metacognitive processes such as self-monitoring and error detection. Anosognosia for apathy in PD patients may affect their QoL perception and leads to misleading self-report evaluations that delay diagnosis and treatment.

Clinical determinants of apathy and its impact on health-related quality of life in early Parkinson disease.

Apathy is a common non-motor symptom of Parkinson disease (PD) that can affect the health-related quality of life (HRQoL) of patients and caregivers. This study aimed to investigate the clinical determinants of apathy and its impact on HRQoL in patients with early PD. We enrolled 324 patients with early PD with modified Hoehn-Yahr stages 1 to 3 and a disease duration ≤5 years. Demographic information was obtained, and motor and non-motor symptoms were evaluated with relevant scales. Apathy was present in 110 of 324 (33.9%) patients. Compared with patients with non-apathetic PD, those with apathetic PD had significantly higher modified Hoehn-Yahr stage, Unified Parkinson's Disease Rating Scale-II (UPDRS-II) score, Non-Motor Symptoms Scale (NMSS) total score, Beck Depression Inventory (BDI) score, and Parkinson's Disease Questionnaire-8 (PDQ-8) score. Clinical variables independently associated with the Apathy Evaluation Scale (AES) score were NMSS domain 3 score and BDI score. The univariate regression analysis revealed that the PDQ-8 score was significantly associated with age; disease duration; formal education duration; and UPDRS-III, UPDRS-II, NMSS total, Mini-Mental Status Examination, BDI, Beck Anxiety Inventory, and AES scores. Independent predictors of the PDQ-8 score in the multivariate regression analysis were UPDRS-III, UPDRS-II, NMSS total, NMSS domain 3, Beck Anxiety Inventory, and AES scores. In the present study, apathy was an independent predictor of HRQoL in patients with early PD. Therefore, identifying and managing apathy could help improve HRQoL in patients with early PD.

Impaired interhemispheric synchrony in Parkinson's disease patients with apathy

BackgroundApathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD. MethodsTwenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index. ResultsCompared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively. LimitationsThis is a cross-sectional study. ConclusionOur findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.

Apathy Reflects Extra-Striatal Dopaminergic Degeneration in de novo Parkinson's Disease.

Apathy represents a core neuropsychiatric symptom in Parkinson's disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated with apathy, the involvement of extra-striatal dopaminergic degeneration remains to be fully explored. To investigate whether apathy in PD reflects increased dopaminergic degeneration extending beyond striatal regions. In the de novo PD cohort of the Parkinson's Progression Markers Initiative (PPMI), we performed whole-brain I123-Ioflupane Single Photon Emission Computed Tomography (DAT-SPECT) analyses to characterize cross-sectional and longitudinal differences in DAT uptake associated with the presence of apathy. We also assessed the relationship between apathy and cognition in this sample, as apathy has been suggested to herald cognitive decline. Apathetic PD patients (N = 70) had similar sociodemographic, clinical, and biomarker profiles compared to the non-apathetic group (N = 333) at baseline. However, apathy was associated with an increased risk of developing cognitive impairment after a four-year follow-up period (p = 0.006). Compared to non-apathetic patients, apathetic patients showed a widespread reduction of extra-striatal DAT uptake at baseline as well as an increased longitudinal loss of DAT uptake (corrected p < 0.05). Isolated apathy in PD is associated with extra-striatal dopaminergic degeneration. As this abnormal dopamine depletion was in turn related to cognitive performance, this might explain, at least partially, the increased risk of apathetic PD patients to develop cognitive impairment or dementia.

The efficacy of repetitive transcranial magnetic stimulation on emotional processing in apathetic patients with Parkinson's disease: A Placebo-controlled ERP study

Background: Few studies have examined the effect of rTMS on impaired emotional processing in apathetic Parkinson's disease (PD) patients, which impelled us to use a combination of repetitive transcranial magnetic stimulation (rTMS) with event-related potentials (ERPs) to gain insight into the underlying mechanisms. Methods: Apathetic and non-apathetic patients diagnosed with PD performed a facial emotion categorization task, and ERP data were collected before and after HF-rTMS or sham stimulation over the right dorsolateral prefrontal cortex (DLPFC). We observed the behavioural results and early components of P100 and N170. Results: After rTMS, accuracy (ACC) was higher for negative expressions, and reaction times (RTs) were shorter for all expressions in both apathetic and non-apathetic patients. P100 amplitudes significantly increased except for negative expressions in the right hemisphere, and hemisphere lateralization was reversed in apathetic patients. P100 amplitudes increased for all expressions bilaterally in non-apathetic patients. N170 amplitudes in apathetic patients increased, and hemisphere lateralization was normalized. Neither the apathetic sham group nor the non-apathetic cohort of patients showed changes in P100 or N170 lateralization. Limitations: The effects of rTMS on PD patients relative to normal subjects should be compared and observed over a long period of time. Conclusions: HF-rTMS over the right DLPFC is beneficial for emotional processing in both apathetic and non-apathetic PD patients but shows different sensitivities. The effect of rTMS on emotional processing impairments in apathetic PD patients is profound. Treatment with rTMS may be an important, novel nonpharmaceutical approach for apathy in PD patients.

Apathy is associated with white matter network disruption and specific cognitive deficits in Parkinson's disease.

Apathy is common in Parkinson's disease (PD) but its underlying white matter (WM) architecture is not well understood. Moreover, how apathy affects cognitive functions in PD remains unclear. We investigated apathy-related WM network alterations and the impact of apathy on cognition in the context of PD. Apathetic PD patients (aPD), non-apathetic PD patients (naPD), and matched healthy controls (HCs) underwent brain scans and clinical assessment. Graph-theoretical and network-based analyses were used for group comparisons of WM features derived from diffusion spectrum imaging (DSI). Path analysis was used to determine the direct and indirect effects of apathy and other correlates on different cognitive functions. The aPD group was impaired on neural integration measured by global efficiency (p = 0.009) and characteristic path length (p = 0.04), executive function (p < 0.001), episodic memory (p < 0.001) and visuospatial ability (p = 0.02), and had reduced connectivity between the bilateral parietal lobes and between the putamen and temporal regions (p < 0.05). In PD, executive function was directly impacted by apathy and motor severity and indirectly influenced by depression; episodic memory was directly and indirectly impacted by apathy and depression, respectively; conversely, visuospatial ability was not related to any of these factors. Neural integration, though being marginally correlated with apathy, was not associated with cognition. Our results suggest compromised neural integration and reduced structural connectivity in aPD. Apathy, depression, and motor severity showed distinct impacts on different cognitive functions with apathy being the most influential determinant of cognition in PD.

Altered EEG alpha and theta oscillations characterize apathy in Parkinson's disease during incentivized movement.

Apathy is a common non-motor symptom of Parkinson's disease (PD) that is difficult to quantify and poorly understood. Some studies have used incentivized motor tasks to assess apathy, as the condition is often associated with a reduction in motivated behavior. Normally event-related desynchronization, a reduction of power in specific frequency bands, is observed in the motor cortex during the peri-movement period. Also, alpha (8–12 Hz) and theta (4–7 Hz) oscillations are sensitive to rewards that are closely related to motivational states however these oscillations have not been widely investigated in relation to apathy in PD. Using EEG recordings, we investigated the neural oscillatory characteristics of apathy in PD during an incentivized motor task with interleaved rest periods. Apathetic and non-apathetic PD subjects on dopaminergic medication and healthy control subjects were instructed to squeeze a hand grip device for a monetary reward proportional to the subject's grip force and the monetary value attributed to that trial. Apathetic PD subjects exhibited higher alpha and theta powers in the pre-trial baseline rest period compared to non-apathetic PD subjects and healthy subjects. Further, we found that both resting power and relative power in alpha and theta bands during incentivized movement predicted PD subjects' apathy scores. Our results suggest that apathetic PD patients may need to overcome greater baseline alpha and theta oscillatory activity in order to facilitate incentivized movement. Clinically, resting alpha and theta power as well as alpha and theta event-related desynchronization during movement may serve as potential neural markers for apathy severity in PD.

Cognitive correlates of “pure apathy” in Parkinson's disease

IntroductionPrevious studies exploring the association between apathy and cognitive deficits in Parkinson's disease (PD) employed scales and questionnaires for apathy, which did not control for the possible confounding effect of motor symptoms. Here we investigated the cognitive correlates of “pure apathy” by the Dimensional Apathy Scale, which allows us to assess apathy minimizing the influence of motor symptoms. MethodsConsecutive PD outpatients referred to our centre were screened. All participants underwent a neuropsychological battery to assess verbal memory, executive functions and visuospatial abilities, apathy and depressive symptoms. ResultsWe enrolled 56 non-depressed and non-demented PD patients, of whom 28 were apathetic and 28 were not. The two groups did not differ on demographic and clinical aspects; apathetic PD patients performed worse than non-apathetic PD patients on the part A, B and B-A of Trail Making Test and the interference task of Stroop test. No significant differences were found on memory and perceptual visuospatial tasks. ConclusionsOur results demonstrated that “pure apathy” is associated with more severe executive dysfunctions such as alteration of set-shifting and inhibitory control, which are mediated by prefrontal cortex and subcortical regions (i.e. basal ganglia). Our findings also supported the hypothesis that co-occurrence of apathy and executive deficits may be the epiphenomenon of damage in prefrontal-striatal cortical circuitries connecting dorsolateral prefrontal cortex, anterior cingulate cortex and basal ganglia.

Assessment of apathy minimising the effect of motor dysfunctions in Parkinson’s disease: a validation study of the dimensional apathy scale

Apathy is associated with motor symptoms in Parkinson's disease (PD); therefore, its evaluation could be influenced by motor disability. The Dimensional Apathy Scale (DAS) evaluates apathy excluding confounding effects of motor symptoms. The present study had three major aims: (a) to explore the psychometric properties of the DAS in non-demented PD patients; (b) to determine an optimal cut-off score of the DAS to identify apathetic PD patients; and (c) to determine a specific apathy profile in PD patients as compared to healthy controls (HC). One hundred and seven PD patients and 100 HC completed the DAS. To explore convergent and divergent validity of the DAS in PD, patients underwent the Apathy Evaluation Scale andtools for assessing depressive symptoms, anxiety and cognition. Clinical aspects were recorded. Receiver operating characteristic curve analyses were carried out to estimate the optimal cut-off score to identify clinically significant apathy. The DAS scores showed high internal consistency and good evidence for convergent and discriminant validity. Maximum discrimination between apathetic and non-apathetic patients was obtained with a cut-off score of 28.5 (total score range: 0-72 with higher score indicating more severe apathy). Comparison between PD and HC groups revealed significant differences on total DAS, behavioural/cognitive initiation and emotional subscales. The DAS is a valid and reliable tool to assess multidimensional apathy in PD, independently of severity of motor symptoms. Reduced initiation of thought and behaviour and emotional blunting characterised PD patients, without confounding effects of motor disability.

Non-demented Parkinson's disease patients with apathy show decreased grey matter volume in key executive and reward-related nodes.

Apathy is a common but poorly understood neuropsychiatric disturbance in Parkinson's disease (PD). In a recent study using event-related brain potentials we demonstrated impaired reward processing and compromised mesocortico-limbic pathways in PD patients with clinical symptoms of apathy. Here we aimed to further investigate the involvement of reward circuits in apathetic PD patients by assessing potential differences in brain structure. Using structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) we quantified grey matter volume (GMV) in a sample of 18 non-demented and non-depressed PD patients with apathy, and 18 matched non-apathetic patients. Both groups were equivalent in terms of sociodemographic characteristics, disease stage, cognitive performance and L-Dopa equivalent daily dose. Apathetic patients showed significant GMV loss in cortical and subcortical brain structures. Various clusters of cortical GMV decrease were found in the parietal, lateral prefrontal cortex, and orbitofrontal cortex (OFC). The second largest cluster of GMV loss was located in the left nucleus accumbens (NAcc), a subcortical structure that is a key node of the human reward circuit. Isolated apathy in our sample is explained by the combined GMV loss in regions involved in executive functions, and cortical and subcortical structures of the mesolimbic reward pathway. The correlations observed between apathy and cognition suggests apathy as a marker of more widespread brain degeneration even in a sample of non-demented PD patients.

Apathy, Novelty Processing, and the P3 Potential in Parkinson's Disease.

Parkinson’s disease (PD) is characterized by deficits in goal-directed behavior as well as mood and motivational symptoms, including apathy, depression, and anxiety. The present study investigated novelty processing in PD, using event-related potentials (ERPs) to characterize electrophysiological reflections of visual novelty processing. Since apathy has been associated with decreased novelty processing (P3 potentials) in highly apathetic PD patients, we were particularly interested to see if this relationship exists in a sample of PD patients with heterogeneous levels of apathy. Non-demented patients with PD receiving dopaminergic treatment (n = 14) and healthy control participants (n = 12) completed a three-stimulus oddball task while EEG was recorded. Relative to controls, the PD patients exhibited reductions in centrofrontally distributed P3 potentials when viewing novel distracters during this task. Distracter-related P3 amplitudes evoked by novel distracters were strongly associated with apathy symptoms, even after controlling for the effects of depression, anxiety, and executive function. Executive dysfunction was also predictive of novelty-related P3 processing, yet this relationship was independent from that of apathy. These findings suggest that the brain’s electrophysiological response to novelty is closely related to both motivational and cognitive symptoms in PD, even for patients whose apathy symptoms are not excessive. These results have significant implications for our understanding of non-motor symptoms in this clinical population.

Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease

IntroductionApathy is a common, disabling symptom in Parkinson's disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. MethodsWe conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. ResultsApathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. ConclusionsThis study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits.

Resting-state frontostriatal functional connectivity in Parkinson's disease-related apathy.

One of the most common neuropsychiatric symptoms in Parkinson's disease (PD) is apathy, affecting between 23% and 70% of patients and thought to be related to frontostriatal dopamine deficits. In the current study, we assessed functional resting-state frontostriatal connectivity and structural changes associated with the presence of apathy in a large sample of PD subjects and healthy controls, while controlling for the presence of comorbid depression and cognitive decline. Thirty-one healthy controls (HC) and 62 age-, sex-, and education-matched PD patients underwent resting-state functional magnetic resonance imaging (MRI). Apathy symptoms were evaluated with the Apathy Scale (AS). The 11 Beck Depression Inventory-II items that measure dysphoric mood symptoms as well as relevant neuropsychological scores were used as nuisance factors in connectivity analyses. Voxel-wise analyses of functional connectivity between frontal lobes (limbic, executive, rostral motor, and caudal motor regions), striata (limbic, executive, sensorimotor regions), and thalami were performed. Subcortical volumetry/shape analysis and fronto-subcortical voxel-based morphometry were performed to assess associated structural changes. Twenty-five PD patients were classified as apathetic (AS > 13). Apathetic PD patients showed functional connectivity reductions compared with HC and with non-apathetic patients, mainly in left-sided circuits, and predominantly involving limbic striatal and frontal territories. Similarly, severity of apathy negatively correlated with connectivity in these circuits. No significant effects were found in structural analyses. Our results indicate that the presence of apathy in PD is associated with functional connectivity reductions in frontostriatal circuits, predominating in the left hemisphere and mainly involving its limbic components.

Impact of apathy on health‐related quality of life in recently diagnosed Parkinson's disease: The ANIMO study

The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (<0.89 [lower HRQOL] vs ≥0.89 [reference]) was examined using multiple logistic regression analysis, adjusting for sociodemographic and clinical variables. We consecutively recruited 557 patients (60.3% men) with a mean age of 68.8 ± 9.7 years. Apathy was diagnosed in 291 (52.2%) and was related to problems in each of the EuroQoL dimensions. Apathetic PD patients showed EuroQol-5D index scores significantly lower than those without apathy (0.64 vs 0.83). In an adjusted model, apathetic PD patients were 2.49 times more likely to have lower HRQOL than nonapathetic patients (odds ratio, 2.49; 95% confidence interval, 1.49-4.15, P < 0.01). Apathy is very common in those with recently diagnosed PD and is one of the major clinical determinants of HRQOL in this disease. It should be one of the primary concerns among clinicians who provide treatment to individuals affected by PD.

Apathy may herald cognitive decline and dementia in Parkinson's disease

Apathy is usually defined as a lack of motivation. It may occur as part of another disorder (notably depression and dementia) or as an isolated syndrome. In Parkinson's disease (PD), apathy is common and several studies have reported an association between this condition and more severe cognitive symptoms, such as executive dysfunction. However, this association has not been thoroughly investigated. The aim of this study (in nondepressed, nondemented PD patients) was to examine whether or not cognitive decline and/or dementia occurred more frequently in apathetic subjects than in nonapathetic subjects. Forty consecutive PD patients participated in the study (20 with apathy and 20 without). None of the subjects were either demented or depressed at the time of study entry. The patients' cognitive functions were extensively assessed twice: at study entry and after an 18-month follow-up period. At study entry, the apathetic PD patients had significantly lower global cognitive status and executive function scores than the nonapathetic subjects. After a median period of 18 months, the rate of conversion to dementia was found to be significantly higher in the apathetic group than in the nonapathetic group (8 of 20 and 1 of 20, respectively). Even in nondemented patients, the decrease over time in cognitive performance (mainly executive function but also memory impairment) was significantly greater in apathetic subjects than in nonapathetic subjects. These findings suggest that in nondemented, nondepressed PD patients, apathy may be a predictive factor for dementia and cognitive decline over time.

Olfaction and apathy in Parkinson's disease

Background Olfactory deficits are frequent among patients with idiopathic Parkinson's disease (PD). Additionally, apathy (as quantified by the Apathy Evaluation Scale), is more prevalent in PD patients compared to the general population. Olfactory impairment and apathy are associated with dysfunction in overlapping brain regions. Neuroimaging studies indicate that the anterior cingulate gyrus and medial orbitofrontal cortex are hypoactive in apathetic patients and are also involved in secondary olfactory processing. However, no study until this point has been published investigating whether there is any association between olfactory dysfunction and apathy in PD patients. Methods In our study seventy consecutive patients with PD took the Brief Smell Identification Test (B-SIT), completed the Apathy Evaluation Scale (AES) and were administered the Folstein Mini-Mental Status exam (MMSE). Results Apathetic PD patients performed poorly on the B-SIT compared with non-apathetic PD patients and olfactory impairment correlated with apathy. The simultaneous disruption of olfaction and emotion in Parkinson's could be the result of disease pathology in brain regions involved in both olfactory and emotional processing and reinforces the idea that this link between olfaction and emotions may have clinical consequences.