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Objectives: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones., Methods: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality., Results: LCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60)., Interpretation: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The tendency to engage in addictive behaviors has long been tied to the actions of the dopamine system. Early theories were based on the fact that all addictive drugs and behaviors (such as gambling) increase dopamine levels in the striatum, and the evidence that dopamine signaled reward or reward prediction error. However, with a changing emphasis of addiction away from purely pharmacological models that emphasize tolerance and withdrawal, towards one of behavioral dyscontrol, is there still a place for abnormal dopamine signaling in addiction? Here we recast the dopamine theory of addiction based on the idea that tonic dopamine may index a continuous phenotype that goes from apathy to impulsivity and compulsivity. Higher tonic dopamine signaling would make individuals vulnerable to drug reinforcement and cue-induced craving. We relate this to computational models of dopamine signaling, and review clinical and neuroimaging evidence from Parkinson's Disease, schizophrenia and bipolar disorder in support of this model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD)., Methods: We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue., Results: Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory)., Conclusion: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.

Background: Amotivation is regarded as a core negative symptom in patients with schizophrenia. There are currently no objective methods for assessing and measuring amotivation in the scientific literature, only a trend towards assessing motivation using effort-orientated, decision-making tasks. However, it remains inconclusive as to whether cognitive effort-avoidance in patients with schizophrenia can reflect their amotivation. Therefore, this study aimed to find out whether cognitive effort-avoidance in patients with schizophrenia can reflect their amotivation., Methods: In total, 28 patients with schizophrenia and 27 healthy controls were selected as participants. The demand selection task (DST) was adapted according to the feedback-based Guilty Knowledge Test (GKT) delayed response paradigm, which was combined with the mean amplitude of contingent negative variation (CNV), considered as the criterion of motivation., Results: Our results showed that: (1) patients with schizophrenia showed a lower CNV amplitude for the target stimuli compared to the probe stimuli, whereas the control group showed the opposite trend (P < 0.05); (2) among patients with schizophrenia, the high cognitive effort-avoidance group showed a smaller CNV amplitude for the target stimuli compared to the probe stimuli, whereas the low cognitive effort avoidance group showed a higher CNV amplitude for the target stimuli compared to the probe stimuli; the opposite trend was observed in the control group (P < 0.05)., Conclusion: These findings support the claim that CNV amplitude can be used as a criterion for detecting amotivation in patients with schizophrenia. Within the context of the DST, the high and low cognitive effort-avoidance of patients with schizophrenia can reflect their state of amotivation; patients with high cognitive effort-avoidance showed severe amotivation.

Background: Apathy is a common symptom in neurological disorders, including dementia, and is associated with a faster rate of cognitive decline, reduced quality of life, and high caregiver burden. There is a lack of effective pharmacological treatments for apathy, and nonpharmacological interventions are a preferred first-line approach to treatment. Virtual reality (VR) using head-mounted displays (HMDs) is being successfully used in exposure- and distraction-based therapies; however, there is limited research on using HMDs for symptoms of neurological disorders., Objective: This feasibility study aimed to assess whether VR using HMDs could be used to deliver tailored reminiscence therapy and examine the willingness to participate, response rates to measures, time taken to create tailored content, and technical problems. In addition, this study aimed to explore the immediate effects between verbal fluency and apathy after exposure to VR., Methods: A mixed methods study was conducted in a sample of older adults residing in aged care, and 17 participants were recruited. Apathy was measured using the Apathy Evaluation Scale (AES), and verbal fluency was used as a proxy measure of improvements in apathy and debriefing interviews to assess feedback from participants. Side effects that can occur from using HMDs were also measured., Results: We recruited participants from a high socioeconomic status setting with a high education level, and the participation rate was 85% (17/20); most responses to measures were positive. Access to a wide range of freely available content and the absence of technical difficulties made the delivery of a VR reminiscence intervention highly feasible. Participants had improved semantic scores (t 14 =-3.27; P=.006) but not phonemic fluency scores (t 14 =0.55; P=.59) immediately after the intervention. Those with higher levels of apathy demonstrated the greatest cognitive improvements after a VR reminiscence experience, which was indicated by a strong positive relationship between the AES and semantic verbal fluency change scores postminus pre-VR (r=0.719; 95% CI 0.327 to 0.900; P=.003). All participants enjoyed the experience despite 35% (6/17) of participants experiencing temporary side effects., Conclusions: This study provides initial evidence that it is feasible to use VR with HMDs for therapy to treat symptoms of apathy in older adults in residential aged care. However, there is a need to closely monitor the side effects of HMD use in older adults. Further research is needed using an active control group to compare the use of VR with traditional forms of reminiscence therapy., (©Dimitrios Saredakis, Hannah AD Keage, Megan Corlis, Tobias Loetscher. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.06.2020.)

Introduction: Apathy is the most common neuropsychiatric syndrome in behavioral variant frontotemporal dementia (bvFTD), and encompasses cognitive, behavioral and affective symptoms. The neural basis of apathy in bvFTD is not completely understood. Previous neuroimaging studies have poorly considered executive impairment and dementia severity as possible confounding factors. Herein we investigated the neural basis of apathy in bvFTD through structural neuroimaging taking into account these factors., Methods: We included patients with probable bvFTD (n = 21) and cognitively healthy controls (HC, n = 22). Participants were matched for age, sex and schooling. All subjects underwent a thorough neuropsychological examination, including tests for executive functions and social cognition. Apathy was assessed with the Starkstein Apathy Scale (SAS). All subjects underwent 3T brain MRI. We investigated correlations between SAS scores and gray matter atrophy within the bvFTD group. Executive function (Frontal Assessment Battery) and disease severity were considered as covariates in neuroimaging analyses., Results: Compared to HC, bvFTD patients had lower scores on global cognitive efficiency, executive functions and social cognition. All bvFTD had clinically relevant apathy (scores greater than 14 in the SAS). Performance in executive function tests did not correlate with apathy scores. The severity of apathy was negatively correlated with gray matter volumes in midline prefrontal regions, namely orbitofrontal cortex and both anterior and dorsal regions of cingulate cortex., Conclusions: Apathy in bvFTD is related to a specific network of prefrontal cortical areas critically involved in effort-based behavior for rewards and appears to be independent of executive dysfunction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Persons with Huntington's disease (HD) often have communication difficulties and cognitive impairments, making mental health assessment difficult. Informants close to the patient are often included in assessments. The authors investigated effects of informant presence during assessment of persons with HD., Methods: Data for four subsamples from ENROLL-HD were examined: manifest for HD (N=4,109), premanifest (N=1,790), genotype negative (N=1,041), and family members with no genetic risk (N=974). Assessment interviews with and without an informant present were identified, and the subsamples were compared on three subscales of the short-form Problem Behaviors Assessment: affect, apathy, and irritability. Differences in scores between participant-only and informant-present interviews were examined via multiple regression, controlling for demographic, disease-related, and individual confounds., Results: Significant differences in apathy and irritability scores were found between participant-only and informant-present conditions for the premanifest, manifest, and genotype-negative subsamples. Affect subscale scores were not influenced by informant presence. When the analysis controlled for confounds, informant presence significantly increased irritability scores in the manifest, and genotype-negative groups and significantly increased apathy scores in the manifest group., Conclusions: Apathy may have been systemically underreported in participant-only interviews, which supports previous findings that persons with HD underreport mental health symptoms. When an informant was present, irritability scores were higher for both HD and non-HD individuals, suggesting that underreporting via self-report may be attributable to non-HD factors. Informant contributions to apathy assessments may be particularly important for persons with HD. Clinicians should note potential underreporting regarding irritability and affect, which was not remediated by informant presence.

Complaints of fatigue following acquired brain injury (ABI) are often associated with depression. However, the nature of this relationship is unclear; furthermore, research among young people with ABI is limited. The objective of this cross-sectional study was (1) to investigate levels of depression in young outpatients with ABI (15-30 years old) and (2) to determine how different dimensions of fatigue relate to depression. Five dimensions of fatigue were assessed with the Multidimensional Fatigue Inventory (MFI-20), and depression was assessed with the Major Depression Inventory (MDI). Mann-Whitney U-tests and multiple regression analyses were conducted. The ABI group ( n  = 105), on average 23.7 years old ( SD  = 4.2) and 31 months post-injury ( SD  = 61), had elevated levels of fatigue and depression compared to a convenience sample of 160 healthy controls, all p 's < .001. In multivariate analyses, the predominantly mental dimensions of fatigue, General Fatigue, Mental Fatigue, and Reduced Motivation, were independently associated with MDI, all p 's < .01, while the physical dimensions, Physical Fatigue and Reduced Activity, were not. Distinctions within the concept of fatigue may be important in relation to depression, and future research could benefit from adopting a multidimensional approach in the development of more targeted and effective treatments of fatigue and depression following ABI.

Background: Research has implicated hypofrontality in the pathogenesis of Negative symptoms of schizophrenia.These symptoms are often resistant to treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to reverse this hypofrontality. Higher frequency rTMS has shown better promise, but so far there has been very little research in this area., Objective: We aimed to evaluate the efficacy of high-frequency (20 Hz) unilateral rTMS over the left Dorso-Lateral Pre-frontal Cortex (DLPFC) in the improvement of Negative symptoms in Schizophrenia., Methods: 100 patients of schizophrenia with predominantly negative symptoms, were enrolled for this randomized, sham-controlled, double-blind trial.Each participant received 20 sessions of rTMS at 20 Hz frequency and 100% motor threshold, via either the active or the sham coil, over 4 weeks. A total of 2000 pulses were imparted in 10 trains per session. Negative symptoms were assessed with the SANS and PANSS. CDSS was used to rule out depressive symptoms. Assessments were carried out at baseline, post-intervention, and 1-month, 2-months, 3-months and 4-months follow ups., Results: The improvement in the negative symptoms (Anhedonia, Alogia, Avolition, Attention impairment) in active group was statistically significant at 0.01 and 0.05 (p-value) as compared to sham group., Conclusions: These results suggest that high-frequency rTMS may lead to improvement in negative symptoms of schizophrenia. It may be worth considering its use as an adjunct to pharmacological treatment of negative symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of Interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Apathy is a reduction in motivated goal-directed behavior (GDB) that is prevalent in cerebrovascular disease, providing an important opportunity to study the mechanistic underpinnings of motivation in humans. Focal lesions, such as those seen in stroke, have been crucial in developing models of brain regions underlying motivated behavior, while studies of cerebral small vessel disease (SVD) have helped define the connections between brain regions supporting such behavior. However, current lesion-based models cannot fully explain the neurobiology of apathy in stroke and SVD. To address this, we propose a network-based model which conceptualizes apathy as the result of damage to GDB-related networks. A review of the current evidence suggests that cerebrovascular disease-related pathology can lead to network changes outside of initially damaged territories, which may propagate to regions that share structural or functional connections. The presentation and longitudinal trajectory of apathy in stroke and SVD may be the result of these network changes. Distinct subnetworks might support cognitive components of GDB, the disruption of which results in specific symptoms of apathy. This network-based model of apathy may open new approaches for investigating its underlying neurobiology, and presents novel opportunities for its diagnosis and treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Severe traumatic brain injury (sTBI) often results in significant morbidity, with fewer than 50% returning to work and only a minority resuming leisure and social activity. Yet few effective interventions are available for non-vocational activity. The aim of the study was to develop a new goal-directed intervention, the Programme for Engagement, Participation and Activities (PEPA), and evaluate its effect. The research design was a multiple-baseline design across behaviours, with direct inter-subject and systematic replications. Seven participants with sTBI, neurobehavioural impairment including apathy, inability to work, and limited leisure/social activities were categorised into two groups. Group 1 ( n  = 4) had cognitive impairments but were functionally independent. Systematic replication was conducted in a further three participants (group 2) with major neurobehavioural impairments and functional disability. Generalisation measures evaluated other life domains in group 1 participants (e.g., mood, community participation). Results of the weighted average Tau- U across the tiers was significant for six out of seven participants, with large effect sizes (≥.64) for five participants. Generalisation effects extended to other domains of life. The PEPA thus shows promise as an effective intervention to increase non-vocational activity and improve mental health outcomes in people with neurobehavioural disability after sTBI. These results add to the evidence for the effectiveness of goal-directed interventions.

Introduction : Fatigue and apathy are two key non-motor symptoms in Parkinson's disease (PD), with documented negative impact on Quality of life (QoL) and a frequent burden for caregivers. Areas covered : In this review, the authors comment on the latest pathophysiology, clinical phenomenology, the most frequently used scales for fatigue and apathy in PD with a focus on available therapeutic strategies. Expert opinion :The identification of fatigue and apathy in PD is mainly hampered by the lack of a clear consensus on these subjective symptoms. The pathophysiological processes remain unclear, and the large variation in prevalence is likely due to the heterogeneous PD populations and the lack of an enriched cohort of people with fatigue and/or apathy as main symptoms. Treatment strategies, and especially level 1 evidence for specific treatments for fatigue and apathy in PD, remain scarce. The best evidence to date is doxepin, rasagiline and levodopa infusion therapy (for fatigue), and rivastigmine (for apathy). Further efforts should be made to properly identify these two major symptoms in PD, to correctly detect those who may benefit most from tailored personalized interventions.

Background: Negative Symptoms (blunted affect, alogia, anhedonia, avolition and asociality) are observed in schizophrenia but also in depressive disorders., Objective: To gather cognitive, neuroanatomical, neurofunctional and neurobiological knowledge of negative symptoms in studies on schizophrenia, depressive disorder, and transnosographic studies., Results: Blunted affect in schizophrenia is characterized by amygdala hyperactivation and frontal hypoactivation, also found in depressive disorder. Mirror neurons, may be related to blunted affect in schizophrenia. Alogia may be related to cognitive dysfunction and basal ganglia area impairments in schizophrenia. Data surrounding alogia in depressive disorder is scarce; wider speech deficits are often studied instead. Consummatory Anhedonia may be less affected than Anticipatory Anhedonia in schizophrenia. Anhedonia is associated with reward impairments and altered striatal functions in both diagnostics. Amotivation is associated with Corticostriatal Hypoactivation in both disorders. Anhedonia and amotivation are transnosographically associated with dopamine dysregulation. Asociality may be related to oxytocin., Conclusion: Pathophysiological hypotheses are specific to each dimension of negative symptoms and overlap across diagnostic boundaries, possibly underpinning the observed clinical continuum., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Bipolar disorder I (BD-I) is defined by episodes of mania, depression and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood., Methods: We first assessed the severity of NS in 25 euthymic BD-I patients compared with 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral (VS) and dorsal striatal (DS) activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS., Results: In BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant VS and DS activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole-brain analyses revealed reduced extra-striatal activation in BD-I patients compared with HC and an association between reduced activation of the inferior frontal gyrus and apathy., Conclusion: This study found that in BD-I patients apathy is present to an extent comparable to SZ, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

Background: Susac syndrome is a very rare cerebral small vessel disease, which can leave patients with cognitive impairment. We aimed at evaluating processing speed slowing, executive dysfunction and apathy and their relationships with whole brain and callosal atrophy., Methods: Patients with Susac syndrome included in a prospective observational cohort study were evaluated, while clinically steady-state, with standardized brain MRI and a neuropsychological battery specifically designed to capture minimal cognitive alterations in non-disabled young patients. Brain volume and corpus callosum area were measured using 3D-T1 sequences, repeatedly overtime. Relationships between neuropsychological data and brain volumetric measures obtained the same day were tested with linear regression while controlling for sex, age, level of education, scores of depression and of apathy., Results: Nineteen patients aged 37.5 ± 10.5 years were included. Mean follow-up time was 2.6 ± 1.3 years (5.8 ± 2.2 evaluations). While Montreal Cognitive Assessment scores were 25.1 ± 3.6, processing speed slowing was obvious (Trail Making Test version A: 43.1 ± 16.2 s; version B: 95.5 ± 67.9 s; reaction time: 314.6 ± 79.6 ms). Brain and corpus callosum atrophy was striking. No relationship was found between cognitive performances and brain volume or corpus callosum area., Conclusion: Patients with Susac syndrome show largely preserved global cognitive functions but important processing speed alterations. Although brain and corpus callosum area atrophy is prominent and evolving, we did not find any relationship with cognitive alterations, questioning the mechanisms underlying cognitive alterations in these patients., Trial Registration: Clinical Trial Registration-URL: https://www.clinicaltrials.gov Unique Identifier: NCT01481662.

Apathy is one of the most prevalent and disabling non-cognitive symptoms of dementia. This loss of motivation and pervasive decline in goal-directed behaviour represents a core diagnostic feature of behavioural-variant frontotemporal dementia (bvFTD) and is also common in Alzheimer's disease (AD). However, despite growing recognition of a multidimensional model, apathy has typically been examined as a unitary symptom. Here, we employed a cross-sectional design to characterise the multidimensional nature of apathy across syndromes and disease course. 92 participants (44 bvFTD, 20 AD, 28 controls) completed the Dimensional Apathy Scale (DAS) to quantify emotional, executive, and initiation apathy. Patients were divided into early and late stages based on time since symptom onset. All participants underwent structural MRI and voxel-based morphometry was used to identify neural correlates of apathy dimensions. In the early stage of the disease (< 5 years since onset), emotional apathy was greater in bvFTD than AD. In contrast, in the late stage (> 5 years since onset), executive apathy was greater in AD than bvFTD, although apathy was elevated across all dimensions compared to controls. Notably, apathy was observed in the absence of self-reported depression in 46.2% of patients, with no patients classified as depressed only. Neuroimaging analyses revealed both common and divergent prefrontal and subcortical neural correlates associated with apathy dimensions. Our results reveal differing profiles of apathy across the disease course, in AD and bvFTD, with distinct brain regions mediating these dimensions. These findings will inform the development of appropriate treatment targets to ameliorate the impact of apathy in dementia.

Objective: Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association., Methods/design: Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status., Results: There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety., Conclusions: Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD., (© 2020 John Wiley & Sons, Ltd.)

This study determines the feasibility of using virtual reality (VR) for residents with and without dementia in the residential aged care (RAC) environment (also referred to as nursing homes or long-term care). A mixed-methods study was conducted with 13 residents of varying cognitive capacity in a residential aged care facility (RACF) operated by a not-for-profit organization in Brisbane, Australia. Residents participated in one facilitated VR session, either as a group or individual session. Residents' mood and apathy were measured by the Observed Emotion Rating Scale (OERS) and the Person-Environment Apathy Rating Scale. Residents also completed a structured interview to provide their feedback after the VR session. In addition, four RACF staff members were interviewed about their experience of using the VR in residents and the ongoing feasibility. The experience of VR administered by a researcher and leisure and lifestyle coordinator as a leisure activity, significantly reduced apathy in residents ( Z  = -2.818, p  = 0.005) through observations of increased facial expression, eye contact, physical engagement, verbal tone, and expression. The study did not find a VR impact on the OERS measures; no significant increase in fear/anxiety was observed. Reminiscence was clearly observed in six of the nine residents with the ability to verbally communicate. VR was found not to be helpful in residents during episodes of acute neuropsychiatric and behavioral symptoms. This study suggested feasibility of using fully immersive VR delivered by mobile phone technologies. It provides preliminary data for a controlled trial presently underway examining the effectiveness of VR as a group activity in RAC to improve mood states, behavioral symptoms, and pro re nata psychotropic medication use. Residents indicated that VR was enjoyable with low levels of physical and emotional discomfort reported or observed.

Objective: Apathy, defined as reduced goal-directed behavior, is a frequent symptom in mental and neurological disorders but has been poorly studied in individuals with obsessive-compulsive disorder (OCD). The primary aim of this study was to examine levels of apathy between individuals with OCD, healthy control subjects, and individuals with schizophrenia, a mental disorder with high levels of apathy. The second aim was to assess whether the psychological factors that have been previously shown as underlying apathy in other mental disorders were associated with apathy in patients with OCD., Methods: This exploratory study included 25 individuals with OCD, 24 individuals with schizophrenia, and 24 healthy control subjects. Apathy was assessed using the Lille Apathy Rating Scale. Measures of depression, sensibility to punishment and reward, defeatist performance beliefs, and cognitive functioning were also assessed., Results: Individuals diagnosed with OCD and schizophrenia scored significantly higher than healthy control subjects on the apathy total score. Levels of apathy among OCD patients were mainly associated with depression but also dysexecutive functioning and defeatist beliefs., Conclusions: These findings suggest that motivational deficits could play a central role in disability caused by OCD. Similar to other mental disorders, various psychological factors, including depression, defeatist beliefs, and dysexecutive functioning, are involved in apathetic manifestations. However, the fact that depression is the variable most associated with apathy indicates that apathetic symptoms in patients with OCD must be considered mainly as secondary rather than primary symptoms.

Background: Behavioral symptoms, such as apathy and depression, are common in multiple sclerosis (MS) but their relationship with cognitive and clinical characteristics often remains underinvestigated and not monitored over time., Objective: The aim of this study was to assess the evolution of cognitive profile of patients affected by MS in relation to apathy and depression using a 2-year follow-up study., Methods: Two years after the first assessment, 100 of 125 MS patients were re-evaluated on a comprehensive neuropsychological battery, and on specific scales for assessment of apathy (Apathy Evaluation Scale-Self-reported) and depression (Hamilton Depression Rating Scale)., Results: After 2 years (T1), we found a relatively consistent prevalence of apathy (about 40%) and a reduction in prevalence of depression (from 44% to 30%). Higher level of apathy at baseline predicted the progressive cognitive changes at follow-up; and patients with apathy without depression ("pure" apathy) than patients without apathy had poorer performance on the interference task of the Stroop test assessing inhibitory control., Conclusion: The present results suggested that apathy in MS was associated with more severe executive dysfunctions (in particular cognitive control). Apathy rather than depression predicted cognitive impairment in MS over time.

Background: Apathy is a predictor of cognitive decline in the course of multiple sclerosis (MS). Early identification of apathetic patients is relevant in clinical settings., Objective: To assess applicability and psychometric properties of the self-rated version of the Dimensional Apathy Scale (DAS) in a large cohort of patients with MS and to compare its diagnosing accuracy with that of the Apathy Evaluation Scale (AES)., Methods: One hundred and twenty-four patients underwent clinical interview based on diagnostic criteria for apathy, DAS, AES, and assessment of depression, global cognitive functioning, and non-verbal intelligence., Results: According to diagnostic criteria, apathy occurred in 33.4% of the patients. The DAS showed high consistency, and good convergent, discriminant and criterion validity. Factor analysis indicated a three-factor structure: executive, behavioural and emotional apathy. Unlike AES, no significant association between DAS score and severity of neurological disability (expressed by EDSS total score) was found, suggesting that the DAS might be less related to levels of disability. Receiver operating characteristics analyses, with clinical diagnostic criteria for apathy as the gold standard, revealed that a DAS score of 28/29 and an AES score of 35/36 were optimal cut-off values for identifying clinically relevant apathy. The two scales had similar diagnostic accuracy in the present sample., Conclusions: The DAS is a valid and reliable multidimensional tool to assess apathy in MS, with diagnostic accuracy similar to that of the AES. However, the DAS score appears to be less strongly related to neurological disability., Competing Interests: Declaration of Competing Interest The Authors declares that there is no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Apathy is a prominent syndrome across neurodegenerative diseases. The Dimensional Apathy Scale (DAS) assesses three apathy subtypes-executive, emotional, and initiation-and is sensitive and valid in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease. This study describes the development of the brief DAS (b-DAS), which will enable apathy to be swiftly detected in the clinic. Method: 102 ALS and 102 AD patients' previously collected data were used. Mokken analyses were performed on item-level data of each informant/carer-rated DAS subscale (executive, emotional, and initiation) for the initial scale reduction. Item-total correlational analyses against standard apathy (convergent validity criteria) and depression (divergent validity criteria) measures and qualitative examination of items aided final item selection. Receiver operating curve analysis determined optimal cutoffs for the reduced subscales. Results: Mokken analyses suggested unidimensionality of each DAS subscale. Three items were removed that failed to satisfy monotone homogeneity model requirements, three items were removed due to validity criteria not being met, and six items were removed due to a combination of lower item scalability and item-total correlations. Item-theme examination further reduced the b-DAS to nine items, three per subscale, with a supplemental awareness deficit assessment being added. Sensitivity- and specificity-based optimal cutoffs were calculated for each b-DAS subscale. Conclusions: This study presents the b-DAS, an informant/carer-based robust yet short multidimensional apathy instrument with good convergent and divergent validity, with recommended clinical cutoffs. The b-DAS is appropriate for use in the clinic and for research to quickly and comprehensively screen for apathy subtype impairments.

Background: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer's disease (AD) are associated with a lower quality of life., Objective: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients., Methods: In the present study, we evaluated the efficacy of sertraline (n = 11; average dose = 31.8 mg), escitalopram (n = 13; average dose = 7.3 mg), and nicergoline (n = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) (>5) or a high Apathy Scale (AS) (>16) scores., Results: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p = 0.05); however, no significant changes were noted in patients receiving nicergoline., Conclusion: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.

Bipolar disorder (BD) is a severe manic-depressive illness. Patients with BD have been shown to have gray matter (GM) deficits in prefrontal, frontal, parietal, and temporal regions; however, the relationship between structural effects and clinical profiles has proved elusive when considered on a region by region or voxel by voxel basis. In this study, we applied parallel independent component analysis (pICA) to structural neuroimaging measures and the positive and negative syndrome scale (PANSS) in 110 patients (mean age 34.9 ± 11.65) with bipolar disorder, to examine networks of brain regions that relate to symptom profiles. The pICA revealed two distinct symptom profiles and associated GM concentration alteration circuits. The first PANSS pICA profile mainly involved anxiety, depression and guilty feelings, reflecting mood symptoms. Reduced GM concentration in right temporal regions predicted worse mood symptoms in this profile. The second PANSS pICA profile generally covered blunted affect, emotional withdrawal, passive/apathetic social withdrawal, depression and active social avoidance, exhibiting a withdrawal or apathy dominating component. Lower GM concentration in bilateral parietal and frontal regions showed worse symptom severity in this profile. In summary, a pICA decomposition suggested BD patients showed distinct mood and apathy profiles differing from the original PANSS subscales, relating to distinct brain structural networks., (Copyright © 2019. Published by Elsevier Inc.)

Background: Apathy, a profound loss of motivation, initiation, and goal directed cognition, is a common comorbidity of Alzheimer's disease (AD). The presence of apathy is associated with rapid progression of AD, long-term impairment, disability, and higher mortality. Pharmacological treatments of apathy are limited., Objective: The primary objective was to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) for apathy in AD., Methods: A randomized, double-blind, parallel-arm, sham-controlled pilot study was conducted in subjects with AD and apathy (N = 20). Subjects were randomized to rTMS or sham treatment (5 days/week) for four weeks. Primary outcome, apathy evaluation scale-clinician version (AES-C), and secondary outcome measures, modified-Mini Mental State Examination (3MS), instrumental activities of daily living (IADL), and clinical global impression (CGI), were assessed at baseline and four weeks. Follow-up visits were conducted at 8 and 12 weeks to test the durability of effects of intervention., Results: Mean age was 77.3 (±7.2) years, 80% were Caucasians and 10% were females. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment (-10.1 (-15.9 to -4.3); t (16)  = -3.69; p = 0.002) at 4 weeks. There was also significantly greater improvement in 3MS (6.9 (1.7 to 12.0); t (15)  = 2.85; p = 0.012), IADL (3.4 (1.0 to 5.9); χ21 = 7.72; p = 0.006), CGI-S (1.4 (0.5 to 2.3), t (16)  = 3.29; p = 0.005), and CGI-I (-2.56 (-3.5 to -1.6), t (17)  = -5.72; p < 0.001) for rTMS compared to the sham at 4 weeks. The effects of rTMS were durable at 12 weeks., Conclusion: rTMS may be safely used in subjects with AD and may improve apathy, function, and some aspects of cognition.

Introduction: Cognitive deficits and neuropsychiatric symptoms occur in parkinsonian and cerebellar subtypes of Multiple System Atrophy (MSA-P and MSA-C). These symptoms have been investigated mainly in cross-sectional studies. The present 1-year follow-up study aimed at evaluating the evolution of cognitive and neuropsychiatric profile in patients with MSA-C and MSA-P., Methods: Twenty-nine patients with MSA-P, 21 with MSA-C and 30 healthy subjects (HCs) underwent a neuropsychological battery and questionnaires assessing depression and apathy (T0). After 1 year (T1), patients with MSA-C and MSA-P underwent the same neuropsychological and neuropsychiatric tools employed at T0., Results: At T0, MSA-P and MSA-C groups were more depressed and apathetic and performed worse on tests assessing repetition abilities, executive and attentive functions than HCs. MSA-P and MSA-C groups did not differ on cognitive variables and neuropsychiatric scales. At T1, a significant worsening in spatial planning and psychomotor speed in MSA-C group and a significant worsening in memory, spatial planning, repetition abilities and functional autonomy in MSA-P group were found. The prevalence of apathy increased in both subtypes, whereas the prevalence of depression was reduced in MSA-C and relatively consistent in MSA-P., Conclusions: The finding revealed a wide-ranging worsening of cognitive functions in MSA-P and a significant decline in processing speed in MSA-C. These results underline the relevance of evaluating cognitive and psychiatric features of MSA over the course of the disease in the daily clinical practice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Apathy, a highly prevalent behavioral disorder in Alzheimer's disease and other related disorders, is currently assessed using clinical scales as it is for all neuropsychiatric disorders., Objective: The aim of this study is to propose a new type of assessment using new technologies designed to assess loss of interest by a more implicit and indirect method., Methods: The Interest Game is a form of interactive self-report, where categories of interests are presented in order to quantify them and identify the activities that constitute them. Two indices can be extracted, the number of categories and the number of activities selected. We compared the scores between three groups: Apathetic (A) and Non-Apathetic (NA) subjects (according to the Apathy Diagnostic Criteria) and controls with no objective cognitive impairment., Results: 95 subjects were included. Results showed that subjects from the A group had significantly less interests (both categories and images selected) than the NA group. As expected, the control group selected a higher number of categories than the other groups. The diagnosis (minor or major neurocognitive disorder) and level of education had also a significant effect on the number of categories selected. Furthermore, subjects with major neurocognitive disorder (NCD) had significantly less interests than minor NCD group. The number of categories measure was more sensitive than the number of images selected., Conclusion: The Interest Game is a promising tool to quantify and identify subject interests and differentiate between apathetic and non-apathetic subjects. Future studies should focus on including more apathetic subjects in the minor NCD group and validating this tool with the general population.

The impairment in social functioning of patients with psychotic disorders is mainly driven by motivational negative symptoms with a widely unknown etiology. Building on the well-confirmed link between specific social risk factors and psychosis, the current study tested the postulated effect of immediate social exclusion on the development of motivational negative symptoms and the association of repeated social exclusion experiences with demotivating beliefs in a community sample (N = 84). Repeated social exclusion experiences and demotivating beliefs were assessed at baseline. We randomized the participants to either an exclusion or an inclusion condition of a virtual ball tossing game. Motivation and anticipatory pleasure were measured before and after the manipulation via self-report and via a behavioral effort paradigm. We found a significant multivariate effect of social exclusion on self-reported motivation (F(4,79) = 4.25, p < .01, η2 = .18), but not on behavioral effort (F(1,82) = 1.24, p = .27, η2 = .02). Repeated social exclusion was significantly associated with demotivating beliefs (r = .58, p < .01) and negative symptoms (r = .43, p < .001). Our findings support the notion that reduced motivation, anticipatory anhedonia and demotivating beliefs can be understood as motivational and cognitive consequences of social exclusion. We also discuss the implications for psychological interventions and for further research on the etiology of negative symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Understanding the longitudinal course of non-motor symptoms, and finding markers to predict cognitive decline in Parkinson's disease (PD), are priorities. Previous work has demonstrated that apathy is one of the only behavioural symptoms that differentiates people with PD and intact cognition from those with mild cognitive impairment (MCI-PD). Other psychiatric symptoms emerge as dementia in PD develops., Objective: We explored statistical models of longitudinal change to detect apathy as a behavioural predictor of cognitive decline in PD., Methods: We followed 104 people with PD intermittently over 2 years, undertaking a variety of motor, behavioural and cognitive measures. We applied a linear mixed effects model to explore behavioural factors associated with cognitive change over time. Our approach goes beyond conventional modelling based on a random-intercept and slope approach, and can be used to examine the variability in measures within individuals over time., Results: Global cognitive scores worsened during the two-year follow-up, whereas the longitudinal evolution of self-rated apathy scores and other behavioural measures was negligible. Level of apathy was negatively (- 0.598) correlated with level of cognitive impairment and participants with higher than average apathy scores at baseline also had poorer cognition. The model indicated that departure from the mean apathy score at any point in time was mirrored by a corresponding departure from average global cognitive score., Conclusion: High levels of apathy are predictive of negative cognitive and behavioural outcomes over time, suggesting that apathy may be a behavioural indicator of early cognitive decline. This has clinical and prognostic implications.

Introduction: Alzheimer's disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting., Methods: CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria., Result: Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers., Discussion: Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nonmotor symptoms, including depression, anxiety, apathy, and cognitive dysfunction, are common in Parkinson's disease (PD). Although a link between mood symptoms and cognitive impairment in PD has been theorized vis-à-vis striatal dopamine depletion, studies have been inconsistent regarding the relationship between mood symptoms and cognitive function. Inconsistencies may reflect the cross-sectional nature of previous studies. The current study examined the bidirectional longitudinal relationship between mood and cognition., Method: Data were obtained from 310 individuals newly diagnosed with PD, who were followed up to 4 years (baseline, 1st, 2nd, 3rd, and 4th annual follow-ups). Apathy, anxiety, depressive symptoms, motor severity, and neurocognitive functioning were assessed at each annual assessment. The longitudinal relationship between apathy, anxiety, depressive symptoms, and cognition was analyzed with multilevel models., Results: Over the 4-year period, more severe depressive symptoms were related to worse performance on tasks of processing speed, verbal learning, and verbal delayed recall. Additionally, there was a significant Depression × Time interaction, suggesting that individuals with more severe depressive symptoms experience more rapid declines in global cognitive functioning and verbal learning. Apathy and anxiety were not significantly related to performance in any cognitive test. Lagged models revealed that changes in depression precede declines in working memory, verbal learning, delayed verbal recall, and global cognition., Conclusion: Findings suggest depressive symptoms may be a harbinger for future cognitive decline among individuals with PD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background: Apathy is a common and early symptom in Alzheimer's disease (AD) and is linked to poorer prognosis. Theoretical interpretations of apathy implicate alterations of connections amongst fronto-striatal and limbic regions., Objective: To test the association between presence of apathy and patterns of brain functional connectivity in patients with clinically-established AD., Methods: Seventy AD patients were included. Thirty-five patients experienced apathy as defined by the screening question of the Neuropsychiatric Inventory, and thirty-five did not. All patients agreed to undergo an MRI protocol inclusive of resting-state acquisitions. The hemodynamic-dependent signal was extracted bilaterally from five regions of interest: ventromedial prefrontal cortices, anterior cingulate cortices, dorsolateral prefrontal cortices, insulae and amygdalae. t tests were run to compare connectivity maps of apathetic and non-apathetic patients. Age, education, Mini Mental State Examination score, gray matter volumes and gray matter fractions served as covariates., Results: At a p FWE < .05 threshold, apathetic patients had reduced connectivity between the left insula and right superior parietal cortex. Apathetic patients had also increased connectivity between the right dorsolateral prefrontal seed and the right superior parietal cortex. Patients with apathy were significantly more likely to experience other psychiatric symptoms., Conclusion: Our findings support a role of frontal and insular connections in coordinating value-based decisions in AD. Both down-regulation and maladaptive up-regulation mechanisms appear to be at play in these regions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Clinical observations regarding apathy and motivation derived from many psychiatric and neurological conditions have generated divergent descriptions of apathy-related syndromes. Stimulated by complex cases presenting with prominent apathy, uses of the term "apathy" and "related phenomena" in the Diagnostic and Statistical Manual of Mental Disorders, diagnostic proposals for apathy as a syndrome and disorder of motivation, Research Domain Criteria (RDoC) systems governing motivational processes, and their clinical intersections are reviewed. Clinical apathy and associated dysfunctions can be addressed using constructs suggested by the RDoC domain of Positive Valence Systems, including approach motivation and component processes of reward valuation, effort valuation/willingness to work, expectancy/reward prediction error, and responses to reward and reward learning. Although apathy syndromes have been validated, defining potentially distinct disorders of motivation (not simply subordinated to mood, psychotic, cognitive, or substance use disorders) will require additional research to better delineate etiology and pathogenesis, predictive validators, reliable diagnostic methods, treatments, and demonstrations of use for these diagnostic proposals.

Objective: Apathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear., Methods: National Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use., Results: Thirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17-1.61; p < 0.0001; Wald χ 2  = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05-1.47; p = 0.01; Wald χ 2  = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95-1.22; p=0.25; Wald χ 2  = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52-0.95; p = 0.02; Wald χ 2  = 5.28; df = 1), compared to those without apathy., Conclusion: MCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cardiovascular risk prediction is mainly based on traditional risk factors that have been validated in middle-aged populations. However, associations between these risk factors and cardiovascular disease (CVD) attenuate with increasing age. Therefore, for older people the authors developed and internally validated risk prediction models for fatal and non-fatal CVD, (re)evaluated the predictive value of traditional and new factors, and assessed the impact of competing risks of non-cardiovascular death. Post hoc analyses of 1811 persons aged 70-78 year and free from CVD at baseline from the preDIVA study (Prevention of Dementia by Intensive Vascular care, 2006-2015), a primary care-based trial that included persons free from dementia and conditions likely to hinder successful long-term follow-up, were performed. In 2017-2018, Cox-regression analyses were performed for a model including seven traditional risk factors only, and a model to assess incremental predictive ability of the traditional and eleven new factors. Analyses were repeated accounting for competing risk of death, using Fine-Gray models. During an average of 6.2 years of follow-up, 277 CVD events occurred. Age, sex, smoking, and type 2 diabetes mellitus were traditional predictors for CVD, whereas total cholesterol, HDL-cholesterol, and systolic blood pressure (SBP) were not. Of the eleven new factors, polypharmacy and apathy symptoms were predictors. Discrimination was moderate (concordance statistic 0.65). Accounting for competing risks resulted in slightly smaller predicted absolute risks. In conclusion, we found, SBP, HDL, and total cholesterol no longer predict CVD in older adults, whereas polypharmacy and apathy symptoms are two new relevant predictors. Building on the selected risk factors in this study may improve CVD prediction in older adults and facilitate targeting preventive interventions to those at high risk., (© 2019 The Authors. The Journal of Clinical Hypertension Published by Wiley Periodicals, Inc.)

Objectives: Investigating the frequency of apathy and disinhibition in patients clinically diagnosed with dementia of the Alzheimer type (DAT) or behavioral variant frontotemporal dementia (bvFTD) with neuropathology of either Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD)., Methods: Retrospective data from 887 cases were analyzed, and the frequencies of apathy and disinhibition were compared at baseline and longitudinally in 4 groups: DAT/AD, DAT/FTLD, bvFTD/FTLD, and bvFTD/AD., Results: Apathy alone was more common in AD (33%) than FTLD (25%), and the combination of apathy and disinhibition was more common in FTLD (43%) than AD (14%; P < .0001). Over time, apathy became more frequent in AD with increasing dementia severity (33%-41%; P < .006)., Conclusions: Alzheimer disease neuropathology had the closest association with the neuropsychiatric symptom of apathy, while FTLD was most associated with the combination of apathy and disinhibition. Over time, the frequency of those with apathy increased in both AD and FTLD neuropathology.

Objective: Depression among older adults predicts mortality after acute hospitalization. Depression is highly heterogeneous in its presentation of symptoms, whereas individual symptoms may differ in predictive value. This study aimed to investigate the prevalence of individual cognitive-affective depressive symptoms during acute hospitalization and investigate the predictive value of both overall and individual cognitive-affective depressive symptoms for mortality between admission up to 3-month postdischarge among older patients., Methods: A prospective multicenter cohort study enrolled 401 acutely hospitalized patients 70 years and older (Hospitalization-Associated Disability and impact on daily Life Study). The predictive value of depressive symptoms, assessed using the Geriatric Depression Scale 15, during acute hospitalization on mortality was analyzed with multiple logistic regression., Results: The analytic sample included 398 patients (M (SD) = 79.6 (6.6) years; 51% men). Results showed that 9.3% of participants died within 3 months, with symptoms of apathy being most frequently reported. The depression total score during hospitalization was associated with increased mortality risk (admission: odds ratio [OR] = 1.2, 95% confidence interval [CI] = 1.2-1.3; discharge: OR = 1.2, 95% CI = 1.2-1.4). Stepwise multiple logistic regression analyses yielded the finding that feelings of hopelessness during acute hospitalization were a strong unique predictor of mortality (admission: OR = 3.6, 95% CI = 1.8-7.4; discharge: OR = 5.7, 95% CI = 2.5-13.1). These associations were robust to adjustment for demographic factors, somatic symptoms, and medical comorbidities., Conclusions: Symptoms of apathy were most frequently reported in response to acute hospitalization. However, feelings of hopelessness about their situation were the strongest cognitive-affective predictor of mortality. These results imply that this item is important in identifying patients who are in the last phase of their lives and for whom palliative care may be important.

Background/aims: The presence of non-motor symptoms in Huntington's disease (HD) has not been systematically assessed so far. Our objective was to know their prevalence and to compare it with a cohort of patients with Parkinson's disease (PD)., Materials and Methods: Participants were consecutively recruited from our outpatient clinic. They were assessed through the motor part of the Unified Huntington's Disease Rating Scale, the motor part of the Unified Parkinson's Disease Rating Scale, the total functional capacity scale and the PD non-motor symptoms questionnaire., Results: We enrolled 123 participants: 53 HD, 45 PD and 25 healthy controls (HC). Non-motor symptoms were significantly more prevalent in HD patients than in HC. The most frequent non-motor symptoms in HD, involving more than 50% of patients, were attentional deficits, apathy, dysphagia, memory complaints, depression falls, insomnia and urinary urgency. The total score of non-motor symptoms correlated with disease duration, total functional capacity and disease stage. HD scored significantly higher than PD in 11 items (dysphagia, constipation, bowel incontinence, faecal tenesmus, weight loss, memory, apathy, attention, falls, nightmares, delusions) and in four domains (cognitive, hallucinations and delusions, digestive and cardiovascular). PD did not score significantly higher than HD in any domain., Conclusions: HD patients have a high prevalence of non-motor symptoms, which is even higher than in PD, and correlates with disease progression.

Objectives: Apathy is a debilitating symptom of Huntington's disease (HD) and manifests before motor diagnosis, making it an excellent therapeutic target in the preclinical phase of Huntington's disease (prHD). HD is a neurological genetic disorder characterized by cognitive and motor impairment, and psychiatric abnormalities. Apathy is not well characterized within the prHD. In previous literature, damage to the caudate and putamen has been correlated with increased apathy in other neurodegenerative and movement disorders. The objective of this study was to determine whether apathy severity in individuals with prHD is related to striatum volumes and cognitive control. We hypothesized that, within prHD individuals, striatum volumes and cognitive control scores would be related to apathy., Methods: We constructed linear mixed models to analyze striatum volumes and cognitive control, a composite measure that includes tasks assessing with apathy scores from 797 prHD participants. The outcome variable for each model was apathy, and the independent variables for the four separate models were caudate volume, putamen volume, cognitive control score, and motor symptom score. We also included depression as a covariate to ensure that our results were not solely related to mood., Results: Caudate and putamen volumes, as well as measures of cognitive control, were significantly related to apathy scores even after controlling for depression., Conclusions: The behavioral apathy expressed by these individuals was related to regions of the brain commonly associated with isolated apathy, and not a direct result of mood symptoms. (JINS, 2019, 25, 462-469).

Objectives: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson's disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington's disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls., Methods: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment - short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S., Results: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington's Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score., Conclusions: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453-461).

Aim: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, β-amyloid (Aβ) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results., Methods: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging-Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aβ 42 , t-tau, and pTau 181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups., Results: The CSF Aβ 42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aβ 42 levels compared to nonapathetic ones., Conclusion: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.

Objectives: To examine the impact of apathy on cognitive performance in the elderly following the conceptual principles proposed by Marin 1 and Stuss et al 2 and to determine the role of the symptoms of apathy in different cognitive domains., Methods: Cross-sectional study with a cohort of healthy elderly subjects over 55 years old (n = 140). One hundred forty healthy-elderly subjects (aged 79.24 ± 8.6 years old) were recruited from 12 day centers in Northern Spain. Participants underwent a neuropsychological battery, which evaluated Mini Mental State Examination (MMSE), attention, processing speed, verbal fluency, visual and verbal memory, working memory, and executive functioning. Apathy was assessed by the Lille Apathy Rating Scale (LARS), which is composed of four factors: intellectual curiosity, emotion, action initiation, and self-awareness. Correlation and linear regression analyses were performed., Results: In the correlational analysis, the LARS total score correlated negatively with global cognition, verbal fluency, and visual and verbal memory. The intellectual curiosity factor correlated negatively with all cognitive domains except attention. The emotion factor correlated negatively with visual memory. No correlation was found between the action initiation and self-awareness factors or any of the cognitive variables. Multiple stepwise regression analysis showed that symptoms of apathy explained cognitive performance in attention, processing speed, verbal fluency, visual and verbal memory, working memory, executive functioning, and MMSE., Conclusions: Apathy was significantly associated with cognitive performance, especially with the intellectual curiosity factor. Our results suggest that specific symptoms of apathy contribute differently to individual cognitive domains., (© 2019 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.)

Objective: The aims of the current study are (1) to explore the differences in neuropsychiatric symptoms (NPS) between young-onset dementia (YOD) and late-onset dementia (LOD), and (2) to investigate whether the possible differences can be attributed to differences in dementia subtype, gender, psychotropic drug use (PDU), or dementia severity., Method: Three hundred and eighty-six nursing home (NH) residents with YOD and 350 with LOD were included. Multilevel modeling was used to compare NPS between the groups . Furthermore, dementia subtype, gender, PDU, and dementia severity were added to the crude multilevel models to investigate whether the possible differences in NPS could be attributed to these characteristics., Results: Higher levels of apathy were found in NH residents with YOD. After the characteristics were added to the models, also lower levels of verbally agitated behaviors were found in YOD ., Conclusion: We recommend that special attention be paid to interventions targeting apathy in YOD. Although no differences in other NPS were found, the PDU rates were higher in YOD, suggesting that the threshold for the use of PDU in the management of NPS is lower. This underscores the need for appropriate attention to non-pharmacological interventions for the management of NPS in YOD.

The aim of this study was to investigate whether apathy in schizophrenia is associated with rigidity in behavior and brain functioning. To this end, we studied associations between variability in dynamic functional connectivity (DFC) in relevant functional brain networks, apathy, and variability in physical activity in schizophrenia. Thirty-one patients with schizophrenia, scoring high on apathy, were included and wore an actigraph. Activity variability was calculated on the activity counts using the root of the Mean Squared Successive Difference (MSSD). Furthermore, we calculated DFC on resting-state data as phase interactions between blood oxygen-level dependent (BOLD) signals of 270 brain regions per volume. Variability (MSSD) in DFC was calculated for 3 networks, including the default-mode network (DMN), frontoparietal network, and salience-reward network (SRN). Finally, we calculated correlations between these DFC estimates and apathy and activity variability. First, lower activity variability was associated with higher levels of apathy. Second, higher levels of apathy were associated with lower variability in DFC in the DMN and SRN. Third, higher activity variability was associated with higher variability in DFC in the SRN. In conclusion, patients with schizophrenia and more severe levels of apathy showed less variability in their physical activity and more rigid functional brain network behavior in the DMN and SRN. These networks have been shown relevant for self-reflection, mental simulation, and reward processing, processes that are pivotal for self-initiated goal-directed behavior. Functional rigidity of these networks may therefore contribute to reduced goal-directed behavior, which is characteristic for these patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)