Apathy and Motivation: Biological Basis and Drug Treatment.

Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behavior in humans and animals have shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed, we summarize trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.

The effect of apathy and compulsivity on planning and stopping in sequential decision-making.

Real-life decision-making often comprises sequences of successive decisions about whether to take opportunities as they are encountered or keep searching for better ones instead. We investigated individual differences related to such sequential decision-making and link them especially to apathy and compulsivity in a large online sample (discovery sample: n = 449 and confirmation sample: n = 756). Our cognitive model revealed distinct changes in the way participants evaluated their environments and planned their own future behaviour. Apathy was linked to decision inertia, i.e., automatically persisting with a sequence of searches for longer than appropriate given the value of searching. Thus, despite being less motivated, they did not avoid the effort associated with longer searches. In contrast, compulsivity was linked to self-reported insensitivity to the cost of continuing with a sequence of searches. The objective measures of behavioural cost insensitivity were clearly linked to compulsivity only in the discovery sample. While the confirmation sample showed a similar effect, it did not reach significance. Nevertheless, in both samples, participants reported awareness of such bias (experienced as "overchasing"). In addition, this awareness made them report preemptively avoiding situations related to the bias. However, we found no evidence of them actually preempting more in the task, which might mean a misalignment of their metacognitive beliefs or that our behavioural measures were incomplete. In summary, individual variation in distinct, fundamental aspects of sequential decision-making can be linked to variation in 2 measures of behavioural traits associated with psychological illness in the normal population.

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

Adaptive coding of reward in schizophrenia, its change over time and relationship to apathy.

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia.

The effect of Huntington's disease on cognitive and physical motivation.

Apathy is one of the most common neuropsychiatric features of Huntington's disease. A hallmark of apathy is diminished goal-directed behaviour, which is characterized by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit and/or is secondary to the progressive cognitive and physical deficits that accompany more advanced disease. We addressed this question by testing 17 individuals with manifest Huntington's disease and 22 age-matched controls on an effort-based decision-making paradigm. Participants were first trained on separate cognitively and physically effortful tasks and provided explicit feedback about their performance. Next, they chose on separate trials how much effort they were willing to exert in each domain in return for varying reward. At the conclusion of the experiment, participants were asked to rate their subjective perception of task load. In the cognitive task, the Huntington's disease group were more averse to cognitive effort than controls. Although the Huntington's disease group were more impaired than controls on the task itself, their greater aversion to cognitive effort persisted even after controlling for task performance. This suggests that the lower levels of cognitive motivation in the Huntington's disease group relative to controls was most likely driven by a primary motivational deficit. In contrast, both groups expressed a similar preference for physical effort. Importantly, the similar levels of physical motivation across both groups occurred even though participants with Huntington's disease performed objectively worse than controls on the physical effort task, and were aware of their performance through explicit feedback on each trial. This indicates that the seemingly preserved level of physical motivation in Huntington's disease was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the Huntington's disease group provided higher ratings of subjective task demand than controls for the cognitive (but not physical) effort task and when assessing the mental (but not the physical) load of each task. Together, these results revealed a dissociation in cognitive and physical motivation deficits between Huntington's disease and controls, which were accompanied by differences in how effort was subjectively perceived by the two groups. This highlights that motivation is the final manifestation of a complex set of mechanisms involved in effort processing, which are separable across different domains of behaviour. These findings have important clinical implications for the day-to-day management of apathy in Huntington's disease.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

Apathy Symptoms, Physical and Cognitive Function, Health-Related Quality of Life, and Mortality in Older Patients With CKD: A Longitudinal Observational Study.

RATIONALE & OBJECTIVE: Apathy reflects diminished motivation, goal-directed behavior, and emotions, as well as less engagement in social interactions. Apathy overlaps with depression and is associated with cognitive decline. In the older individuals with chronic kidney disease (CKD), both depression and cognitive impairments are common, but apathy symptoms have been underreported. We investigated the occurrence of apathy symptoms and their associations with physical and cognitive functioning, health-related quality of life (HRQoL), and mortality in older patients with CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 180 outpatients aged≥65 years with estimated glomerular filtration rate≤20mL/min/1.73m2 from 5 Dutch nephrology centers. EXPOSURE: Apathy symptoms at baseline were considered present when a Geriatric Depression Scale's 3-item apathy subscale score was≥2 points. OUTCOME: Physical and cognitive functioning, HRQoL (assessed in annual geriatric assessments), and 4-year mortality. ANALYTICAL APPROACH: Linear regression for cross-sectional associations, linear regression models for longitudinal associations, and Cox regression models for mortality over 4 years of observation. RESULTS: Apathy symptoms were present in 64 patients (36%; 67% men; median age 75.5 years), of whom 32 (50%) had no depressive symptoms. At baseline, the presence of apathy symptoms was associated with significantly more frailty, more functional dependence, less physical capacity, lower visuoconstructive performance, worse delayed recall, and lower HRQoL scores. The presence of apathy symptoms at baseline was also associated with a higher mortality risk (hazard ratio, 2.3 [95% CI, 1.3-4.2], P=0.005 adjusted for age, sex, and high education level), but not with changes in physical and cognitive functioning or HRQoL during the follow-up period. LIMITATIONS: Risk of selection bias and residual confounding. CONCLUSIONS: Apathy symptoms were highly prevalent and associated with concurrent lower physical and cognitive status, lower HRQoL, and increased mortality. These findings highlight apathy as a potentially important clinical phenotype in older CKD patients. PLAIN-LANGUAGE SUMMARY: We observed that older kidney patients often present apathy symptoms, such as less motivation, fewer goal-directed behaviors, fewer emotions, and less social engagement. Prior research has not extensively described apathy in kidney disease. We investigated the link between apathy symptoms and poor outcomes. We measured physical functioning, cognitive functioning, and quality of life. We learned that one-third of our older kidney patients showed symptoms of apathy, only half of whom had symptoms of depression. Patients with apathy symptoms showed lower quality of life and lower physical and cognitive performance. They also had a higher risk of death. These findings highlight the need for awareness of apathy symptoms in older kidney patients.

Increased apathy post-interstitial laser capsulotomy for refractory obsessive-compulsive disorder.

BACKGROUND: MRI guided laser interstitial thermal therapy (M-LITT) capsulotomy has proven to be efficacious in decreasing refractory obsessive-compulsive disorder (OCD) related symptomatology yet capsulotomy either via radiosurgery or radiofrequency ablation has in some patients led to increased apathy following surgery. The current case series aims to investigate objective patient-reported change in apathy, disinhibition, depression, and executive dysfunction following anterior capsulotomy via M-LITT for OCD. METHODS: Ten consecutive patients pre- and post-M-LITT completed measures of OCD, apathy, disinhibition, executive dysfunction, and depression (Mtime between = 1.3 years; 0.42-3.7 years). Reliable Change Index (RCI) was used to evaluate change in pre- and post-M-LITT. OCD symptom response was evaluated using percent change (Y-BOCS scores: 24-34 % reduction indicating partial response; ≥35% reduction indicating full response). RESULTS: Positive post-surgical change was noted in OCD symptomatology with >65% reporting a partial or full response. However, six patients endorsed increased apathy with half of the non-responders (e.g., less than <24% score reduction on Y-BOCS) reporting increases in apathy. Patients reported relatively stable disinhibition and executive dysfunction, while over half reported a decrease in depression symptoms. Two of the non-responders and one responder endorsed increased apathy despite stable or improved depression symptoms, disinhibition, and executive dysfunction. CONCLUSIONS: Most patients in the current cohort achieved full-or-partial OCD recovery. Yet, 60% of patients also reported significant increases in apathy, despite experiencing a decrease in depression symptoms, with stable disinhibition and executive dysfunction. Despite these promising improvements in OCD symptomatology following M-LITT, further investigations of the impact of surgery and lesion location on apathy levels is clearly warranted using objective, quantifiable methods.

Clinical and radiological correlates of apathy in multiple sclerosis.

BACKGROUND: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). OBJECTIVES: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). METHODS: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. RESULTS: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. CONCLUSIONS: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

Emerging therapies for treatment of agitation, psychosis, or apathy in Alzheimer's disease.

INTRODUCTION: Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS. AREAS COVERED: This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD. EXPERT OPINION: Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis, while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.

Neuropsychiatric Symptom Profile in Alzheimer's Disease and Their Relationship With Functional Decline.

OBJECTIVE: Understanding the course of individual neuropsychiatric symptoms (NPS) and their relationship with function is important for planning targeted interventions for preventing and delaying functional decline. This study aims to disentangle relative contributions of individual NPS on functional decline. METHODS: Longitudinal study of 9,358 well-characterized participants with baseline diagnoses of Mild Cognitive Impairment or AD in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured using the Functional Assessment Questionnaire (FAQ). Clinician judgment of seven common behavioral symptoms were examined simultaneously: apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, and agitation. RESULTS: Apathy was the most common NPS at baseline (33.7%) and throughout follow-up, endorsed by clinicians in 63.7% of visits. Apathy was the most persistent with 36.7% of participants having clinician-endorsed apathy in ≥50% of their visits. Apathy strongly correlated with faster rate of functional decline. Compared to those who never had apathy, baseline FAQ was worse in those with intermittent or persistent/always apathy (intermittent: estimated coefficient ±SE=1.228±0.210, 95% CI=[0.817, 1.639]; persistent/always: 2.354±0.244 (95% CI=[1.876, 2.832], both p <0.001). Over time, rate of functional decline was faster in those with intermittent and persistent/always apathy (intermittent: 0.454±0.091, 95% CI=[0.276, 0.632]; persistent/always: 0.635±0.102, 95% CI=[0.436, 0.835], both p <0.001). Worse agitation, delusions, and hallucinations also correlated with functional decline, but magnitudes of the estimates were smaller. CONCLUSION: Individual NPS may be sensitive targets for tracking longitudinal change in function. The study raises awareness of the need for more comprehensive assessment of functional decline in AD patients with noncognitive symptoms.

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

Establishing the link between motivational disturbances and behavioural rigidity in frontotemporal dementia.

BACKGROUND: Rigid and inflexible behaviours are common in frontotemporal dementia (FTD), manifesting in compulsive pursuit of specific interests, routines, and rituals. Paradoxically, these changes occur alongside profound motivational disturbances including apathy and anhedonia. While posited to be related, no study to date has explored the link between motivational changes and behavioural rigidity in FTD. METHODS: Carer ratings for 71 FTD participants (26 semantic dementia [SD], 45 behavioural variant [bvFTD]) were obtained on the Dimensional Apathy Scale (apathy), the Snaith-Hamilton Pleasure Scale (hedonic tone) and the Cambridge Behavioural Inventory-Revised (CBI-R; behavioural changes). A rigidity index was created from existing items on the CBI-R. Whole-brain voxel-based morphometry was used to explore associations between rigidity and grey matter intensity in the combined FTD group. RESULTS: Behavioural rigidity was significantly related to apathy severity (r = 0.57) and decreased hedonic tone (r = -0.36) in the combined FTD group. Multiple linear regression revealed a significant diagnosis × hedonic tone interaction (ß = -1.40), whereby lower hedonic tone predicted rigidity in SD (r = -0.65) but not in bvFTD (r = -0.18). In contrast, the relationship between rigidity and apathy did not differ between the groups (ß = -0.42). At the neural level, rigidity correlated with degeneration of predominantly right-sided frontostriatal structures including, notably, the nucleus accumbens. CONCLUSIONS: As the first study to demonstrate a link between motivational changes and behavioural rigidity in FTD, our findings have important clinical implications. By identifying candidate mechanisms of behavioural rigidity, our findings can inform targeted interventions to manage inflexible patterns of thought and behaviour in daily life.

Mixed effects models but not t-tests or linear regression detect progression of apathy in Parkinson's disease over seven years in a cohort: a comparative analysis.

INTRODUCTION: While there is an interest in defining longitudinal change in people with chronic illness like Parkinson's disease (PD), statistical analysis of longitudinal data is not straightforward for clinical researchers. Here, we aim to demonstrate how the choice of statistical method may influence research outcomes, (e.g., progression in apathy), specifically the size of longitudinal effect estimates, in a cohort. METHODS: In this retrospective longitudinal analysis of 802 people with typical Parkinson's disease in the Luxembourg Parkinson's study, we compared the mean apathy scores at visit 1 and visit 8 by means of the paired two-sided t-test. Additionally, we analysed the relationship between the visit numbers and the apathy score using linear regression and longitudinal two-level mixed effects models. RESULTS: Mixed effects models were the only method able to detect progression of apathy over time. While the effects estimated for the group comparison and the linear regression were smaller with high p-values (+ 1.016/ 7 years, p = 0.107, -0.056/ 7 years, p = 0.897, respectively), effect estimates for the mixed effects models were positive with a very small p-value, indicating a significant increase in apathy symptoms by + 2.345/ 7 years (p < 0.001). CONCLUSION: The inappropriate use of paired t-tests and linear regression to analyse longitudinal data can lead to underpowered analyses and an underestimation of longitudinal change. While mixed effects models are not without limitations and need to be altered to model the time sequence between the exposure and the outcome, they are worth considering for longitudinal data analyses. In case this is not possible, limitations of the analytical approach need to be discussed and taken into account in the interpretation.

Does Social Support Play a Role in the Expression and Everyday Functioning Impact of Apathy in HIV Disease?

Clinically notable apathy occurs in approximately one-third of persons living with HIV (PLWH). Drawing from psychological theory, this cross-sectional study examined the interplay between apathy and social support in persons with (n = 143) and without (n = 61) HIV disease. Analyses were conducted using multiple regression and mediation procedures with 95th percentile bootstrap confidence intervals. Positive HIV serostatus and lower social support were associated with more frequent apathy, independent of other mood symptoms. Social support did not moderate apathy's associations with everyday functioning among PLWH, but post hoc analyses revealed that apathy mediated the relationship between social support and everyday functioning among PLWH. Stronger social support may provide a buffer against the frequency of apathy symptoms in persons with and without HIV disease. The relationship between lower social support and poorer everyday functioning in HIV might be partly explained by apathy. Longitudinal research is needed to examine the mechanisms of these relationships.

RESUMEN: La apatía clínicamente notable se produce en aproximadamente un tercio de las personas que viven con el VIH (PVVS). A partir de la teoría psicológica, este estudio transversal examinó la interacción entre la apatía y el apoyo social en personas con (n = 143) y sin (n = 61) enfermedad de VIH. Los análisis se llevaron utilizando procedimientos de regresión múltiple y mediación con intervalos de confianza bootstrap del 95º percentil. El estado serológico positivo respecto al VIH y un menor apoyo social se asociaron con una apatía más frecuente, independientemente de otros síntomas del estado de ánimo. El apoyo social no moderó las asociaciones de la apatía con el funcionamiento cotidiano entre las PVVS, pero los análisis post hoc revelaron que la apatía mediaba la relación entre el apoyo social y el funcionamiento cotidiano entre las PVVS. Un apoyo social más fuerte puede atenuar la frecuencia de los síntomas de apatía en personas con y sin VIH. La relación entre un menor apoyo social y un peor funcionamiento cotidiano en personas con VIH podría explicarse en parte por la apatía. Se necesitan investigaciones longitudinales para examinar los mecanismos de estas relaciones.

Minor Phenomena in Parkinson's Disease-Prevalence, Associations, and Risk of Developing Psychosis.

BACKGROUND: Minor phenomena, including passage phenomena, feeling of presence, and illusions, are common and may represent a prodromal form of psychosis in Parkinson's disease (PD). We examined the prevalence and clinical correlates of minor phenomena, and their potential role as a risk factor for PD psychosis. METHODS: A novel questionnaire, the Psychosis and Mild Perceptual Disturbances Questionnaire for PD (PMPDQ), was completed by Fox Insight cohort participants with and without PD. Additional assessments included the Non-Motor Symptoms Questionnaire (NMSQuest), REM Sleep Behavior Disorder Single Question Screen (RBD1Q), Movement Disorder Society-Unified Parkinson Disease Rating Scale Part II, demographic features, and medication usage. For participants with PD, we used regression models to identify clinical associations and predictors of incident psychosis over one year of follow-up. RESULTS: Among participants with PD (n = 5950) and without PD (n = 1879), the prevalence of minor phenomena was 43.1% and 31.7% (P < .001). Of the 3760 participants with PD and no baseline psychosis, independent correlates of minor phenomena included positive responses on the NMSQuest apathy/attention/memory (OR 1.7, 95% CI 1.3-2.1, P < .001) or sexual function domain (OR 1.3, 95% CI 1.1-1.6, P = .01) and positive RBD1Q (OR 1.3, 95% CI 1.05-1.5, P = .01). Independent risk factors for incident PD psychosis included the presence of minor phenomena (HR 3.0, 95% CI 2.4-3.9, P < .001), positive response on the NMSQuest apathy/attention/memory domain (HR 1.8, 95% CI 1.3-2.6, P < .001), and positive RBD1Q (HR 1.5, 95% CI 1.1-1.9, P = .004). CONCLUSIONS: Minor phenomena are common, associated with specific non-motor symptoms, and an independent predictor of incident psychosis in PD.

The Relationship Between Apathy and Cognitive Impairment Among Hispanic/Latin Americans: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses Systematic Review.

OBJECTIVES: The primary aim was to evaluate apathy assessment measures in relation to cognitive impairment among Hispanic/Latin Americans. METHODS: A systematic review on the relationship between apathy and cognitive impairment among Hispanic/Latin Americans across normal aging and neurocognitive disorders was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and using APA PsycInfo, Embase, and PubMed databases. Inclusion criteria required (1) a sample of English or Spanish-speaking adults ages 18 years and older, (2) with measures of apathy, (3) assessment of cognitive functioning or diagnosis of neurocognitive disorder, (4) with at least 18.5% Hispanic/Latin American represented in the sample. RESULTS: Only 14 papers met criteria to be included in this review. Of the 12 cross-sectional studies, 9 demonstrated significant associations between increased apathy and cognitive impairment, 1 demonstrated a descriptive difference between apathy and cognitive status (ie, no hypothesis test conducted), while 2 demonstrated null effects. These cross-sectional studies consisted of community and clinic samples of participants across North and South America. Two longitudinal studies conducted in North America demonstrated non-significant associations of apathy with cognitive status. CONCLUSIONS: The Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) apathy subscales were the most used measures for apathy in this review (85.7% of included studies). However, validity evidence from a review of apathy measures has warranted caution against the use of the NPI outside the context of screening for apathy. This potential measurement bias with Hispanic/Latin Americans apathy research limits conclusions drawn from the present review.

The Starkstein Apathy Scale-Italian Version: An Update.

Apathy can manifest in various neuropsychiatric conditions, as well as in individuals who experience significant stressful life events or suffer from underlying internal medical conditions. The Starkstein Apathy Scale (SAS) is recognized as a reliable screening tool, besides being endorsed by the International Parkinson and Movement Disorder Society to assess apathy in patients with Parkinson's disease. Recently, the Italian version of this scale (SAS-I) has been introduced. Furthermore, normative data have been provided on a large sample of Italian healthy individuals. Here we present the official Italian translation of the SAS, along with clarifications regarding its administration. Also, we supply details concerning the scale's factorial structure, inter-item conditional associations and item performance by using EFA, Network analysis, and IRT modelling for polytomous items.

Apathy and Depression Among People Aging With Traumatic Brain Injury: Relationships to Cognitive Performance and Psychosocial Functioning.

OBJECTIVE: Apathy and depression are both common after moderate to severe traumatic brain injury (TBI) and may be especially important to distinguish in older adults with TBI. The authors examined apathy and depression in relation to cognitive performance domains and their potentially unique contribution to psychosocial functioning in this patient population. METHODS: A total of 106 participants (mean±SD age=64±8 years) with chronic moderate to severe TBI (≥1 year) completed questionnaires assessing severity of apathy (Frontal Systems Behavior Scale-apathy subscale) and depression (Geriatric Depression Scale-15) symptoms, health-related quality of life (HRQoL), and societal participation. Participants also completed neuropsychological tests of episodic memory, processing speed, and executive functioning. RESULTS: Apathy symptom severity was significantly associated with all cognitive performances in correlations adjusted for the familywise error rate; a relationship with executive functioning remained after controlling for demographic and injury variables. Depression symptom severity was not significantly associated with cognition after statistical correction. Both symptomatologies uniquely contributed to HRQoL. Only depression symptoms contributed to societal participation. On the basis of clinical cutoffs, half the sample had neither depression nor apathy, approximately 25% met criteria for only apathy, and 25% had both apathy and depression. The combined presence of clinical depression and apathy was associated with worse HRQoL and societal participation. CONCLUSIONS: This is the first study to examine apathy and depression in relation to cognition and psychosocial functioning in an older sample with a history of TBI. Findings suggest that the two syndromes can be dissociated in clinically meaningful ways, which may help to refine psychiatric and behavioral interventions in this vulnerable population.