Safety, tolerability, and efficacy outcomes of the Investigation of Levetiracetam in Alzheimer's disease (ILiAD) study: a pilot, double-blind placebo-controlled crossover trial.

OBJECTIVE: To assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimer's disease who have not previously experienced a seizure. METHODS: We performed a randomized, double-blind, placebo-controlled crossover pilot study in individuals with mild-to-moderate Alzheimer's disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded. Eligible participants were randomized to placebo for 12 weeks or an active arm of oral levetiracetam (4 weeks up-titration to levetiracetam 500 mg twice daily, 4 weeks maintained on this dose followed by 4 weeks down-titration to nil). Participants then crossed over to the other arm. The primary outcome was change in cognitive function assessed by the Oxford Memory Task, a task sensitive to hippocampal memory binding. Secondary outcomes included tolerability, other neuropsychological scales, and general questionnaires. RESULTS: Recruitment numbers were severely limited owing to restrictions from the COVID-19 pandemic at the time of the study. Eight participants completed both arms of the study (mean age 68.4 years [SD = 9.2]; 5 females [62.5%]). No participants withdrew from the study and there was no significant difference between reported side effects in the active levetiracetam or placebo arm. Measures of mood and quality of life were also not significantly different between the two arms based on participant or carer reports. In limited data analysis, there was no statistically significant difference between participants in the active levetiracetam and placebo arm on the memory task. SIGNIFICANCE: This pilot study demonstrates that levetiracetam was well tolerated in individuals with Alzheimer's disease who do not have a history of seizures and has no detrimental effect on mood or quality of life. Larger studies are needed to assess whether levetiracetam may have a positive effect on cognitive function in subsets of individuals with Alzheimer's disease. PLAIN LANGUAGE SUMMARY: Abnormal electrical activity within the brain, such as is seen in seizures, might contribute to memory problems in people with dementia. We completed a clinical trial to see if an antiseizure medication, levetiracetam, could help with memory difficulties in people with Alzheimer's disease (the most common cause of dementia). In this pilot study, we could not prove whether levetiracetam helped memory function. We did show that the drug is safe and well tolerated in people with dementia who have not had a seizure. This work, therefore, offers a platform for future research exploring antiseizure medications in people with dementia.

A computational approach to understanding effort-based decision-making in depression.

Background: Motivational dysfunction is a core feature of depression, and can have debilitating effects on everyday function. However, it is unclear which disrupted cognitive processes underlie impaired motivation, and whether impairments persist following remission. Decision-making concerning exerting effort to collect rewards offers a promising framework for understanding motivation, especially when examined with computational tools which can offer precise quantification of latent processes. Methods: Effort-based decision-making was assessed using the Apple Gathering Task, in which participants decide whether to exert effort via a grip-force device to obtain varying levels of reward; effort levels were individually calibrated and varied parametrically. We present a comprehensive computational analysis of decision-making, initially validating our model in healthy volunteers (N=67), before applying it in a case-control study including current (N=41) and remitted (N=46) unmedicated depressed individuals, and healthy volunteers with (N=36) and without (N=57) a family history of depression. Results: Four fundamental computational mechanisms that drive patterns of effort-based decisions, which replicated across samples, were identified: an overall bias to accept effort challenges; reward sensitivity; and linear and quadratic effort sensitivity. Traditional model-agnostic analyses showed that both depressed groups showed lower willingness to exert effort. In contrast with previous findings, computational analysis revealed that this difference was driven by lower effort acceptance bias, but not altered effort or reward sensitivity. Conclusions: This work provides insight into the computational mechanisms underlying motivational dysfunction in depression. Lower willingness to exert effort could represent a trait-like factor contributing to symptoms, and might represent a fruitful target for treatment and prevention.

Apathy and effort-based decision-making in Alzheimer's disease and subjective cognitive impairment.

INTRODUCTION: Apathy is a significant feature in Alzheimer's disease (AD) and subjective cognitive impairment (SCI), though its mechanisms are not well established. METHODS: An effort-based decision-making (EBDM) framework was applied to investigate apathy in 30 AD patients, 41 SCI participants, and 55 healthy controls (HC). Data were analyzed using a drift-diffusion model (DDM) to uncover latent psychological processes. RESULTS: SCI participants reported higher apathy than AD patients and HC. However, informant reports of apathy in AD patients were higher than self-reports and indicated significant apathy compared to HC. Both the AD and SCI groups showed reduced sensitivity to effort changes, linked to executive dysfunction in AD and apathy in SCI. Increased resting functional cortical connectivity with the nucleus accumbens (NA) was associated with higher apathy in SCI. DISCUSSION: These results highlight a similar disruption of EBDM in AD and SCI, differentially related to executive functioning in AD and apathy in SCI. Highlights: This is the first study investigating apathy using an effort-based decision-making (EBDM) framework in Alzheimer's disease (AD) and subjective cognitive impairment (SCI).Self-reports underestimate apathy in AD patients when compared to informant reports and healthy controls (HC). SCI participants, in whom self and informant reports were more concordant, also showed higher degrees of apathy.Both AD and SCI groups showed reduced sensitivity to effort.Reduced sensitivity to effort correlates with executive dysfunction in AD and apathy, but not depression, in SCI.Increased nucleus accumbens (ventral striatum) connectivity with the frontoparietal network was associated with higher apathy scores in SCI.The results thus suggest that while AD and SCI can have similar deficits in EBDM, these deficits correlate with distinct clinical manifestations: executive dysfunction in AD and apathy in SCI.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Apathy and Impulsivity Co-Occur in Huntington's Disease.

BACKGROUND: Apathy is a debilitating behavioral change in Huntington's disease (HD), but impulsivity in HD has not been well documented, and the co-occurrence of these behaviors in HD has not been investigated. OBJECTIVE: Our objective was to determine whether apathy and impulsivity co-occur in people with HD and their associations with quality of life. METHODS: Carriers of Huntington's gene expansion (premanifest to mild motor manifest disease; n = 42) along with healthy controls (n = 20) completed measures of apathy (Apathy Evaluation Scale and Apathy Motivation Index) and impulsivity (Barratt Impulsiveness Scale-11 and UPPS-P impulsivity scale), along with mood, cognition, clinical, and quality of life measures. Apathy and impulsivity measures were each reduced to a single metric per patient using principal component analysis. Correlations and multiple linear regression models determined associations between apathy and impulsivity and the potential influence of other covariates. RESULTS: Apathy and impulsivity were significantly correlated (r = 0.6, p < 0.001, 95% CI [0.36, 0.76]) in HD, with this association remaining after controlling for depressive symptoms, motor disease severity, and cognitive function. Furthermore, apathy and depressive symptoms were associated with poorer quality of life. CONCLUSIONS: Apathy and impulsivity co-occur in individuals with premanifest to mild manifest HD and have a significant impact on wellbeing. We add to a growing evidence body that apathy and impulsivity may be intrinsically linked.

Decision cost hypersensitivity underlies Huntington's disease apathy.

The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease (HD). However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to utilise a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with HD pathology, we hypothesised that a general hypersensitivity to costs would underpin HD apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease (n=53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with HD accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition, or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and also drift rate, where there was moderate evidence of HD apathy drifting faster towards the immediately available (low cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in HD, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that HD pathology may cause a domain-general disruption of cost processing, which is distinct to apathy occurrence in other brain disorders, and may require different therapeutic approaches.

Increased Sensitivity to Effort and Perception of Effort in People with Schizophrenia.

OBJECTIVE: Motivational deficits in schizophrenia are proposed to be attributable in part to abnormal effort-cost computations, calculations weighing the costs vs. the benefits of actions. Several reports have shown that people with schizophrenia display a reduced willingness to exert effort for monetary rewards when compared to controls. The primary goal of the current study was to further characterize reduced willingness to exert effort in schizophrenia by determining whether reduced willingness reflects (1) reduced sensitivity to reward, (2) increased sensitivity to effort, or (3) a combination of both. DESIGN: We assessed effort-cost decision-making in 30 controls and 30 people with schizophrenia, using 2 separate experimental tasks. Critically, one paradigm allowed for independent estimation of effects of reward and effort sensitivity on choice behavior. The other task isolated effort sensitivity by measuring effort in the absence of reward. Clinical interviews and self-report questionnaires were administered to people with schizophrenia to determine negative symptom severity. RESULTS: Across both tasks, we found evidence for reduced willingness to exert effort in people with schizophrenia compared to controls. Further, in both paradigms reduced willingness to exert effort was driven by increased sensitivity to effort in people with schizophrenia compared to controls. In contrast, measures of reward sensitivity did not significantly differ between groups. Surprisingly, we did not find correlations between task variables and measures of negative symptom severity. CONCLUSIONS AND RELEVANCE: These findings further specify prior work by identifying a specific contributory role for increased effort sensitivity in effort-cost decision-making deficits in schizophrenia.

Older adults are relatively more susceptible to impulsive social influence than young adults.

People differ in their levels of impulsivity and patience, and these preferences are heavily influenced by others. Previous research suggests that susceptibility to social influence may vary with age, but the mechanisms and whether people are more influenced by patience or impulsivity remain unknown. Here, using a delegated inter-temporal choice task and Bayesian computational models, we tested susceptibility to social influence in young (aged 18-36, N = 76) and older (aged 60-80, N = 78) adults. Participants completed a temporal discounting task and then learnt the preferences of two other people (one more impulsive and one more patient) before making their choices again. We used the signed Kullback-Leibler divergence to quantify the magnitude and direction of social influence. We found that, compared to young adults, older adults were relatively more susceptible to impulsive social influence. Factor analyses showed that older adults with higher self-reported levels of affective empathy and emotional motivation were particularly susceptible to impulsive influence. Importantly, older and young adults showed similar learning accuracy about others' preferences, and their baseline impulsivity did not differ. Together, these findings suggest highly affectively empathetic and emotionally motivated older adults may be at higher risk for impulsive decisions, due to their susceptibility to social influence.

A Cognitive-Behavioral Model of Apathy in Parkinson's Disease.

Apathy is recognized to be a common, disabling syndrome that occurs across a range of psychiatric and neurological conditions, including Parkinson's disease. It can have a significant impact on quality of life, both for people affected and those around them. Currently, there are no established, evidence-based treatments for this debilitating syndrome. Assessment and treatment have been complicated by overlaps with depression and anhedonia, as well as a lack of understanding of the underlying mechanisms. Emerging lines of evidence conceptualize apathy as a reduction of motivation associated with disordered effort-based decision-making and dysfunction of distinct neural circuitry between the basal ganglia and medial prefrontal cortex. Here, we introduce a novel cognitive-behavioral framework that can inform a clinician's conceptualization and treatment of apathy, using cognitive-behavioral therapy (CBT) techniques. We focus on people with Parkinson's disease in our model, but our approach is transdiagnostic and can be applied to other conditions. It considers both individual targets for therapy as well as maintenance and intervention at a systemic level. The generalizability and parsimony of the framework provides a structured assessment and formulation of apathy, while also allowing clinicians to remain sensitive to other neuropsychiatric symptoms that can occur alongside apathy, such as depression and anxiety.

Beta and theta oscillations track effort and previous reward in the human basal ganglia and prefrontal cortex during decision making.

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.

LGI1-antibody encephalitis: how to approach this highly treatable dementia mimic in memory and mental health services.

Leucine-rich glioma-inactivated 1-antibody-encephalitis is a treatable and potentially reversible cause of cognitive and psychiatric presentations, and may mimic cognitive decline, rapidly progressive dementia and complex psychosis in older patients. This aetiology is of immediate relevance given the alternative treatment pathway required, compared with other conditions presenting with cognitive deficits.

Feasibility of multiorgan risk prediction with routinely collected diagnostics: a prospective cohort study in the UK Biobank.

OBJECTIVES: Despite rising rates of multimorbidity, existing risk assessment tools are mostly limited to a single outcome of interest. This study tests the feasibility of producing multiple disease risk estimates with at least 70% discrimination (area under the receiver operating curve, AUROC) within the time and information constraints of the existing primary care health check framework. DESIGN: Observational prospective cohort study SETTING: UK Biobank. PARTICIPANTS: 228 240 adults from the UK population. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Myocardial infarction, atrial fibrillation, heart failure, stroke, all-cause dementia, chronic kidney disease, fatty liver disease, alcoholic liver disease, liver cirrhosis and liver failure. RESULTS: Using a set of predictors easily gathered at the standard primary care health check (such as the National Health Service Health Check), we demonstrate that it is feasible to simultaneously produce risk estimates for multiple disease outcomes with AUROC of 70% or greater. These predictors can be entered once into a single form and produce risk scores for stroke (AUROC 0.727, 95% CI 0.713 to 0.740), all-cause dementia (0.823, 95% CI 0.810 to 0.836), myocardial infarction (0.785, 95% CI 0.775 to 0.795), atrial fibrillation (0.777, 95% CI 0.768 to 0.785), heart failure (0.828, 95% CI 0.818 to 0.838), chronic kidney disease (0.774, 95% CI 0.765 to 0.783), fatty liver disease (0.766, 95% CI 0.753 to 0.779), alcoholic liver disease (0.864, 95% CI 0.835 to 0.894), liver cirrhosis (0.763, 95% CI 0.734 to 0.793) and liver failure (0.746, 95% CI 0.695 to 0.796). CONCLUSIONS: Easily collected diagnostics can be used to assess 10-year risk across multiple disease outcomes, without the need for specialist computing or invasive biomarkers. Such an approach could increase the utility of existing data and place multiorgan risk information at the fingertips of primary care providers, thus creating opportunities for longer-term multimorbidity prevention. Additional work is needed to validate whether these findings would hold in a larger, more representative cohort outside the UK Biobank.

Human ventromedial prefrontal cortex is necessary for prosocial motivation.

Ventromedial prefrontal cortex (vmPFC) is vital for decision-making. Functional neuroimaging links vmPFC to processing rewards and effort, while parallel work suggests vmPFC involvement in prosocial behaviour. However, the necessity of vmPFC for these functions is unknown. Patients with rare focal vmPFC lesions (n = 25), patients with lesions elsewhere (n = 15) and healthy controls (n = 40) chose between rest and exerting effort to earn rewards for themselves or another person. vmPFC damage decreased prosociality across behavioural and computational measures. vmPFC patients earned less, discounted rewards by effort more, and exerted less force when another person benefited, compared to both control groups. Voxel-based lesion mapping revealed dissociations between vmPFC subregions. While medial damage led to antisocial behaviour, lateral damage increased prosocial behaviour relative to patients with damage elsewhere. vmPFC patients also showed reduced effort sensitivity overall, but reward sensitivity was limited to specific subregions. These results reveal multiple causal contributions of vmPFC to prosocial behaviour, effort and reward.

The role of the human hippocampus in decision-making under uncertainty.

The role of the hippocampus in decision-making is beginning to be more understood. Because of its prospective and inferential functions, we hypothesized that it might be required specifically when decisions involve the evaluation of uncertain values. A group of individuals with autoimmune limbic encephalitis-a condition known to focally affect the hippocampus-were tested on how they evaluate reward against uncertainty compared to reward against another key attribute: physical effort. Across four experiments requiring participants to make trade-offs between reward, uncertainty and effort, patients with acute limbic encephalitis demonstrated blunted sensitivity to reward and effort whenever uncertainty was considered, despite demonstrating intact uncertainty sensitivity. By contrast, the valuation of these two attributes (reward and effort) was intact on uncertainty-free tasks. Reduced sensitivity to changes in reward under uncertainty correlated with the severity of hippocampal damage. Together, these findings provide evidence for a context-sensitive role of the hippocampus in value-based decision-making, apparent specifically under conditions of uncertainty.

Relationship of plasma biomarkers to digital cognitive tests in Alzheimer's disease.

INTRODUCTION: A major limitation in Alzheimer's disease (AD) research is the lack of the ability to measure cognitive performance at scale-robustly, remotely, and frequently. Currently, there are no established online digital platforms validated against plasma biomarkers of AD. METHODS: We used a novel web-based platform that assessed different cognitive functions in AD patients (N = 46) and elderly controls (N = 53) who were also evaluated for plasma biomarkers (amyloid beta 42/40 ratio, phosphorylated tau ([p-tau]181, glial fibrillary acidic protein, neurofilament light chain). Their cognitive performance was compared to a second, larger group of elderly controls (N = 352). RESULTS: Patients with AD were significantly impaired across all digital cognitive tests, with performance correlating with plasma biomarker levels, particularly p-tau181. The combination of p-tau181 and the single best-performing digital test achieved high accuracy in group classification. DISCUSSION: These findings show how online testing can now be deployed in patients with AD to measure cognitive function effectively and related to blood biomarkers of the disease. Highlights: This is the first study comparing online digital testing to plasma biomarkers.Alzheimer's disease patients and two independent cohorts of elderly controls were assessed.Cognitive performance correlated with plasma biomarkers, particularly phosphorylated tau (p-tau)181.Glial fibrillary acidic protein and neurofilament light chain, and less so the amyloid beta 42/40 ratio, were also associated with performance.The best cognitive metric performed at par to p-tau181 in group classification.