Estimating demand for potential disease-modifying therapies for Alzheimer's disease in the UK.

BACKGROUND: Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring. AIMS: To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK. METHOD: We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment. RESULTS: We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally. CONCLUSIONS: Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.

Cognition, hallucination severity and hallucination-specific insight in neurodegenerative disorders and eye disease.

Introduction: Hallucinations occur across neurodegenerative disorders, with increasing severity, poorer cognition and impaired hallucination-specific insight associated with worse outcomes and faster disease progression. It remains unclear how changes in cognition, temporal aspects of hallucinations, hallucination-specific insight and distress relate to each other.Methods: Extant samples of patients experiencing visual hallucinations were included in the analyses: Parkinson's Disease (n = 103), Parkinson's Disease Dementia (n = 41), Dementia with Lewy Bodies (n = 27) and Eye Disease (n = 113). We explored the relationship between factors of interest with Spearman's correlations and random-effect linear models.Results: Spearman's correlation analyses at the whole-group level showed that higher hallucination-specific insight was related to higher MMSE score (rs = 0.39, p < 0.001) and less severe hallucinations (rs = -0.28, p < .01). Linear mixed-models controlling for diagnostic group showed that insight was related to higher MMSE (p < .001), to hallucination severity (p = 0.003), and to VH duration (p = 0.04). Interestingly, insight was linked to the distress component but not the frequency component of severity. No significant relationship was found between MMSE and hallucination severity in these analyses.Conclusion: Our findings highlight the importance of hallucination-specific insight, distress and duration across groups. A better understanding of the role these factors play in VH may help with the development of future therapeutic interventions trans-diagnostically.

Octopaminergic neurons have multiple targets in Drosophila larval mushroom body calyx and can modulate behavioral odor discrimination.

Discrimination of sensory signals is essential for an organism to form and retrieve memories of relevance in a given behavioral context. Sensory representations are modified dynamically by changes in behavioral state, facilitating context-dependent selection of behavior, through signals carried by noradrenergic input in mammals, or octopamine (OA) in insects. To understand the circuit mechanisms of this signaling, we characterized the function of two OA neurons, sVUM1 neurons, that originate in the subesophageal zone (SEZ) and target the input region of the memory center, the mushroom body (MB) calyx, in larval Drosophila We found that sVUM1 neurons target multiple neurons, including olfactory projection neurons (PNs), the inhibitory neuron APL, and a pair of extrinsic output neurons, but relatively few mushroom body intrinsic neurons, Kenyon cells. PN terminals carried the OA receptor Oamb, a Drosophila α1-adrenergic receptor ortholog. Using an odor discrimination learning paradigm, we showed that optogenetic activation of OA neurons compromised discrimination of similar odors but not learning ability. Our results suggest that sVUM1 neurons modify odor representations via multiple extrinsic inputs at the sensory input area to the MB olfactory learning circuit.

Experiencing hallucinations in daily life: The role of metacognition.

BACKGROUND: Hallucinations have been linked to failures in metacognitive reflection suggesting an association between hallucinations and overestimation of performance, although the cross-sectional findings are inconsistent. This inconsistency may relate to the fluctuating hallucinatory experiences that are not captured in cross-sectional studies. Ecological Momentary Assessment (EMA) captures in-the-moment experiences over time so can identify causal relationships between variables such as the associations between metacognition and hallucinatory experience in daily life and overcome problems in cross-sectional designs. METHODS: Participants (N = 41) experiencing daily hallucinations completed baseline questionnaires and smartphone surveys 7 times per day for 14 days. They were prompted to identify a task they would complete in the next 4 h and to make metacognitive predictions around the likelihood of completing the task, the difficulty of the task, and how well they would complete it (standard of completion). RESULTS: 76 % finished the 14-days of assessment with an average of 42.2 % survey completion. Less accurate metacognition was associated with more hallucinations, but less accurate likelihood and standard of completion was associated with fewer hallucinations. Using a cross-lagged analysis, metacognitive predictions around the likelihood of completion (p < .001) and standard of completion (p = .01) predicted hallucination intensity at the following timepoint, and metacognitive predictions regarding likelihood of completion (p = .02) predicted hallucination control at the following timepoint. DISCUSSION: Interventions that aim to improve metacognitive ability in-the-moment may serve to reduce the intensity and increase the control of hallucinations.

Metacognition and psychosis-spectrum experiences: A study of objective and subjective measures.

BACKGROUND: Metacognition refers to appraising one's thoughts and behaviours. Deficits in metacognition are associated with psychosis-spectrum experiences, such as hallucinations and delusions, in both clinical and non-clinical populations. Assessments of metacognitive function and abilities in clinical populations often vary in administration duration, and subjectivity of scores. This study investigates associations between different measures of metacognition and their prediction of psychosis spectrum experiences using objective and self-report measures in a cross-sectional study of psychosis-spectrum disorder (PSD) participants and controls. METHOD: Twenty-three individuals with PSD and forty-four controls were recruited online and completed in-the-moment objective ratings of metacognitive accuracy (meta-Dots Task), and retrospective self-report of metacognitive self-reflection (Beck Cognitive Insight Scale) and abilities (Metacognition Self-Assessment Scale). RESULTS: There were group differences in self-reported metacognition, with PSD participants having lower scores of metacognitive ability, but no differences in self-reflectiveness or objective metacognitive accuracy. In the PSD group, only self-reported metacognitive ability was associated with and predicted distress about, and conviction in, delusional thoughts. CONCLUSIONS: The findings demonstrate group differences in some self-reported, but not objective, measures of metacognition, and highlight that prediction of PSD experiences depends on the metacognitive construct being measured, and the type of measurement used.

Cognitive and visual processing performance in Parkinson's disease patients with vs without visual hallucinations: A meta-analysis.

IMPORTANCE: Cognitive and visual impairments in Parkinson's Disease Psychosis (PDP) raise the question of whether a specific profile of impaired cognition and visual function is linked to vulnerability to visual hallucinations (VHs). Previous studies have limited sample sizes and only included a sub-sample of tests. This is the first meta-analysis quantifying visuo-cognitive impairments in PDP patients across a spectrum of tests and taking into account potential confounding factors such as levodopa medication, illness duration and general cognitive ability. OBJECTIVE: Compare visual processing and cognitive performance between PD patients with and without VHs (PDVH and PDnoVH). METHODS: Four databases (PubMed, PsychINFO, Scopus, WebOfScience) were searched for studies on visual and/or cognitive performance of PDnoVH and PDVH published up to 02/2020. For each task, means and SDs were extracted and standardized-mean-differences (SMDs) between-groups calculated. Effect-sizes (Hedges' g) were calculated for all comparisons and synthesized in random-effects meta-analyses with robust-variance-estimation (accounting for multiple correlated measures within each study per cognitive/visual domain). Publication bias was assessed with funnel plots and Egger intercept. RESULTS: N = 99 studies including 2508 PDVH patients (mean age 68.4 years) and 5318 PDnoVH (mean age 66.4 years) were included in the seven meta-analyses. PDVH patients performed worse than PDnoVH across all measures of cognition and visual processing, with the greatest between-group effect-sizes in executive functions, attention, episodic memory and visual processing. Study characteristics were not significantly associated with between-group differences in the domains investigated. Age-differences were significantly associated with performance differences in general cognition, working memory and executive functions. CONCLUSION: Models of PDVH need to incorporate a wider range of cognitive and processing domains than currently included. There is a need for studies disentangling the temporal relationship between cognitive/visual deficits and VHs as early identification of risk before the onset of VHs could mitigate later outcomes such as progression to dementia.

A Review of Multimodal Hallucinations: Categorization, Assessment, Theoretical Perspectives, and Clinical Recommendations.

Hallucinations can occur in different sensory modalities, both simultaneously and serially in time. They have typically been studied in clinical populations as phenomena occurring in a single sensory modality. Hallucinatory experiences occurring in multiple sensory systems-multimodal hallucinations (MMHs)-are more prevalent than previously thought and may have greater adverse impact than unimodal ones, but they remain relatively underresearched. Here, we review and discuss: (1) the definition and categorization of both serial and simultaneous MMHs, (2) available assessment tools and how they can be improved, and (3) the explanatory power that current hallucination theories have for MMHs. Overall, we suggest that current models need to be updated or developed to account for MMHs and to inform research into the underlying processes of such hallucinatory phenomena. We make recommendations for future research and for clinical practice, including the need for service user involvement and for better assessment tools that can reliably measure MMHs and distinguish them from other related phenomena.

Reinforcement learning as an intermediate phenotype in psychosis? Deficits sensitive to illness stage but not associated with polygenic risk of schizophrenia in the general population.

BACKGROUND: Schizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning. METHODS: We administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n = 29, F|M = 0.81), At Risk Mental State for psychosis (ARMS, n = 23, F|M = 0.35) and FEP (First-episode psychosis, n = 26, F|M = 0.18). Study 2 included healthy adolescents (n = 735, F|M = 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated. RESULTS: Patients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology. CONCLUSIONS: Reinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.