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Introduction : Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods : A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 ( C9orf72 ) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results : For the ALS group, the statistical model explained 38.8% of variance in ECAS total ( p  < 0.001), 59.4% of executive functions ( p  < 0.001), and 55% of behavioral symptoms ( p  < 0.001). For controls, it accounted for 52.8% of variance in ECAS total ( p  < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups ( p  < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls ( p  = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients ( p  = 0.009). Conclusion : This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.

Background and Objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy., Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 ( c9orf72 ), progranulin ( GRN ), or microtubule-associated protein tau ( MAPT ) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms., Results: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness., Discussion: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Studies exploring the brain correlates of behavioral symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioral symptoms. We analyzed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behavior Scale, and Neurobehavioral Rating Scale. We used a data-driven approach to identify the principal components underlying behavioral variability, then related the identified components to brain variability using a newly developed method fusing maps of grey matter volume and FDG metabolism. A component representing apathy, executive dysfunction, and emotional withdrawal was associated with atrophy in bilateral anterior insula and putamen, and with hypometabolism in the right prefrontal cortex. Another component representing the disinhibition versus depression/mutism continuum was associated with atrophy in the right striatum and ventromedial prefrontal cortex for disinhibition, and hypometabolism in the left fronto-opercular region and sensorimotor cortices for depression/mutism. A component representing psychosis was associated with hypometabolism in the prefrontal cortex and hypermetabolism in auditory and visual cortices. Behavioral symptoms in FTD are associated with atrophy and altered metabolism of specific brain regions, especially located in the frontal lobes, in a hierarchical way: apathy and disinhibition are mostly associated with grey matter atrophy, whereas psychotic symptoms are mostly associated with hyper-/hypo-metabolism., Competing Interests: Declarations. Ethics approval and patients consents statement: Written informed consent for the study, approved by the NINDS Institutional Review Board and in accordance with the Declaration of Helsinki, was obtained from a family member. Assent from the patient was always required in all circumstances. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Behavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. We applied a multilevel framework to identify subsyndromes (between-person factors) that represent clinically relevant profiles of BPSD and identify symptom clusters (within-person factors) that represent contextually driven daily symptom experiences., Methods: This study used an intensive longitudinal design in which 68 co-residing family caregivers to persons living with dementia were recruited to proxy report on their care recipient's daily symptom experiences of 23 different BPSD for eight consecutive days (n = 443 diaries). A multilevel exploratory/confirmatory factor analysis was used to account for nested data and separate within-person variances from between-level factor estimates., Results: Exploratory factor analysis identified a 4-between 3-within factor structure based on fit statistics and clinical interpretability., Discussion: This study offers major methodological and conceptual advancements for management of BPSD within Alzheimer's disease and related dementias by introducing two related but distinct concepts of subsyndromes and symptom clusters., Highlights: Because behavioral and psychological symptoms of dementia (BPSD) are dynamic temporal phenomenon, this introduces measurement error into aggregate group-level estimates when trying to create subsyndromes. We propose a multilevel analysis to provide a more valid and reliable estimation by separating out variance due to within-person daily fluctuations. Using a multilevel exploratory factor analysis with intensive longitudinal data, we identified distinct and meaningful groups of BPSD. The four factors at the between-person level represented subsyndromes that are based on how BPSD co-occurred among persons with Alzheimer's disease (AD). These subsyndromes are clinically relevant because they share features of established clinical phenomena and may have similar neurobiological etiologies. We also found three within-person factors representing distinct symptom clusters. They are based on how BPSD clustered together on a given day for an individual with AD and related dementias. These clusters may have shared environmental triggers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose of Review: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature., Findings: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives., Summary: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies., Methods: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal., Results: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training., Discussion: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data., Conclusions: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training., Competing Interests: Declarations Ethical approval None. Research involving human participants and/or animals This systematic review did not involve animal participants. All the included studies in this review follow ethical standards regardless to research involving human participants. Competing interest The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Introduction: Cumulative low-level blast exposure during military training may be a significant occupational hazard, increasing the risk of poor long-term outcomes in brain function. US Public Law 116-92 section 717 mandates that US Department of Defense agencies document the blast exposure of each Service member to help inform later disability and health care decisions. However, which empirical measures of training blast exposure, such as the number of incidents, peak overpressure, or impulse, best inform changes in the neurobehavioral symptoms reflecting brain health have not been established., Materials and Methods: This study was approved by the US Army Special Operations Command, the University of North Carolina at Chapel Hill, and the VA Puget Sound Health Care System. Using methods easily deployable across different organizational structures, this study sought to identify and measure candidate risk factors related to career occupational blast exposure predictive of changes in neurobehavioral symptom burden. Blast dosimetry-symptom relationships were first evaluated in mice and then tested in a military training environment. In mice, the righting time neurobehavioral response was measured after exposure to a repetitive low-level blast paradigm modeled after Special Operations training. In the military training environment, 23 trainees enrolled in a 6-week explosive breaching training course, 13 instructors, and 10 Service member controls without blast exposure participated in the study (46 total). All participants provided weekly Neurobehavioral Symptom Inventory (NSI) surveys. Peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service were analyzed by Bayesian analysis of regression modeling to determine their probability of influence on the post-training symptoms reported by participants., Results: We tested the hypothesis that cumulative measures of low-level blast exposure were predictive of changes in neurobehavioral symptoms. In mice, repetitive blast resulted in reduced righting times correlated with cumulative blast impulse. In Service members, peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service all showed strong evidence of influence on NSI scores after blast exposure. However, only models including baseline NSI scores and cumulative blast impulse provided significant predictive value following validation., Conclusions: These results indicate that measures of cumulative blast impulse may have utility in predicting changes in NSI scores. Such paired dosimetry-symptom measures are expected to be an important tool in safely guiding Service members' occupational exposure and optimizing force readiness and lethality., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs)., Methods: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis., Results: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform., Conclusions: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.

Background: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design : Randomized, parallel, multi-center, feasibility trial., Setting: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23., Participants: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control., Intervention: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables., Main Outcomes: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period., Conclusion: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.

Background: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit., Methods: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically., Results: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home., Conclusions: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial., (© 2024. The Author(s).)

This study examined daily occurrences of behavioral and psychological symptoms of dementia (BPSD) and whether caregivers' perceived distress towards BPSD varies throughout four phases of the day (i.e., morning, daytime, evening, and night). Family caregivers residing with relatives who were using adult day services (ADS) participated in an 8-day daily diary study (caregiver N = 173; caregiver-day N = 1,359). BPSD occurred most frequently in the evenings. ADS use, sleep disturbances, and dementia severity were significantly associated with BPSD occurrence for some phases of the day. Caregivers' distress towards BPSD occurrences increased throughout the day (i.e., most stressful at night). However, caregivers showed lower reactivity to BPSD at night on days when their relatives used ADS. Evidence of temporal patterns of BPSD in community-dwelling older adults and caregiver distress demonstrated the importance of ADS use for BPSD reactivity and identified potential target windows and associated contextual factors for individualized interventions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The seven tiered behavioural and psychological symptoms of dementia (BPSD) model of service delivery has been used by inpatient units. The classification of each tier is broadly defined and not always agreed upon by clinicians. The case study uses novel approach by combining the BPSD classification criteria with clinical presentation to identify the clinical characteristics of the case and match these characteristics against the BPSD classification. This process was enhanced by using case specific measures such as the Neuropsychiatric Inventory (NPI) and Cohen Mansfield Agitation Inventory (CMAI) scales and key clinical data., Case Presentation: A case study of 76 year old male diagnosed with mixed Alzheimer's and Vascular dementia. The clinical presentation of the symptomatology was deemed to be extreme, thus fitting into the seventh tier (Extreme) of the BPSD model of service delivery. The case is considered to fit into the Extreme BPSD category given the high levels of aggression, which were consistently reflected in high scores on NPI and CMAI, as well as long length of inpatient stay (over 3 years). The average number of Pro re nata (PRN) psychotropics medications per month was 56 and seclusion episodes of 6 times per month, with each episode lasting on average 132 min shows severity of behaviours. His level of aggression had resulted in environmental damage and staff injuries., Conclusion: We recommend patient clinical characteristics, relevant hospital data and specific measures should be used to develop consensus around defining and classifying cases into Extreme BPSD., (© 2024. Crown.)

Background: The term Behavioral and Psychological Symptoms of Dementia (BPSD) covers a group of phenomenologically and medically distinct symptoms that rarely occur in isolation. Their therapy represents a major unmet medical need across dementias of different types, including Alzheimer's disease. Understanding of the symptom occurrence and their clusterization can inform clinical drug development and use of existing and future BPSD treatments., Objective: The primary aim of the present study was to investigate the ability of a commonly used principal component analysis to identify BPSD patterns as assessed by Neuropsychiatric Inventory (NPI)., Methods: NPI scores from the Aging, Demographics, and Memory Study (ADAMS) were used to characterize reported occurrence of individual symptoms and their combinations. Based on this information, we have designed and conducted a simulation experiment to compare Principal Component analysis (PCA) and zero-inflated PCA (ZI PCA) by their ability to reveal true symptom associations., Results: Exploratory analysis of the ADAMS database revealed overlapping multivariate distributions of NPI symptom scores. Simulation experiments have indicated that PCA and ZI PCA cannot handle data with multiple overlapping patterns. Although the principal component analysis approach is commonly applied to NPI scores, it is at risk to reveal BPSD clusters that are a statistical phenomenon rather than symptom associations occurring in clinical practice., Conclusions: We recommend the thorough characterization of multivariate distributions before subjecting any dataset to Principal Component Analysis.

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this framework. The first steps in the management of behavioral symptoms in AD involve defining the target and investigating potential causes and/or aggravating factors. Once these factors are addressed, non-pharmacological approaches are preferred as first-line interventions. Following the optimization of anticholinesterase treatments, specific pharmacological approaches (e.g., antidepressants, antipsychotics) can be considered weighing potential side effects., Competing Interests: Ther is no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Neuropsychiatric symptoms are intrinsic to Progressive Supranuclear Palsy (PSP) and a spoonful of studies investigated their imaging correlates. Describe (I) the frequency and severity of neuropsychiatric symptoms in PSP and (II) their structural imaging correlates. Twenty-six PSP patients underwent Neuropsychiatric Inventory (NPI) and brain 3D T1-weighted MRI. Spearman's rho with Bonferroni correction was used to investigate correlations between NPI scores and volumes of gray matter regions. More than 80% of patients presented at least one behavioral symptom of any severity. The most frequent and severe were depression/dysphoria, apathy, and irritability/lability. Significant relationships were found between the severity of irritability and right pars opercularis volume (p < 0.001) as well as between the frequency of agitation/aggression and left lateral occipital volume (p < 0.001). Depression, apathy, and irritability are the most common neuropsychiatric symptoms in PSP. Moreover, we found a relationship between specific positive symptoms as irritability and agitation/aggression and greater volume of the right pars opercularis cortex and lower volume of the left occipital cortex, respectively, which deserve further investigations., (© 2023. The Author(s).)

About 10 million new cases of dementia develop worldwide each year, of which up to 70% are attributable to Alzheimer's disease (AD). In addition to the widely known symptoms of memory loss and cognitive impairment, AD patients frequently develop non-cognitive symptoms, referred to as behavioral and psychological symptoms of dementia (BPSDs). Sleep disorders are often associated with AD, but mood alterations, notably depression and apathy, comprise the most frequent class of BPSDs. BPSDs negatively affect the lives of AD patients and their caregivers, and have a significant impact on public health systems and the economy. Because treatments currently available for AD are not disease-modifying and mainly aim to ameliorate some of the cognitive symptoms, elucidating the mechanisms underlying mood alterations and other BPSDs in AD may reveal novel avenues for progress in AD therapy. Purinergic signaling is implicated in the pathophysiology of several central nervous system (CNS) disorders, such as AD, depression and sleep disorders. Here, we review recent findings indicating that purinergic receptors, mainly the A 1 , A 2A , and P2X7 subtypes, are associated with the development/progression of AD. Current evidence suggests that targeting purinergic signaling may represent a promising therapeutic approach in AD and related conditions. This article is part of the Special Issue on "Purinergic Signaling: 50 years"., 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 © 2022. Published by Elsevier Ltd.)

Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer's disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD., Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia., Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n = 40) that received three times a week one session per day of 20 minutes in the NSC and a control group (n = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis., Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score -18.87±5.56 versus -1.74±0.67, p = 0.004), agitation (mean change score -2.32±2.02 versus -0.78±1.44, p = 0.003) and irritability (mean change score -3.35±2.93 versus -1.42±1.31, p = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score -9.67±7.67 versus -7.66±6.08, p = 0.003)., Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia.

Behavioral and psychological symptoms of dementia (BPSD) may occur in most patients with dementia. Symptoms such as agitation, aggression, and psychosis often lead to higher rates of hospitalization, morbidity, and mortality. Despite the prevalence of BPSD, safe and effective treatment options are limited. This often leads to off-label prescribing and trends toward polypharmacy. Notwithstanding modest efficacy in BPSD, antipsychotics seem to be one of the most commonly prescribed medications in its treatment. Polypharmacy with antipsychotics is particularly troublesome due to the increased risk of potentially lethal adverse effects. As such, their use should be judiciously monitored with the goal of gradual dose reduction., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hospitalized persons living with dementia (PLWD) often experience behavioral symptoms that challenge medical care., Objective: This study aimed to identify clinical practices and outcomes associated with behavioral symptoms in hospitalized PLWD., Design: A retrospective cross-sectional study., Settings and Participants: The study included PLWD (65+) admitted to one of severe health system hospitals in 2019., Intervention: Behavioral symptoms were defined as the presence of (1) a psychoactive medication for behavioral symptoms; (2) an order for physical restraints or constant observation; and/or (3) physician documentation of delirium, encephalopathy, or behavioral symptoms., Main Outcome and Measures: Associations between behavioral symptoms and patient characteristics and hospital practices (e.g., bladder catheter) were examined. Multivariable logistic/linear regression was used to evaluate the association between behavioral symptoms and clinical outcomes (e.g., mortality)., Results: Of hospitalized PLWD (N = 8637), the average age was 84.5 years (IQR = 79-90), 61.7% were female, 60.1% were white, and 9.4% (n = 833) were Hispanic. Behavioral symptoms were identified in 40.6% (N = 3606) of individuals. Behavioral symptoms were significantly associated with male gender (40.3% vs. 36.9%, p = .001), white race (62.7% vs. 58.3%, p < .001), and residence in a facility prior to admission (26.6% vs. 23.7%, p < .001). Regarding hospital practices, indwelling bladder catheters (11.2% vs. 6.0%, p < .001) and dietary restriction (41.9% vs. 33.8%, p < .001) were associated with behavioral symptoms. In multivariable models, behavioral symptoms were associated with increased hospital mortality (odds ratio [OR]: 1.90, CI95%: 1.57-2.29), length of stay (parameter estimate: 2.10, p < .001), 30-day readmissions (OR: 1.14, CI95%: 1.014-1.289), and decreased discharge home (OR: 0.59, CI95%: 0.53-0.65, p < .001)., Conclusions: Given the association between behavioral symptoms and poor clinical outcomes, there is an urgent need to improve the provision of care for hospitalized PLWD., (© 2022 Society of Hospital Medicine.)

Purpose of Review: To provide a comprehensive overview on the evaluation and management of behavioral and psychological symptoms of dementia (BPSD) using evidence from literature., Recent Findings: Evidence indicates efficacy for some non-pharmacological techniques including education of caregivers and cognitive stimulation therapy and pharmacological agents like antidepressant and antipsychotics for the management of BPSD. The use of antipsychotics has generated controversy due to the recognition of their serious adverse effect profile including the risk of cerebrovascular adverse events and death. BPSD is associated with worsening of cognition and function among individuals with dementia, greater caregiver burden, more frequent institutionalization, overall poorer quality of life, and greater cost of caring for these individuals. Future management strategies for BPSD should include the use of technology for the provision of non-pharmacological interventions and the judicious use of cannabinoids and interventional procedures like ECT for the management of refractory symptoms., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dravet Syndrome (DS) is caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which results in febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved for the management of seizures in DS patients, but it appears to be also active against associated comorbidities. In this new study, we have investigated β-caryophyllene (BCP), a cannabinoid with terpene structure that appears to also have a broad-spectrum profile, as a useful therapy against both seizuring activity and progression of associated comorbidities. This has been studied in heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the Central Nervous System (Syn-Cre/Scn1a WT/A1783V ), using two experimental approaches. In the first approach, an acute treatment with BCP was effective against seizuring activity induced by pentylenetetrazole (PTZ) in wildtype (Scn1a WT/WT ) and also in Syn-Cre/Scn1a WT/A1783V mice, with these last animals having a greater susceptibility to PTZ. Such benefits were paralleled by a BCP-induced reduction in PTZ-induced reactive astrogliosis (labelled with GFAP) and microgliosis (labelled with Iba-1) in the prefrontal cortex and the hippocampal dentate gyrus, which were visible in both wildtype (Scn1a WT/WT ) and Syn-Cre/Scn1a WT/A1783V mice. In the second approach, both genotypes were treated repeatedly with BCP to investigate its effects on several DS comorbidities. Thus, BCP corrected important behavioural abnormalities of Syn-Cre/Scn1a WT/A1783V mice (e.g. delayed appearance of hindlimb grasp reflex, induction of clasping response, motor hyperactivity, altered social interaction and memory impairment), attenuated weight loss, and slightly delayed premature mortality. Again, these benefits were paralleled by a BCP-induced reduction in reactive astrogliosis and microgliosis in the prefrontal cortex and the hippocampal dentate gyrus typical of Syn-Cre/Scn1a WT/A1783V mice. In conclusion, BCP was active in Syn-Cre/Scn1a WT/A1783V mice against seizuring activity (acute treatment) and against several comorbidities (repeated treatment), in both cases in association with its capability to reduce glial reactivity in areas related to these behavioural abnormalities. This situates BCP in a promising position for further preclinical evaluation towards a close translation to DS patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cerebral malaria is one of the most severe complications attributed to protozoal infection by Plasmodium falciparum, gaining prominence in children mortality rates in endemic areas. This condition has a complex pathogenesis associated with behavioral, cognitive and motor sequels in humans and current antimalarial therapies have shown little effect in those aspects. Natural products with antioxidant and anti-inflammatory properties have become a valuable alternative therapeutic option in the treatment of distinct conditions. In this context, this study investigated the neuroprotective effect of Euterpe oleracea (açai) enriched diet during the development of experimental cerebral malaria induced by the inoculation of Swiss albino mice with Plasmodium berghei ANKA strain., Methods: After Plasmodium infection, animals were maintained on a feeding with Euterpe oleracea enriched ration and parameters such as survival curve, parasitemia and body weight were routinely monitored. The present study has also evaluated the effect of açai-enriched diet on the blood-brain barrier leakage, histological alterations and neurocognitive impairments in mice developing cerebral malaria., Results: Our results demonstrate that between 7th-19th day post infection the survival rate of the group treated with açai enriched ration was higher when compared with Plasmodium-infected mice in which 100% of mice died until the 11th days post-infection, demonstrating that açai diet has a protective effect on the survival of infected treated animals. The same was observed in the brain vascular extravasation, where Evans blue dye assays showed significantly less dye extravasation in the brains of Plasmodium-infected mice treated with açai enriched ration, demonstrating more preserved blood-brain barrier integrity. Açai-enriched diet also attenuate the histopathological alterations elicited by Plasmodium berghei infection. We also showed a decrease of the neurological impairments arising from the exposure of cerebral parenchyma in the group treated with açai diet, ameliorating motor and neuropsychiatric changes, analyzed through the SHIRPA protocol., Conclusion: With these results, we conclude that the treatment with açai enriched ration decreased the mortality of infected animals, as well as protected the blood-brain barrier and the neurocognitive deficits in Plasmodium-infected animals., (© 2022. The Author(s).)

Background: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden., Objective: To characterize BPSD in Alzheimer's disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities., Methods: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs., Results: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD., Conclusion: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD.24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration.In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. Correlations were small to medium.

Background: The Frontal Behavioral Inventory (FBI) is a questionnaire designed to quantify behavioral changes in frontotemporal dementia (FTD). Literature showed heterogeneous FBI profiles in FTD versus Alzheimer's disease (AD) with variable occurrence of positive and negative symptoms., Objective: In this study, we constructed a short FBI version (i.e., mini-FBI) with the aim to provide clinicians with a brief tool for the identification of early behavioral changes in behavioral variant of FTD (bvFTD), also facilitating the differential diagnosis with AD., Methods: 40 bvFTD and 33 AD patients were enrolled. FBI items were selected based on internal consistency and exploratory factor analysis. Convergent validity of mini-FBI was also assessed. A behavioral index (i.e., B-index) representing the balance between positive and negative mini-FBI symptoms was computed in order to analyze its distribution in bvFTD through a cluster analysis and to compare performance among patient groups., Results: The final version of the mini-FBI included 12 items, showing a significant convergent validity with the Neuropsychiatric Inventory scores (rp = 0.61, p &lt; 0.001). Cluster analysis split patients in four clusters. bvFTD were included in three different clusters characterized by prevalent positive symptoms, both positive and negative symptoms, or prevalent negative behavioral alterations, similar to a subset of AD patients. A fourth cluster included only AD patients showing no positive symptoms., Conclusion: The mini-FBI is a valuable easily administrable questionnaire able to early identify symptoms effectively contributing to the bvFTD behavioral syndrome, aiding clinician in diagnosis and management.

This study aims to identify neuropsychiatric manifestations in neurological Wilson disease (NWD), and their correlation with MRI changes and glutamate excitotoxicity. Forty-three consecutive patients with NWD from a tertiary care teaching hospital were evaluated prospectively who fulfilled the inclusion criteria. The neuropsychiatric evaluation was done using Neuropsychiatric Inventory (NPI) battery that assesses 12 domains including delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor activity, appetite change, and abnormal nighttime behavior. Cranial MRI was done using a 3 T machine, and locations of signal changes were noted including the total number of MRI lesions. Serum glutamate level was measured by a fluorescence microplate reader. Abnormal NPI in various domains and total NPI scores were correlated with MRI lesions, serum and urinary copper, and glutamate level. The median age of the patients was 16 years. Forty-one (48.8%) patients had cognitive impairment and 37 (86%) had movement disorder. Neurobehavioral abnormality was detected in all-commonest being agitation (90.7%) followed by appetite change (81.4%), elation (74.4%), irritability (69.8%), anxiety (67.4%), depression (65.1%), apathy (44.2%), night time abnormal behavior (32.6%), aberrant motor behavior (20.9%), delusions (16.3%), and hallucination (18.6%). The thalamic lesion was associated with depression, globus pallidus with depression and anxiety, caudate with anxiety and agitation, brainstem with irritability, and frontal cortex with apathy. Serum glutamate level was higher in NWD. NPI sum score correlated with MRI load and glutamate level. Varying severity of neurobehavioral abnormalities are common in the patients with NWD and correlate with the location of MRI lesion and glutamate level., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Potential precipitating factors for the recent onset of altered mental status (AMS) include primary central nervous system insults, systemic infections, metabolic disturbances, toxin exposure, medications, chronic systemic diseases, and psychiatric conditions. Delirium is also an important manifestation of AMS, especially in older people who are hospitalized. Clinicians should identify and treat reversible causes of the AMS, some of which require urgent intervention to minimize morbidity and mortality. A history and physical examination guide diagnostic testing. Laboratory testing, chest radiography, and electrocardiography help diagnose infections, metabolic disturbances, toxins, and systemic conditions. Neuroimaging with computed tomography or magnetic resonance imaging should be performed when the initial evaluation does not identify a cause or raises concern for intracranial pathology. Lumbar puncture and electroencephalography are also important diagnostic tests in the evaluation of AMS. Patients at increased risk of AMS benefit from preventive measures. The underlying etiology determines the definitive treatment. When intervention is needed to control patient behaviors that threaten themselves or others, nonpharmacologic interventions are preferred to medications. Physical restraints should rarely be used and only for the shortest time possible. Medications should be used only when nonpharmacologic treatments are ineffective.

Objectives: Cognitive Stimulation Therapy (CST) is one of the most popular evidence-based interventions for people with dementia. The aim of the present study was to assess the effectiveness in the short- and long-term (on completing the treatment and 3 months later) of an Italian adaptation of the CST protocol (CST-IT)., Method: Older adults with mild-to-moderate dementia at 16 residential care homes were randomly assigned to a CST-IT group (N = 123) or an active control group (N = 102). The following domains were examined for potential benefits: general cognitive functioning (Mini-Mental State Examination [MMSE] and the Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog]), language (Narrative Language Test), mood and behavior (Cornell scale and Neuropsychiatric Inventory), everyday life functioning (Disability Assessment for Dementia), and quality of life (Quality of Life-Alzheimer's Disease scale)., Results: At both the short- and long-term assessments, the CST-IT group's MMSE scores remained stable, while the control group's scores decreased slightly from pretest to posttest and at follow-up. The CST-IT group also had short-term benefits in other cognitive measures (ADAS-Cog and Narrative Language Test) and mood and behavior measures, which were generally maintained at follow-up. No other differences were observed., Discussion: The effectiveness of CST in sustaining cognitive and emotional functioning, and counteracting the progression of behavioral/neuropsychiatric symptoms in people with dementia was confirmed, and a long-term benefit was demonstrated. CST is a promising option for the treatment of people with dementia in clinical practice., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Past research has found a relationship between the apolipoprotein E (APOE) e4 allele and worse neurobehavioral functioning following mild traumatic brain injury (MTBI) in civilian populations. The purpose of this study was to examine this relationship in service members and veterans (SMVs) following MTBI. Participants were 151 SMVs (103 uncomplicated MTBI; 48 Injured Controls [IC]) prospectively enrolled in the DVBIC-TBICoE 15-Year Longitudinal TBI Study. Participants completed a battery of self-reported neurobehavioral symptom measures on average 76.2 months post-injury (SD = 31.8). APOE genotyping was undertaken using non-fasting blood samples. Participants were classified into four subgroups based on injury (MTBI vs. IC) and APOE e4 allele status (e4 present/absent). In the IC group, there were no significant differences across APOE e4 status subgroups for all measures. In the MTBI group, participants with the APOE e4 allele had significantly worse scores on measures of depression, pain, anxiety, grief, positive well-being, social participation, and resilience compared to those without the e4 allele (d = .44 to d = .69). When comparing the number of 'clinically elevated' neurobehavioral measures simultaneously, the MTBI/e4 present subgroup consistently had a higher number of elevated measures compared to the MTBI/e4 absent, IC/e4 present, and IC/e4 absent subgroups. The APOE e4 allele was associated with poorer neurobehavioral outcome in SMVs in the chronic phase of recovery following MTBI. APOE e4 could be incorporated into screening tools to predict SMVs at risk for poor long-term neurobehavioral outcome in an effort to provide early intervention to improve long-term clinical outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study aimed to clarify the neuropsychiatric symptoms of right-sided predominant semantic dementia (SD-R) by comparing them with those of behavioral variant frontotemporal dementia (bvFTD), left-sided predominant SD (SD-L), and Alzheimer's disease (AD). This study also aimed to identify clinical factors related to caregiver burden for bvFTD, SD-R, and SD-L., Methods: The neuropsychiatric symptoms of 28 patients with bvFTD, 14 patients with SD-R, 24 patients with SD-L, and 43 patients with AD were evaluated using the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Dementia severity was assessed using the Clinical Dementia Rating. Activities of daily living were assessed using the Lawton Instrument Activities of Daily Living (IADL) scale and the Physical Self-Maintenance Scale. We compared the NPI and SRI scores among the four groups using the Kruskal-Wallis test. In addition, clinical factors related to caregiver burden, represented by the Japanese version of the Zarit Burden Interview (J-ZBI), were analyzed using multiple regression analysis in the bvFTD, SD-R, and SD-L groups., Results: The NPI total score and the NPI subscale scores of apathy and disinhibition were significantly higher in the bvFTD group than in the SD-L and AD groups. The SD-R group scores were closer to those of the bvFTD group than the SD-L group. The SRI total score and SRI subscale scores for eating and cooking and speaking were significantly higher in the bvFTD, SD-R, and SD-L groups than in the AD group. The NPI total score was significantly associated with the J-ZBI score in the bvFTD group. The NPI total score and Lawton IADL scale score were independently associated with the J-ZBI score in the SD-R group. Furthermore, the NPI total score and MMSE score were independently associated with the J-ZBI score in the SD-L group., Conclusions: SD-R seemed to be a similar condition to bvFTD rather than SD-L regarding behavioral symptoms. Our results suggest that each frontotemporal dementia subgroup requires different approaches to reduce the caregiver burden., (© 2021. The Author(s).)

Chronic heart failure (HF) is a serious disorder that afflicts more than 26 million patients worldwide. HF is comorbid with depression, anxiety and memory deficits that have serious implications for quality of life and self-care in patients who have HF. Still, there are few studies that have assessed the effects of severely reduced ejection fraction (≤40 %) on cognition in non-human animal models. Moreover, limited information is available regarding the effects of HF on genetic markers of synaptic plasticity in brain areas critical for memory and mood regulation. We induced HF in male rats and tested mood and anxiety (sucrose preference and elevated plus maze) and memory (spontaneous alternation and inhibitory avoidance) and measured the simultaneous expression of 84 synaptic plasticity-associated genes in dorsal (DH) and ventral hippocampus (VH), basolateral (BLA) and central amygdala (CeA) and prefrontal cortex (PFC). We also included the hypothalamic paraventricular nucleus (PVN), which is implicated in neurohumoral activation in HF. Our results show that rats with severely reduced ejection fraction recapitulate behavioral symptoms seen in patients with chronic HF including, increased anxiety and impaired memory in both tasks. HF also downregulated several synaptic-plasticity genes in PFC and PVN, moderate decreases in DH and CeA and minimal effects in BLA and VH. Collectively, these findings identify candidate brain areas and molecular mechanisms underlying HF-induced disturbances in mood and memory., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Background: Behavioural disturbances such as agitation are common following traumatic brain injury and can interfere with treatments, cause self-harm and delay rehabilitation. As there is a lack of evidence on the optimal approach to manage agitation in recovering TBI patients, various pharmacological agents are used including antipsychotics, anticonvulsants and sedative agents. Among sedatives, the safety and efficacy of dexmedetomidine to control agitation in traumatic brain injury patients is not well documented., Objective: To describe the safety, use and efficacy of dexmedetomidine for the management of agitation following traumatic brain injury in the intensive care unit., Methods: Medical records of all patients admitted to the intensive care unit of the Hôpital Sacré-Coeur de Montréal for a traumatic brain injury who received dexmedetomidine for agitation between 1 January 2017 and 31 December 2017 were reviewed. Patients who received dexmedetomidine for indications other than agitation were excluded. Data on dexmedetomidine prescription practices and safety were extracted. Frequency of agitation and concomitant psychoactive medication use was explored over a period starting two days prior to the initiation of dexmedetomidine to six days after or discontinuation, whichever came first., Results: We identified 41 patients in whom dexmedetomidine was initiated. Dexmedetomidine was started on median ICU day 3 (25 th -75 th percentiles: 2-7) and had a median treatment duration of 3 days (25 th -75 th percentiles: 3-6) and a mean average rate of 0.62 mcg/kg/h (SD 0.25). Although hypotension (76%) and bradycardia (54%) were common, only one patient required intervention. The proportion of patients with at least one episode of agitation decreased from 100% on day 0, to 88%, 69% and 63% on days 1, 2 and 3 of dexmedetomidine, respectively. The decrease was statistically significant difference between days 0 and 2 as well as between days 0 and 3. Concomitant use of propofol and benzodiazepines also decreased over the course of dexmedetomidine treatment., Conclusion: Dexmedetomidine use was safe and associated with a reduction in agitation in traumatic brain injury patients in the 96 hours following its initiation., (© 2021 John Wiley & Sons Ltd.)

Introduction: Impulse control disorders (ICDs) have been described as a side effect of dopamine agonists (DAs) in neurological as well as endocrine conditions. Few studies have evaluated the neuropsychological effect of DAs in hyperprolactinemic patients, and these have reported a relationship between DAs and ICDs. Our objective was to screen for ICD symptoms in individuals with DA-treated endocrine conditions., Materials and Methods: A cross-sectional analysis was conducted on 132 patients with pituitary disorders treated with DAs (DA exposed), as well as 58 patients with pituitary disorders and no history of DA exposure (non-DA exposed). Participants responded to the full version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP)., Results: Compared with the non-DA-exposed group, a higher prevalence of DA-exposed patients tested positive for symptoms of any ICD or related behavior (52% vs. 31%, p < 0.01), any ICD (46% vs. 24%, p < 0.01), any related behavior (31% vs. 17%, p < 0.05), compulsive sexual behavior (27% vs. 14%, p < 0.04), and punding (20% vs. 7%, p < 0.02) by QUIP. On univariate analysis, DA treatment was associated with a two- to threefold increased risk of any ICD or related behavior [odds ratio (OR) 2.43] and any ICD (OR 2.70). In a multivariate analysis, independent risk factors for any ICD or related behavior were DA use (adjusted OR 2.22) and age (adjusted OR 6.76). Male gender was predictive of the risk of hypersexuality (adjusted OR 3.82)., Discussion: Despite the QUIP limitations, a clear sign of increased risk of ICDs emerges in individuals with DA-treated pituitary disorders. Our data contribute to the growing evidence of DA-induced ICDs in endocrine conditions., (© 2020. The Author(s).)

Introduction: A polymorphism in the type 2 deiodinase (Thr92Ala-DIO2) gene has been associated with behavioral and cognitive dysfunction as well as neurodegeneration and oxidative stress in the central nervous system., Objective: To test whether the minor allele (Ala92) frequency (MAF) is increased in children in the autism spectrum disorder (ASD), and whether carriers of the minor allele exhibit more severe symptoms and/or worse adaptive behavior., Study Design: ASD children were evaluated at baseline and yearly throughout the study by psychologists using the following tools: autism behavior checklist, Vineland Adaptative Behaviour Scales II, non-verbal intelligence test SON-R 2 1/2 -7, SON-R 6-40, Weschler scale for intelligence, and autism treatment evaluation checklist., Settings: Academic outpatient mental health facility in Sao Paulo, Brazil., Participants: ASD boys and girls younger than 18 years of age. 132 consecutive ASD children, mostly boys (~ 80%); ~ 50% was classified as verbal. Exclusion criteria were coexistence of sensory and/or physical impairment, or any associated genetic syndromes., Results: Median follow-up was for an uninterrupted period of 937 days (139-1375 days), which did not vary significantly among the genotypes. The MAF was 47% in ASD patients vs. 51% in a local reference population with similar ethnic background; the clinical severity and progression were not affected by the minor allele. Carriers of the minor allele exhibited higher adaptive behavior in the domains "daily living skills" and "communication", which correlated positively with the dose of the minor allele., Conclusion: The MAF is not different in ASD children, but carriers of the Thr92Ala-DIO2 polymorphism exhibited higher adaptive behavior., (© 2021. Italian Society of Endocrinology (SIE).)

Background: Prader-Willi syndrome (PWS) is a rare genetic disorder that in many cases is associated with mental health disorders, in addition to characteristic symptoms such as hyperphagia. The current Sars-CoV-2 coronavirus pandemic has led to massive restrictions in health care and social life worldwide. People with PWS represent a particularly vulnerable population group to these restrictions, with unknown impact on their mental health., Methods: We conducted an online questionnaire to assess the impact of the restrictions associated with the COVID-19 pandemic on the mental health of people with PWS., Results: One hundred and eight caregivers completed the survey about individuals with PWS. Individuals with PWS > 6 years (n = 89) were included for evaluation with regard to psychopathological change. Respondents frequently reported an increase in psychopathological symptoms associated with PWS during the lockdown, with 51.7% reporting increased temper outbursts, 43.8% showing signs of sadness, 38.2% being anxious, 55.0% more irritable, and 39.3% showing more food seeking behaviour. Adjusted for the type of accommodation food seeking behaviour and irritability is increased to a significantly lesser extent in people with PWS accommodated in specialised care facilities compared with those living in their family home. No significant difference could be found between the sexes., Conclusion: The COVID-19 pandemic has had a significant effect on the mental health of individuals with PWS, evidenced by an increase in behaviours associated with PWS, including temper outbursts, food-seeking, and irritability, which again underlines their need for specialised care. Individuals living with their families were particularly vulnerable, indicating that they and their families are in special need of support., (© 2021 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.)

A cross-sectional study was conducted to evaluate patterns of gray matter changes in cognitively normal elderly adults with mild behavioral impairment (MBI). Sixteen MBI patients and 18 healthy controls were selected. All the participants underwent a neuropsychological assessment battery, including the Mini-mental State Examination (MMSE), Geriatric Depression Scale (GDS), Self-rating Anxiety Scale (SAS), and Chinese version of the mild behavioral impairment-checklist scale (MBI-C), and magnetic resonance imaging (MRI) scans. Imaging data was analyzed based on voxel-based morphometry (VBM). There was no significant difference in age, gender, MMSE score, total intracranial volume, white matter hyperdensity, gray matter volume, white matter volume between the two groups ( p > 0.05). MBI group had shorter education years and higher MBI-C score, GDS and SAS scores than the normal control group ( p < 0.05). For neuroimaging analysis, compared to the normal control group, the MBI group showed decreased volume in the left brainstem, right temporal transverse gyrus, left superior temporal gyrus, left inferior temporal gyrus, left middle temporal gyrus, right occipital pole, right thalamus, left precentral gyrus and left middle frontal gyrus(uncorrected p < 0.001). The grey matter regions correlated with the MBI-C score included the left postcentral gyrus, right exterior cerebellum, and left superior frontal gyrus. This suggests a link between MBI and decreased grey matter volume in cognitively normal elderly adults. Atrophy in the left frontal cortex and right thalamus in MBI patients is in line with frontal-subcortical circuit deficits, which have been linked to neuropsychiatric symptoms (NPS) in dementia. These initial results imply that MBI might be an early harbinger for subsequent cognitive decline and dementia., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: To test for cerebellar involvement in motor and nonmotor impairments in Parkinson disease (PD) and to determine patterns of metabolic correlations with supratentorial brain structures, we correlated clinical motor, cognitive, and psychiatric scales with cerebellar metabolism., Methods: We included 90 patients with PD. Motor, cognitive, and psychiatric domains were assessed, and resting-state 18 FDG-PET metabolic imaging was performed. The motor, cognitive, and psychiatric scores were entered separately into a principal component analysis. We looked for correlations between these 3 principal components and cerebellar metabolism. Furthermore, we extracted the mean glucose metabolism value for each significant cerebellar cluster and looked for patterns of cerebrum-cerebellum metabolic correlations., Results: Severity of impairment was correlated with increased metabolism in the anterior lobes and vermis (motor domain); the right crus I, crus II, and declive (cognitive domain); and the right crus I and crus II (psychiatric domain). No results survived multiple testing corrections regarding the psychiatric domain. Moreover, we found distributed and overlapping, but not identical, patterns of metabolic correlations for motor and cognitive domains. Specific supratentorial structures (cortical structures, basal ganglia, and thalamus) were strongly correlated with each of the cerebellar clusters., Conclusions: These results confirm the role of the cerebellum in nonmotor domains of PD, with differential but overlapping patterns of metabolic correlations suggesting the involvement of cerebello-thalamo-striatal-cortical loops., (© 2021 American Academy of Neurology.)

Neuropsychiatric symptoms (NPSs) are common in patients with Alzheimer's disease (AD) and are associated with accelerated cognitive impairment and earlier deaths. This review aims to explore the neural pathogenesis of NPSs in AD and its association with the progression of AD. We first provide a literature overview on the onset times of NPSs. Different NPSs occur in different disease stages of AD, but most symptoms appear in the preclinical AD or mild cognitive impairment stage and develop progressively. Next, we describe symptom-general and -specific patterns of brain lesions. Generally, the anterior cingulate cortex is a commonly damaged region across all symptoms, and the prefrontal cortex, especially the orbitofrontal cortex, is also a critical region associated with most NPSs. In contrast, the anterior cingulate-subcortical circuit is specifically related to apathy in AD, the frontal-limbic circuit is related to depression, and the amygdala circuit is related to anxiety. Finally, we elucidate the associations between the NPSs and AD by combining the onset time with the neural basis of NPSs.

Introduction: Faced with surging infections and considering that 80% of cases were mild and moderate, the city government transformed stadiums and exhibition centers into the Fangcang shelter hospitals in Wuhan. The aims of this study were to evaluate mental health outcomes among patients with COVID-19 treated in the Fangcang shelter hospitals and analyze potential risk factors associated with these symptoms, including PTSS, symptoms of anxiety, depression, insomnia, and perceived stress., Method: This cross-sectional study used an online survey to assess mental health problems of 461 confirmed COVID-19 patients in a Jianghan Fangcang shelter from February 15 to 22, 2020. A multivariable logistic regression analysis was performed to explore potential risk factors., Results: Overall, 25.2%, 50.1%, 54.4%, 10.2%, and 39.7% of all patients reported symptoms of posttraumatic stress, anxiety, depression, insomnia, and perceived stress, respectively. Multivariable logistic regression analysis showed that female sex was associated with all investigated outcomes except insomnia. Patients with lower education level were more likely to endorse anxiety, depression, and higher perceived stress, while patients' family members with other diseases were more likely to endorse severe insomnia. Patients with illness onset to admission less than 7 days were associated with higher perceived stress., Discussion: In this survey study, patients reported high rates of symptoms of posttraumatic stress, anxiety, depression, insomnia, and perceived stress. Combining with the special environment of the shelter hospitals and patient's psychological needs, the health care workers should give more effective interventions to relieve the patients' stress and improve their mental symptoms., (© 2020 John Wiley & Sons Australia, Ltd.)

Objective: To provide a brief description of COVID-19-related issues presented by callers to a tele-counseling helpline in Bangladesh., Method: Counselors who receive calls write brief descriptions of each call. These descriptions were coded and analyzed., Results: Eighty-six percent of callers displayed anxiety and/or sleeplessness; these callers also displayed a range of issues including family/interpersonal problems, financial difficulties, physical health concerns, mental illness, and difficulty managing quarantine., Conclusion: These findings indicate the mental health challenges faced in Bangladesh due to lockdown and can inform future interventions., (© 2020 John Wiley & Sons Australia, Ltd.)

Aim: Behavioral and psychological symptoms of dementia (BPSD) are common in patients with moderate-severe dementia and have negative impacts on both patients and caregivers. There is a lack of a tool for caregivers to monitor patients' BPSD by themselves. This study aimed to develop and validate a mobile application for caregivers to use in monitoring BPSD., Methods: A total of 104 pairs of patients with moderate-severe dementia and their caregivers completed the study. The Neuropsychiatric Inventory (NPI) was modified and digitally transformed to a caregiver-rating mobile application to quantify nine domains of BPSD for their frequency and impact on the emotion of the caregivers. Data collected from the application were compared with the paper-and-pencil NPI for prevalence, concurrent validity (Spearman's rho) and internal consistency (Cronbach's alpha)., Results: The application was able to detect 93% of BPSD compared with the NPI. Concurrent validity was good-very good when compared with the Frequency × Severity score (ρ = 0.77, P < 0.001) and the burden score (ρ = 0.85, P < 0.001) from the NPI. Levels of internal consistency were acceptable for both frequency (α = 0.73) and impact (α = 0.79) scores. 80% of the caregivers reported that the application was "very likely to be helpful in caregiving"., Conclusions: The mobile application for monitoring BPSD in patients with moderate-severe dementia had an excellent sensitivity, and good-very good validity and consistency. The caregivers had a positive perception of the application as an aid in caregiving. Geriatr Gerontol Int 2021; 21: 472-477., (© 2021 Japan Geriatrics Society.)

Objective: We describe the clinical features and outcomes of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in infants and toddlers., Methods: This was a single-center retrospective study. Infants and toddlers who met the diagnostic criteria for anti-NMDAR encephalitis were recruited for the study. Data on clinical features, treatment, and long-term outcomes were collected retrospectively., Results: A total of 41 patients (age range: six to 34 months; median age: 23 months; female: 19) were enrolled in this study. Nineteen (46%) patients exhibited classical anti-NMDAR encephalitis, whereas 22 (54%) patients exhibited anti-NMDAR encephalitis after viral encephalitis. There was a high presentation of movement disorders (100%), developmental regression (90%), abnormal behaviors (90%). All patients were administered first-line therapy, with only 17% of them being administered second-line immunotherapy. Two patients succumbed to the disease, whereas none of them relapsed. At the long-term follow-up (more than one year), 20 of 35 (57%) exhibited satisfactory outcomes (modified Rankin Scale ≤2). Compared with patients with classical anti-NMDAR encephalitis (n = 18), patients after viral encephalitis (n = 17) were more likely to have worse clinical outcomes. They exhibited a higher modified Rankin Scale/Pediatric Cerebral Performance Category score and more frequent seizures. A predictor of poor outcome was presentation after viral encephalitis (odds ratio 35.7, 95% confidence interval 4.64 to 275.03, P = 0.001)., Conclusion: Anti-NMDAR encephalitis in infants and toddlers clinically presents with movement disorders, developmental regression, and abnormal behaviors. Interestingly, this group had a higher proportion of patients after viral encephalitis, which is regarded as the only risk factor for poor outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

COVID-19 presents significant social, economic, and medical challenges. Because COVID-19 has already begun to precipitate huge increases in mental health problems, clinical psychological science must assert a leadership role in guiding a national response to this secondary crisis. In this article, COVID-19 is conceptualized as a unique, compounding, multidimensional stressor that will create a vast need for intervention and necessitate new paradigms for mental health service delivery and training. Urgent challenge areas across developmental periods are discussed, followed by a review of psychological symptoms that likely will increase in prevalence and require innovative solutions in both science and practice. Implications for new research directions, clinical approaches, and policy issues are discussed to highlight the opportunities for clinical psychological science to emerge as an updated, contemporary field capable of addressing the burden of mental illness and distress in the wake of COVID-19 and beyond. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: During Covid-19 pandemic, the Italian government adopted restrictive limitations and declared a national lockdown on March 9, which lasted until May 4 and produced dramatic consequences on people's lives. The aim of our study was to assess the impact of prolonged lockdown on behavioral and psychological symptoms of dementia (BPSD)., Methods: Between April 30 and June 8, 2020, we interviewed with a telephone-based questionnaire the caregivers of the community-dwelling patients with dementia who had their follow-up visit scheduled from March 9 to May 15 and canceled due to lockdown. Among the information collected, patients' BPSDs were assessed by the Neuropsychiatric Inventory (NPI). Non-parametric tests to compare differences between NPI scores over time and logistic regression models to explore the impact of different factors on BPSD worsening were performed., Results: A total of 109 visits were canceled and 94/109 caregivers completed the interview. Apathy, irritability, agitation and aggression, and depression were the most common neuropsychiatric symptoms experienced by patients both at baseline and during Covid-19 pandemic. Changes in total NPI and caregiver distress scores between baseline and during lockdown, although statistically significant, were overall modest. The logistic regression model failed to determine predictors of BPSD worsening during lockdown., Conclusion: This is one of the first studies to investigate the presence of BPSD during SARS-CoV-2 outbreak and related nationwide lockdown, showing only slight, likely not clinically relevant, differences in BPSD burden, concerning mostly agitation and aggression, anxiety, apathy and indifference, and irritability.

This review weighs the risk of infection with SARS-CoV-2 against the side effects of school closures on physical and mental health, education, and well-being of those affected by the school closures. Whereas short term effects - decreased learning and food security, and increased anxiety, violence against children, child labor and teen pregnancies - are frequently discussed, the long-term effects of school closures will be much more detrimental across the lifespan of the "Generation Corona": Existing pandemics of inactivity and myopia, already affecting billions of people, are worsening due to less physical exercise and less time spent outdoors, poor diet, weight gain, and increased screen time during lockdowns, causing future increases of stroke, heart attack, cancer, and blindness. Socio-emotional complications of isolation, learned helplessness, economic and existential insecurity will include increased depression and suicide, decreased empathy and increased loneliness. Together with decreased educational attainment and economic productivity, the amount of ensuing increased future global morbidity and mortality justifies immediate action of school reopening., (Copyright © 2021.)