Neuropsychiatric Symptoms Of Dementia Research Articles

Role of fronto-limbic circuit in neuropsychiatric symptoms of dementia: clinical evidence from an exploratory study

BackgroundNeuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment.MethodsOf 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer’s disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry.ResultsAll significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT.ConclusionOur findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed.

NEUROPSYCHIATRIC SYMPTOMS OF DEMENTIA AND CAREGIVERS’ BURDEN

Abstract Informal caregiving (IC) is a major health and social asset although simultaneously a potential burden and depression risk factor for those who care. Neuropsychiatric symptoms of dementia are disturbing and may contribute to a negative experience of care. To understand the neuropsychiatric symptoms of dementia in caregiving we have two objectives: to know the prevalence of neuropsychiatric symptoms perceived by ICs and if there is an association of neuropsychiatric symptoms and burden and depression of caregiver. We study a community-based sample (N=101) of primary care users with mental health concerns, referred by GPs. Instruments include sociodemographic information; Neuropsychiatric Inventory (NPI-Q), Caregiver Burden Scale (CBS) and Geriatric Depression Scale (ABCDS). The sample mean age was 79.4 (sd=7.7) years, 54 (53.5%) were female and 34 (33.7%) had no formal education. Half of the sample were married and 41 (41.90%) were widowed. The NPI-Q total score and the Distress dimension score were 10.1 (sd=5.6) and 11.9 (sd=9.1), respectively. The more reported symptoms were agitation/aggression (69.3%), and apathy/indifference (65.3%). We found a significant positive association between NPI-Q and caregivers’ burden (0.296) and depression (0.227) and between Distress and caregivers’ burden (0.417) and depression, 0.416. Conclusion: Neuropsychiatric symptoms of dementia appear associated with the burden and depression of informal caregivers. Training ICs to cope with care receiver symptoms is a priority to increase the quality of care and reduce burden and depression of caregivers.

THE ASSOCIATION BETWEEN PSYCHOTROPIC DRUGS AND PHYSICAL FUNCTION IN HOSPITALIZED OLDER ADULTS WITH DEMENTIA

Abstract The aim of this study was to test if the use of psychotropic medications (antipsychotics, sedatives, antiseizure, antidepressants, and anxiolytics) was associated with physical function in hospitalized older adults living with dementia. This study was a secondary data analysis using baseline data from the Function Focused Care for Acute Care Using the Evidence Integration Triangle (FFC-AC-EIT) study. FFC-AC-EIT is an ongoing randomized controlled trial and this study included the first 290 participants. A path analysis was conducted to test the relationship between psychotropic drugs and physical function while controlling for age, gender, race, comorbidities, cognitive function, neuropsychiatric symptoms of dementia, and pain. Overall, 63.4% of participants took one or more psychotropic drugs, with the most used psychotropic drugs being antidepressants (39%), followed by antiseizure drugs (23.4%), antipsychotics (16.6%), anxiolytics (13.8%), and sedatives (4.1%). No significant association was found between the use of psychotropic medications and physical function. Cognitive function (β=1.489, SE 0.265, p< 0.001), comorbidities (β=-2.680, SE 1.093, p=0.014), and pain (β=-2.837, SE 0.865, p=0.001) were directly associated with physical function. Cognitive function was also indirectly associated with function through pain. The findings support prior research showing a lack of association between the use of psychotropic medications and physical function. Additional research may be needed to investigate the mediating effects of pain between cognition and physical function in older adults with dementia.

Neuropathological correlates of neuropsychiatric symptoms in the Brains for Dementia Research study

AbstractBackgroundNeuropsychiatric symptoms are a common feature of many dementia syndromes, and are frequently associated with poor clinical prognosis, reduction in quality of life, earlier institutionalisation, greater disability, and increased caregiver distress, particularly during later stages of disease. It has also been postulated that NPS may occur during prodromal stages of dementia, preceding or alongside early cognitive symptoms. Clinical profiles of dementia are both heterogenous and intersecting, which may reflect that up to 90% of cases have multiple pathologies post‐mortem. Comprehensive clinicopathological studies of neuropsychiatric symptoms in dementia are lacking, thus this study sought to investigate potential neuropsychiatric profiles resulting from mixed underlying pathology.MethodThis analysis aimed to identify pathological correlations of neuropsychiatric symptoms and included 840 post‐mortem brains donated to the Brains for Dementia Research project, a longitudinal study with post‐mortem neuropathological assessment across several brain banks, between 2008 and 2020. Patterns of neuropsychiatric symptoms were compared between pathology subtypes using clinical data including the Neuropsychiatric Inventory (NPI‐Q) and Clinical Dementia Rating scale, and neuropathological assessment of degenerative pathologies and vascular features. Confirmatory factor analysis was used to identify latent variables for psychosis, mood, and behaviour. Associations between pathological variables assessed at autopsy and neuropsychiatric features during life were explored using bivariate and multivariate statistical methods.ResultAlmost 80% of the 494 dementia cases included had at least one neuropsychiatric symptom across the course of disease. Apathy (51.2%) and aggression (41.7%) were the most prevalent neuropsychiatric features across all dementia subtypes. Preliminary results indicate that different underlying pathologies, including neurodegenerative pathologies (amyloid, neurofibrillary tangles, Lewy bodies, TDP‐43 inclusions) and vascular features may be associated with increased likelihood of specific neuropsychiatric symptoms, such as psychosis, mood and behaviour, during life. Co‐occurring substantial AD and Lewy body pathology was associated with the presence of anxiety, depression, and aberrant motor activity during life. AD in the absence of substantial Lewy body pathology, was associated with agitation, apathy, and disinhibition. Lewy body pathology, in the absence of substantial AD pathology, was associated with hallucinations, depression and sleep disturbances.ConclusionThe interaction of multiple pathologies may contribute to differing neuropsychiatric profiles during life.

Virtual behavioural medicine program: An innovative model of care for neuropsychiatric symptoms in dementia

Virtual behavioural medicine program: An innovative model of care for neuropsychiatric symptoms in dementia

P160: Electroconvulsive therapy for neuropsychiatric symptoms in dementia: survey among Dutch physicians

Objective:Neuropsychiatric symptoms (NPS) are common in people with dementia and have a negative effect. Commonly used pharmacological and psychosocial interventions are not always effective and NPS can become refractory. Electroconvulsive therapy (ECT) may be effective for (severe) agitation and aggression and is well tolerated. Nevertheless, its application seems limited in the Netherlands. We explored the application of and attitudes of physicians towards ECT for (severe) NPS in older people with dementia in the Netherlands.Methods:A survey study among geriatricians, elderly care physicians and old-age psychiatrists in the Netherlands in July 2020. An online invitation was included in the digital newsletter of the professional society or directly sent to the professional network of one of the authors (in case of old-age psychiatrists). The questionnaire included 20 closed- and open ended questions on demographic characteristics, experiences with (consideration of) referral for/application of ECT and attitudes towards ECT.Results:Sixty-one respondents completed the survey, eight had ever considered ECT. Two of these eight referred patient(s) for depressive behavior, sometimes combined with agitation. Lack of experience, ECT not being included in guidelines for this indication, unfamiliarity with possible (side) effects and risks, ethical and practical issues were the main reasons of the respondents for not considering ECT. Most respondents were open to referring patients with dementia for ECT to treat (severe) NPS, specifically in case of refractory symptoms.Conclusion:Respondents are not negative about ECT, yet rarely consider it due to lack of awareness and knowledge and the ethical and practical issues related to its application. Although the response to our survey was low and the number of respondents is limited, we do feel that ECT may be an alternative for palliative sedation, which is used incidentally in cases of refractory NPS in the Netherlands. Further exploring the support base and possibilities for application of ECT-treatment for refractory NPS might therefore be worthwhile.

Greenness and neuropsychiatric symptoms in dementia

ObjectivesIt is acknowledged that living in a green environment may help mental well-being and this may be especially true for vulnerable people. However, the relationship between greenness and neuropsychiatric symptoms in dementia has not been explored yet. MethodsWe collected clinical, neuropsychiatric, and residential data from subjects with dementia living in the province of Modena, Northern Italy. Neuropsychiatric symptoms were measured with the Neuropsychiatry Inventory, a questionnaire administered to the caregiver who assesses the presence and severity of neuropsychiatric symptoms, including delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, sleep disturbances, and appetite/eating changes. Normalized Difference Vegetation Index (NDVI) was used as a proxy of greenness. Regression models were constructed to study the association between greenness and neuropsychiatric features. Results155 patients with dementia were recruited. We found that greenness is variably associated with the risk of having neuropsychiatric symptoms. The risk of apathy was lower with lower levels of greenness (OR = 0.42, 95% CI 0.19–0.91 for NDVI below the median value). The risk of psychosis was higher with lower levels of greenness but with more imprecise values (OR = 1.77, 95% CI 0.84–3.73 for NDVI below the median value). ConclusionOur results suggest a possible association between greenness and neuropsychiatric symptoms in people with dementia. If replicated in larger samples, these findings will pave the road for identifying innovative greening strategies and interventions that can improve mental health in dementia.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). We included 59 trials (15,781 participants; mean age, 76.6years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

The relationship of apathy with daily life activities, quality of life and caregiver burden in patients with dementia

AbstractBackgroundApathy is one of the most common neuropsychiatric symptoms in dementia. The aim of this study is to evaluate apathy and its relationships with activities of daily living, quality of life and caregiver burden in patients with dementia.MethodThe research was conducted in a descriptive analytic type. The sample consisted of 88 patients with a definite diagnosis of dementia attending outpatient clinic of a university hospital in Istanbul between October 2019‐March 2020 and their family caregivers. Depressive patients (assessed by Cornell Scale) and paid caregivers were not included. Apathy Evaluation Scale‐Clinician (AES‐C) and Informant (AES‐I) Forms, Neuropsychiatric Inventory (NPI), Mini Mental Test (MMSE), Quality of Life in Alzheimer’s Disease Scale (QoL‐AD), Lawton Instrumental (Lawton IADL) and the Katz Activities of Daily Living Scale (Katz ADL) were used for patients and Caregiver Burden Inventory (CBI) was used for caregivers.ResultsThe mean age of the patients was 73.11±11.68, and diagnosis duration was 3.9±3.1 years, 64.8% had Alzheimer’s type dementia and 53.4% (n = 47) had mild‐1 dementia. The mean MMSE score was 16.4±6.6, NPI‐Symptom score was 16.6±13.7, AES‐C score was 52.9±10.2. The QoL‐AD score was 28.8±6.1 in patient evaluation and 27.6±6.4 in caregiver evaluation. The AES‐C scores were correlated with NPI, MMSE, ADL, Cornell, QoL‐AD, and CBI. Apathy was found to be an important predictor of both the patient’s QoL and CBI.ConclusionIn dementia patients, apathy was found to be associated with patient’s activities of daily living, quality of life, and caregiver burden. It is recommended that patients be evaluated for apathy.

MBI‐apathy, ApoEɛ2, and risk for Alzheimer disease dementia

AbstractBackgroundApathy, characterized by decreased interest, initiative, and emotional reactivity, is amongst the most common neuropsychiatric symptoms in dementia. However, apathy can emerge before dementia and constitutes a domain of mild behavioral impairment (MBI), an at‐risk state for incident cognitive decline and dementia. MBI‐apathy is the de novo emergence of persistent apathy in dementia‐free older adults and may be a driving factor in dementia risk conferred by MBI. Apolipoprotein E (ApoE) is a risk marker for Alzheimer disease (AD) dementia. Compared to ApoEɛ3 homozygotes, ApoEɛ2 carriers are 40% less likely to develop AD while ApoEɛ4 carriers are 3.2‐14.9 times more likely. We investigated the association between MBI‐apathy, ApoE, and incident dementia. We hypothesized that ɛ2 would have protective effects for MBI‐apathy associated risk, compared to ɛ3 and ɛ4.MethodDementia‐free participants in the National Alzheimer’s Coordinating Centre were stratified as MBI‐apathy and no‐NPS until dementia diagnosis, based on Neuropsychiatric Inventory Questionnaire scores at 2 consecutive visits. ApoE genotypes were categorized by ɛ2 (ɛ2/ɛ2, ɛ2/ɛ3), ɛ3 (ɛ3/ɛ3), and ɛ4 (ɛ4/ɛ3, ɛ4/ɛ4) alleles. Group characteristics were contrasted to determine covariate inclusion in regression modelling. Cox regressions assessed risk of incident dementia and included an interaction term for MBI‐apathy and ApoE allele.ResultsOf the 3,644 participants (3,022 Normal‐Cognition); 314 had MBI‐apathy (Table 1). Significant main effects were found for MBI‐apathy and incident dementia (HR:2.51, 95% CI:1.99‐3.17, p<0.001) as well as interaction effects with ApoE. In MBI‐apathy (ɛ3 as reference), the ɛ2 group had a 60% lower dementia risk (adjusted HR:0.40, 95% CI:0.19‐0.85) while ɛ4 had a 16% higher risk (adjusted HR:1.16, 95% CI:0.80‐1.69) (Figure 1). Of the 125 participants with apathy who progressed to dementia, 80.8% had AD. In the no‐NPS group (ɛ3 as reference), ɛ2 individuals had a 17% lower dementia risk (adjusted HR:0.83, 95% CI:0.52‐1.33) while ɛ4 individuals had a 177% higher risk (adjusted HR:2.77, 95% CI:2.13‐3.59) (Figure 2).ConclusionTo our knowledge, this is the first study examining the relationship between MBI‐apathy and ApoE status in determining dementia risk. Results suggest that ApoE modifies the association between MBI‐apathy and incident dementia with the ɛ2 allele acting as a protective factor.

Neuropathological correlates of neuropsychiatric symptoms in dementia

AbstractBackgroundNeuropsychiatric symptoms (NPS) are very common in Lewy body dementias (LBD), but their aetiology is poorly understood. In a post‐mortem study we aimed to characterise the contribution of neuropathological substrates to some of the most common NPS in dementia.MethodParticipants who passed away between 2004 and 2021 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies. Neuropathological data was collected for Lewy body neuropathology (LBD Braak score), neurofibrillary tangles (NFT Braak score), amyloid‐β burden (CERAD‐NP), TDP‐43, lacunar infarcts, cerebral amyloid angiopathy and hyaline atherosclerosis. Post‐mortem interviews were used to collect information regarding neuropsychiatric and cognitive status using the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). A total of 948 cases were classified according to neuropathological assessment: (1) No pathology (NP) (n = 678); (2) Alzheimer’s Disease (AD) (n = 183); (3) LBD (n = 57); (4) AD+LBD (n = 30).ResultMultinomial logistic regression models comparing LBD, AD and AD+LBD to NP, adjusted for age, ethnicity, sex, and education level, showed significantly higher odds of hallucination and delusions across all groups compared to NP with the relative risk of hallucinations most elevated in AD+LBD cases (RRR = 19.3,[95%CI = 8.00‐46.3], p<0.001). All groups had increased risk of higher NPI scores relative to NP, but the greatest increase was for AD+LBD (RRR = 1.04, [95%CI = 1.02‐1.06], p<0.001). There were significantly greater risk of agitation and apathy in AD and AD+LBD groups relative to NP. (Table 1) Additionally, hallucinations were associated with higher Lewy body Braak scores (OR = 1.30, 95%CI = 1.13‐1.49, p<0.001). Higher NFT Braak scores were associated with depression (OR = 1.28, 95%CI = 1.09‐1.50, p<0.001), agitation (OR = 1.30, 95% CI = 1.07‐1.57, p = 0.009) and overall NPI score (IRR = 1.15, 95%CI = 1.05‐1.27, p = 0.004). Lacunar infarcts were associated with delusions (OR = 4.68, 95%CI = 1.12‐19.5, p = 0.03). More frequent neuritic plaques was inversely associated with apathy (OR = 0.70, 95%CI = 0.52‐0.93, p = 0.01). Cerebral amyloid angiopathy, hyaline atherosclerosis, and TDP‐43 did not associate with any of the neuropsychiatric symptoms in the multivariable logistic models. (Table 2)ConclusionLewy body pathology was the most significant contributor to the aetiology of hallucinations, while NFT were important contributors to depression and agitation in dementia. Supporting the dual importance of these pathologies, subjects with AD and LBD co‐pathology showed the greatest burden of NPS.

The Effect of Cannabidiol 3% on Neuropsychiatric Symptoms in Dementia – Six-Month Follow-Up

ABSTRACT Objectives To investigate the beneficial outcomes of giving cannabidiol (CBD) 3% over a six-month period in the BPSD, the management of which is a crucial issue for everyday clinical praxis and to compare the progress in BPSD of patients who receive Cannabidiol 3% with those who follow usual medical treatment (UMT) in everyday clinical praxis. Methods A total of 20 PwD with severe BPSD were recruited from the database of Alzheimer Hellas with NPI score >30. Ten of them were assigned to UMT, while ten were assigned to a six-month treatment with CBD drops. The follow-up assessment was performed with NPI, both clinically and by structured telephone interview. Results The follow-up assessment with NPI showed significant improvement of the BPSD in all our patients who received CBD, and no or limited improvement in the second group, regardless of the underlying neuropathology of dementia. Conclusions We suggest that CBD may be a more effective and safe choice for managing BPSD than the typical intervention. Future large randomized clinical trials are needed to re-assure these findings. Clinical Implications Healthcare professionals should consider incorporating CBD 3% into their practices to reduce BPSD in PwD. Regular assessments are necessary to ensure long-term effectiveness.

Probing the relevance of the accelerated aging mouse line SAMP8 as a model for certain types of neuropsychiatric symptoms in dementia.

People with dementia (PwD) often present with neuropsychiatric symptoms (NPS). NPS are of substantial burden to the patients, and current treatment options are unsatisfactory. Investigators searching for novel medications need animal models that present disease-relevant phenotypes and can be used for drug screening. The Senescence Accelerated Mouse-Prone 8 (SAMP8) strain shows an accelerated aging phenotype associated with neurodegeneration and cognitive decline. Its behavioural phenotype in relation to NPS has not yet been thoroughly investigated. Physical and verbal aggression in reaction to the external environment (e.g., interaction with the caregiver) is one of the most prevalent and debilitating NPS occurring in PwD. Reactive aggression can be studied in male mice using the Resident-Intruder (R-I) test. SAMP8 mice are known to be more aggressive than the Senescence Accelerated Mouse-Resistant 1 (SAMR1) control strain at specific ages, but the development of the aggressive phenotype over time, is still unknown. In our study, we performed a longitudinal, within-subject, assessment of aggressive behaviour of male SAMP8 and SAMR1 mice at 4, 5, 6 and 7 months of age. Aggressive behaviour from video recordings of the R-I sessions was analysed using an in-house developed behaviour recognition software. SAMP8 mice were more aggressive relative to SAMR1 mice starting at 5 months of age, and the phenotype was still present at 7 months of age. Treatment with risperidone (an antipsychotic frequently used to treat agitation in clinical practice) reduced aggression in both strains. In a three-chamber social interaction test, SAMP8 mice also interacted more fervently with male mice than SAMR1, possibly because of their aggression-seeking phenotype. They did not show any social withdrawal. Our data support the notion that SAMP8 mice might be a useful preclinical tool to identify novel treatment options for CNS disorders associated with raised levels of reactive aggression such as dementia.

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

Elderly Female of Type 2 Diabetes (T2D) and Dementia with Clinical Improvement by Imeglimin (Twymeeg)

Background: Recent diabetic focus includes imeglimin (Twymeeg). Case Presentation: The case was an 83-year-old female with 19 years of type 2 diabetes (T2D) associated with recent treatment for dementia. Result: HbA1c decreased from 10.0% to 6.6% for 4 months by Twymeeg 2000 mg/day. For neuropsychiatric symptoms in dementia, memantine and tiapride were provided and controlled. Furthermore, zinc acetate hydrate (Novelzin) was continued for T2D and dementia. Discussion and Conclusion: Twymeeg administration was effective as the results of Trials of IMeglimin for Efficacy and Safety (TIMES) 2 and 3. Perspectives on the efficacy of zinc were discussed including Alzheimer’s-Plus with low zinc (APLZ).

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Development of a Home-Based Stress Management Toolkit for Dementia Caring Dyads: Protocol for A Pilot Intervention Development and Feasibility Study.

People living with dementia and their care partners (dementia caring dyads) are at a heightened risk of experiencing stress-related symptoms and conditions. Yet, many dyadic stress-management interventions have had limited uptake by healthcare systems and in the community. An intervention that combines simple, safe, easy-to-use, non-pharmacologic tools (e.g., animatronic social pets, weighted blankets and garments, aromatherapy and bright light therapy devices, acupressure and massage tools) that can be used in the home may be a promising approach to promote stress management among dementia caring dyads. The proposed study aims to develop and user-test a dyadic toolkit intervention composed of simple, tangible stress management tools for community-dwelling people living with dementia and their care partners. This study will also explore the feasibility of collecting several stress-related outcome measures to inform measurement selection for future studies. A human-centered design approach will be used to increase the likelihood of developing an intervention that will be translatable to real world settings. This study consists of 2 phases. The first phase will address the discover, define, and design stages of human-centered design by using qualitative focus groups with dementia caring dyads (N=12-16 dyads). Dyadic focus groups (3-4 groups anticipated) will be convened to understand participants' stress experiences and to co-design a stress management toolkit prototype. Rapid qualitative analysis will be used to analyze focus group data. In Phase 2, the toolkit prototype will be user-tested for 2 weeks in a new sample to address the validation step of human-centered design. A within-subjects (N=10 dyads), pre-post design will be used with measures of usability (frequency of toolkit use), feasibility (enrollment and withdrawal rates, adverse events/injuries) and acceptability (satisfaction, benefit) collected via questionnaires (at end of weeks 1 and 2 of user-testing) and focus groups (n=3-4 dyads/group at end of week 2). The feasibility of collecting participant-reported, stress-related outcomes (neuropsychiatric symptoms of dementia, caregiver stress, dyadic relationship strain) and salivary cortisol as a physiologic measure of stress will be assessed at baseline and post user-testing. This study will yield a working prototype of a stress management toolkit for dementia caring dyads, as well as preliminary data to support the feasibility and acceptability of the intervention. User-testing will elucidate areas to refine the prototype and provide data to inform preliminary testing of the intervention. As of September 2022, this study has received institutional ethics board approval with Phase 1 recruitment anticipated to begin in October 2022. Few interventions have focused on combining simple, safe, low burden tools to promote stress management among community-dwelling dementia caring dyads. By involving families and exploring feasibility and acceptability at the onset of development, this intervention will have greater potential to be implemented and sustained in the future. Clinicaltrials.gov ID NCT05465551.

The importance of co-pathologies on neuropsychiatric symptoms in dementia.

The importance of co-pathologies on neuropsychiatric symptoms in dementia.

Alzheimer's disease and depression in the elderly: A trajectory linking gut microbiota and serotonin signaling.

The occurrence of neuropsychiatric symptoms in the elderly is viewed as an early sign of subsequent cognitive deterioration and conversion from mild cognitive impairment to Alzheimer's disease. The prognosis in terms of both the severity and progression of clinical dementia is generally aggravated by the comorbidity of neuropsychiatric symptoms and decline in cognitive function. Undeniably, aging and in particular unhealthy aging, is a silent "engine of neuropathology" over which multiple changes take place, including drastic alterations of the gut microbial ecosystem. This narrative review evaluates the role of gut microbiota changes as a possible unifying concept through which the comorbidity of neuropsychiatric symptoms and Alzheimer's disease can be considered. However, since the heterogeneity of neuropsychiatric symptoms, it is improbable to describe the same type of alterations in the bacteria population observed in patients with Alzheimer's disease, as well as it is improbable that the variety of drugs used to treat neuropsychiatric symptoms might produce changes in gut bacterial diversity similar to that observed in the pathophysiology of Alzheimer's disease. Depression seems to be another very intriguing exception, as it is one of the most frequent neuropsychiatric symptoms in dementia and a mood disorder frequently associated with brain aging. Antidepressants (i.e., serotonin reuptake inhibitors) or tryptophan dietary supplementation have been shown to reduce Amyloid β-loading, reinstate microbial diversity and reduce the abundance of bacterial taxa dominant in depression and Alzheimer's disease. This review briefly examines this trajectory by discussing the dysfunction of gut microbiota composition, selected bacterial taxa, and alteration of tryptophan and serotonin metabolism/neurotransmission as overlapping in-common mechanisms involved with depression, Alzheimer's disease, and unhealthy aging.

What evidence is there for implicating the brain orexin system in neuropsychiatric symptoms in dementia?

Neuropsychiatric symptoms (NPS) affect people with dementia (PwD) almost universally across all stages of the disease, and regardless of its exact etiology. NPS lead to disability and reduced quality of life of PwD and their caregivers. NPS include hyperactivity (agitation and irritability), affective problems (anxiety and depression), psychosis (delusions and hallucinations), apathy, and sleep disturbances. Preclinical studies have shown that the orexin neuropeptide system modulates arousal and a wide range of behaviors via a network of axons projecting from the hypothalamus throughout almost the entire brain to multiple, even distant, regions. Orexin neurons integrate different types of incoming information (e.g., metabolic, circadian, sensory, emotional) and convert them into the required behavioral output coupled to the necessary arousal status. Here we present an overview of the behavioral domains influenced by the orexin system that may be relevant for the expression of some critical NPS in PwD. We also hypothesize on the potential effects of pharmacological interference with the orexin system in the context of NPS in PwD.