Treatment Of Dementia Research Articles

Early Identification of Cognitive Impairment in Community Environments Through Modeling Subtle Inconsistencies in Questionnaire Responses: Machine Learning Model Development and Validation

Background The underdiagnosis of cognitive impairment hinders timely intervention of dementia. Health professionals working in the community play a critical role in the early detection of cognitive impairment, yet still face several challenges such as a lack of suitable tools, necessary training, and potential stigmatization. Objective This study explored a novel application integrating psychometric methods with data science techniques to model subtle inconsistencies in questionnaire response data for early identification of cognitive impairment in community environments. Methods This study analyzed questionnaire response data from participants aged 50 years and older in the Health and Retirement Study (waves 8-9, n=12,942). Predictors included low-quality response indices generated using the graded response model from four brief questionnaires (optimism, hopelessness, purpose in life, and life satisfaction) assessing aspects of overall well-being, a focus of health professionals in communities. The primary and supplemental predicted outcomes were current cognitive impairment derived from a validated criterion and dementia or mortality in the next ten years. Seven predictive models were trained, and the performance of these models was evaluated and compared. Results The multilayer perceptron exhibited the best performance in predicting current cognitive impairment. In the selected four questionnaires, the area under curve values for identifying current cognitive impairment ranged from 0.63 to 0.66 and was improved to 0.71 to 0.74 when combining the low-quality response indices with age and gender for prediction. We set the threshold for assessing cognitive impairment risk in the tool based on the ratio of underdiagnosis costs to overdiagnosis costs, and a ratio of 4 was used as the default choice. Furthermore, the tool outperformed the efficiency of age or health-based screening strategies for identifying individuals at high risk for cognitive impairment, particularly in the 50- to 59-year and 60- to 69-year age groups. The tool is available on a portal website for the public to access freely. Conclusions We developed a novel prediction tool that integrates psychometric methods with data science to facilitate “passive or backend” cognitive impairment assessments in community settings, aiming to promote early cognitive impairment detection. This tool simplifies the cognitive impairment assessment process, making it more adaptable and reducing burdens. Our approach also presents a new perspective for using questionnaire data: leveraging, rather than dismissing, low-quality data.

Frailty Trajectories Preceding Dementia in the US and UK

ImportanceAn accessible marker of both biological age and dementia risk is crucial to advancing dementia prevention and treatment strategies. Although frailty is a candidate for that role, the nature of the relationship between frailty and dementia is not well understood.ObjectiveTo clarify the temporal relationship between frailty and incident dementia by investigating frailty trajectories in the years preceding dementia onset.Design, Setting, and ParticipantsParticipant data came from 4 prospective cohort studies: the English Longitudinal Study of Ageing, the Health and Retirement Study, the Rush Memory and Aging Project, and the National Alzheimer Coordinating Center. Data were collected between 1997 and 2024 and were analyzed from July 2023 to August 2024. The settings were retirement communities, national-level surveys, and a multiclinic-based cohort. Included individuals were 60 years or older and without cognitive impairment at baseline. Included individuals also had data on age, sex, education level, and ethnicity and a frailty index score calculated at baseline.ExposureFrailty was the main exposure, with participants’ degrees of frailty quantified using retrospectively calculated frailty index scores.Main Outcomes and MeasuresIncident all-cause dementia ascertained through physician-derived diagnoses, self- and informant-report, and estimated classifications based on combinations of cognitive tests.ResultsThe participant number before exclusions was 87 737. After exclusions, data from 29 849 participants (mean [SD] age, 71.6 [7.7] years; 18 369 female [62%]; 257 963 person-years of follow-up; 3154 cases of incident dementia) were analyzed. Bayesian generalized linear mixed regression models revealed accelerations in frailty trajectories 4 to 9 years before incident dementia. Overall, frailty was positively associated with dementia risk (adjusted hazard ratios [aHRs] ranged from 1.18; 95% CI, 1.13-1.24 to 1.73; 95% CI, 1.57-1.92). This association held among participants whose time between frailty measurement and incident dementia exceeded the identified acceleration period (aHRs ranged from 1.18; 95% CI, 1.12-1.23 to 1.43; 95% CI, 1.14-1.80).Conclusions and RelevanceThese findings suggest that frailty measurements may be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioral and societal approaches to dementia prevention.

Trace Lithium for Suicide Prevention and Dementia Prevention: A Qualitative Review

Background: Anti-manic effects of lithium and the nature of trace element in lithium were first observed in 1949. In this review, we explore the potential effects of trace lithium in the prevention of suicide and dementia. Methods: This is a qualitative and non-systematic review. Results: While most studies to date have been cross-sectional, limiting the establishment of causal relationships, the potential benefits of trace lithium for suicide prevention and dementia prevention are notable, especially in the absence of radical treatments for suicide and dementia. Furthermore, trace lithium appears to lack many of the adverse effects associated with so-called therapeutic lithium levels. Conclusions: The present findings suggest that trace lithium may be associated with lower suicide rates and reduced dementia rates. Probably, trace lithium may inhibit testosterone and thereby mitigate aggression and impulsivity and decrease suicide. Also, trace lithium may inhibit GSK-3β and thereby lower amyloid β and tau hyperphosphorylation and inhibit pro-inflammatory cytokines such as IL 6 and IL 8 and thereby mitigate inflammation, whereas trace lithium may promote BDNF and neurogenesis in the general population.

The efficacy of cognitive stimulation, cognitive training, and cognitive rehabilitation for people living with dementia: a systematic review and meta-analysis.

Cognition-oriented treatments (COTs) are a group of non-pharmacological treatments aimed at maintaining or improving cognitive functioning. Specific recommendations on the use of these interventions in people living with dementia (PLwD) are included in the Italian Guideline on the Diagnosis and Treatment of Dementia and Mild Cognitive Impairment, developed by the Italian National Institute of Health. This systematic review and meta-analysis, based on the GRADE methodology, is part of the guideline. Considered outcomes included the cognitive functions, quality of life, and functional abilities of PLwD, taking into account disease severity, modality and system of delivery, and form of the intervention. The effectiveness of these interventions on caregivers' outcomes was also assessed. Both group and individual cognitive stimulation were reported as effective in supporting cognitive functions in PLwD at any degree of severity. Individual cognitive training and group cognitive training were reported as effective in improving global cognitive functions in people with mild dementia. Cognitive rehabilitation appeared to be effective only in improving the functional abilities of people with mild dementia. Cognitive rehabilitation appeared to be the most effective in improving caregivers' outcomes, with results suggesting a reduction in care burden. The observed differences in the effectiveness of these interventions in people with different disease severity can be explained by the intrinsic characteristics of each intervention. Despite the large number of available studies, a high clinical, statistical, and methodological heterogeneity was observed. More methodologically rigorous studies are needed to clarify the effectiveness of each protocol and modality of intervention.

Phytoactive drugs used in the treatment of Alzheimer's disease and dementia.

The prevalence of Alzheimer's disease and other forms of dementia is increasing worldwide, and finding effective treatments for these conditions is a major public health challenge. Natural bioactive drugs have been identified as a promising source of potential treatments, due to their ability to target multiple pathways and their low toxicity. This paper reviews the current state of research on natural bioactive drugs used in the treatment of Alzheimer's disease and other dementias. The paper summarizes the findings of studies on various natural compounds, including curcumin, resveratrol, caffeine, genistein, quercetin, GinkoBiloba, Withaniasomnifera, Ginseng Brahmi, Giloy, and huperzine, and their effects on cognitive function, neuroinflammation, and amyloid-beta accumulation. In this review, we discuss the mechanism of action involved in the treatment of Alzheimer's disease. The paper also discusses the challenges associated with developing natural bioactive drugs for dementia treatment, including issues related to bioavailability and standardization. Finally, the paper suggests directions for future research in this area, including the need for more rigorous clinical trials and the development of novel delivery systems to improve the efficacy of natural bioactive drugs. Overall, this review highlights the potential of natural bioactive drugs as a promising avenue for the development of safe and effective treatments for Alzheimer's disease and other dementias.

The molecular mechanisms of steroid hormone effects on cognitive function

ObjectiveThere is a lack of information on the molecular mechanisms by which steroid hormones (testosterone, estrogen, and progesterone) regulate cognitive impairment. Thus, we aimed to identify the protective effects of steroid hormones on cognitive function. MethodsWe analyzed the literature on the molecular mechanisms, biological activities, physicochemical properties, and pharmacokinetics of steroid hormones. ResultsSteroid hormones can protect against cognitive impairment by regulating key genes (INS, TNF, STAT3, ESR1). Specific microRNAs, namely hsa-miR-335-5p, hsa-miR-16-5p, and hsa-miR-26b-5p, along with transcription factors NFKB1, PPARG, NR3C1, GATA2, EGR1, ATF3, and CEBPA, play a significant role in this protective mechanism. The involvement in cognitive processes, regulation of phosphorylation, neuronal apoptosis, and signaling pathways related to Alzheimer's disease significantly influence the protein-protein interaction network underlying these effects. Additionally, steroid hormones exhibit anti-hypercholesterolemic properties, anti-inflammatory activity, antitoxic properties, and function as inhibitors of acetylcholine neuromuscular transmission. They also hold promise as therapeutic agents for the treatment of dementia. Promising therapeutic interventions for cognitive impairment include the use of miRNA sponges targeting hsa-miR-16-5p, along with the administration of capsaicin, minocycline, dopamine, sertraline, and minaprine. The gut microbiota species Lactobacillus amylovorus, Paraprevotella clara, Libanicoccus massiliensis, Prevotella oris, Turicibacter sanguinis, and Dubosiella newyorkensis were identified as significant contributors to cognitive impairment and altered levels of steroid hormones. ConclusionSteroid hormones are promising compounds for improving cognitive function. Further research is needed to validate these findings through focused investigations into apoptosis, regulation of neuronal cell death, miRNA sponges, interactions with gut microbiota, and the potential efficacy of pharmaceutical agents.

Person Profile Dementia Intervention in Long-Term Care: A Stepped-Wedge Cluster-Randomized Trial

ObjectivesWe aimed to assess the efficacy of a person-centered care intervention in improving quality of life (QoL) for people with dementia in long-term care facilities. DesignThis study was a stepped-wedge cluster-randomized clinical trial of monthly person-centered outcome measurements, followed by collaborative nurse-led person profile interventions involving nursing staff and family members, compared with monthly person-centered outcome measurements alone. Setting and ParticipantsWe included people with a medical diagnosis of Alzheimer's disease or vascular dementia or with clinical symptoms of dementia from 23 long-term care facilities in the German-speaking part of Switzerland. MethodsThe primary outcome was QoL, as assessed using the QUALIDEM. Secondary outcomes were the QUALIDEM subscales and the Integrated Palliative Care Outcome Scale for People with Dementia subscales. The study duration was 15 months, and linear mixed-effect models were used for the analysis. ResultsWe recruited 240 people with dementia from 23 long-term care facilities. Modeling 1143 observations, we found a statistically significant positive intervention effect of 2.6 points according to the QUALIDEM (95% CI, 1.34–3.86; P < .001; total QUALIDEM intervention: 67; 95% CI, 64.8–69.1 vs 64.4; 95% CI, 62.3–66.4 for the control). We also found positive effects of the intervention on all secondary outcomes. Conclusions and ImplicationsOnce-a-month person profile interventions based on person-centered outcome measurements provided a small but significant improvement in QoL. Thus, our findings suggest a potential benefit to the broader implementation of person profiles involving nursing staff and family members in long-term care facilities.

Design, Synthesis, and Anti-Inflammatory Activity Evaluation of Novel Indanone Derivatives for the Treatment of Vascular Dementia.

Vascular dementia (VaD) is a neurodegenerative disease resulting from cerebral vascular obstruction, leading to cognitive impairment, and currently lacks effective treatment options.Due to its complex pathogenesis, multi-target drug design (MTDLs) strategies are considered among the most promising therapeutic approaches. In this study, we designed and synthesized a series of novel indanone derivatives targeting targets related to vascular health and dementia. The results indicated that compound C5exhibited excellent acetylcholinesterase inhibitory activity (IC50= 1.16 ± 0.41 μM) and anti-platelet aggregation activity (IC50= 4.92 ± 0.10 μM) within ranges of 0.1-1000 μM and 0.03-300 μM, respectively, possibly mediated by molecular docking interactions. Furthermore, compound C5demonstrated protective effects on cells at concentrations ≤50 μM, significantly reducing the release of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) in a concentration-dependent manner, showcasing its potent neuroinflammatory inhibitory effects. Anti-inflammatory therapies are regarded as effective strategies for treating VaD. Therefore, compound C5holds promise as a novel candidate drug for further investigation into the treatment of vascular dementia.

Ability to Select AAC Graphic Symbols by Severity of Alzheimer’s Disease and Number of Symbols

Purpose: This study aimed to examine the graphic-symbol selection ability of patients with dementia of Alzheimer's type (DAT) based on the severity of dementia by conducting symbol identification and symbol discrimination tasks with increasing numbers of symbols. These tasks were performed with both normal elderly individuals and DAT patients to explore how cognitive load affects them differently.Methods: A total of 21 normal elderly individuals, 17 mild DAT patients, and 20 moderate to severe DAT patients were assessed. They performed symbol identification and symbol discrimination tasks using the Augmentative and Alternative Communication Symbol Assessment Tool. The number of symbols increased in six steps, from 4 to 72. Accuracy and response time were measured for statistical analysis.Results: In the symbol identification task, there was no significant difference in accuracy among the three groups. However, normal group showed significantly faster responses compared to moderate to severe DAT group. In the symbol discrimination task, normal group showed higher accuracy and significantly faster responses than moderate to severe DAT group. As the number of symbols increased, response times increased across all groups, with more time required for the symbol discrimination task.Conclusion: It was confirmed that the greater the severity of DAT, the more cognitive load and impaired information processing were reflected in symbol selection. Findings suggest that response time is a more sensitive indicator of cognitive decline in DAT patients and highlight the need to adjust the number of symbols and presentation methods according to the severity of the patient’s condition in dementia interventions.

Oxytocin in old age psychiatry: A systematic review of the safety of using intranasal oxytocin in older adults.

To examine the literature for evidence of adverse events associated with the use of intranasal oxytocin in older adults (60+). A systematic review was undertaken according to PRISMA guidelines. Peer-reviewed literature was searched for studies involving intranasal oxytocin use in older populations. The Joanna Briggs Institute's (JBI) critical appraisal tool was used to assess the quality of included studies. The search identified nine randomized controlled trials (RCTs) that investigated the effects of intranasal oxytocin on a total sample size of 331 older participants. Adverse effects associated with oxytocin administration were predominantly mild and varied inconsistently between studies. Compared to placebo intranasal oxytocin was not significantly associated with severe adverse outcomes in doses ranging from 24 to 72 IU after single dose and or repeated doses in the short-term. In a population of older adults, intranasal oxytocin is devoid of serious adverse events. Although this review offers valuable insights, it may not fully reflect the potential adverse events associated with the long-term administration of intranasal oxytocin such as would be expected in its clinical application if approved for the treatment of dementia.

Assessment of Integrated Care Pathways for dementia in Italy according to the National Guidance

Abstract Background Italy counts 1 million people with dementia and 3 million caregivers. An integrated management system provides comprehensive care for people with non-communicable diseases, including dementia, through integrated care pathways (ICPs). Our study identified available dementia ICPs and assessed their compliance with the National Guidance on ICPs for People with Dementia (NGICPD). The project is carried out with the technical and financial support of the Ministry of Health (Chapter 2302). Methods We located ICPs by browsing all the websites of regions and Local Health Authorities (LHAs), contacting by email all LHAs, collecting ICPs from a survey carried out by the Dementia Observatory of the Italian National Institute of Health, and communicating with regional contacts. We included the ICPs produced after the NGICPD by the end of 2023. We applied a checklist developed on NGICPD consisting of 3 domains: Reference framework (0-15), Elements of the ICP (0-14), Construction of the ICP (0-14). ICPs were assessed by two researchers; a third solved the conflict points. The concordance was expressed by the intra-class correlation coefficient. Results We analysed 39 ICPs (11 regional, 28 LHAs) out of 87 collected. 15/21 regions and 30/110 LHAs developed an ICP. The observed mean total score was 23.5±7.9 for the regional ICPs and 23.1±5 for the LHAs ICPs. We observed low compliance with NGICPD, particularly in domain 3. The development of a health information system was included in 5/11 of regional and 12/28 of ICPs of LHAs; a monitoring system was present in 8/11 of regional and 25/28 LHAs ICPs. Concordance analysis showed an excellent correlation for regional ICPs and good for LHAs ICPs. Conclusions Our analysis highlighted low compliance of ICPs with the NGICPD and critical issues in monitoring. Our analysis stresses the need for all regions and LHAs to develop or update ICPs in line with NGICPD and the Italian Guidance on diagnosis and treatment of dementia. Key messages • Developing a pathway of efficient and coordinated care is essential to guarantee the quality of care for people with dementia and their families. All regions and LHAs must develop or update ICPs. • Monitoring ICP with indicators is crucial to planning cost-effective healthcare services.

Mechanisms of ozone-induced neurotoxicity in the development and progression of dementia: a brief review

Dementia encompasses a spectrum of neurodegenerative disorders significantly impacting global health, with environmental factors increasingly recognized as crucial in their etiology. Among these, ozone, has been identified as a potential exacerbator of neurodegenerative processes, particularly in Alzheimer’s disease (AD). Ozone exposure induces the production of reactive oxygen species (ROS), which penetrate the BBB, leading to oxidative damage in neuronal cells. This oxidative stress is closely linked with mitochondrial dysfunction and lipid peroxidation, processes that are foundational to the pathology observed in dementia, such as neuronal death and protein aggregation. Furthermore, ozone triggers chronic neuroinflammation, exacerbating these neurodegenerative processes and perpetuating a cycle of CNS damage. Recent studies highlight the role of peripheral biomarkers like High Mobility Group Box 1 (HMGB1) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in mediating ozone’s effects. Disruption of these and other identified proteins by ozone exposure impairs microglial function and response to amyloid plaques, suggesting a novel pathway through which ozone may influence AD pathology via immune dysregulation. This review discusses the concept of a bidirectional lung-brain axis, illustrating that systemic responses to air pollutants like ozone may reflect and contribute to neurodegenerative processes in the CNS. By delineating these mechanisms, we emphasize the critical need for integrating environmental health management into strategies for the prevention and treatment of dementia.

A network meta-analysis of different acupuncture therapy in the treatment of poststroke cognitive impairment and dementia.

Poststroke cognitive impairment and dementia (PSCID) is a major cause of stroke-related morbidities and mortalities. Over the last few years, there has been growing evidence supporting the effectiveness of needle-related treatments in PSCID. Our goal was to rate the included therapies and assess the clinical effectiveness of various needle-related treatments in patients with PSCID. We searched PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Chinese Biomedical Literature Service System (SinoMed), Wanfang, FDA.gov, and ClinicalTrials.gov. A mix of subject terms and free words was used to search the databases. The retrieval period was from the inception date of the database to February, 2023. We included SRs and MAs from acupuncture RCTs of patients with PSCID. The Cochrane Risk Assessment Scale was used to evaluate the risk of bias in the included studies. State 17.0 was used for network meta-analysis in accordance with the Bayesian framework. There were 34 studies total of 2690 patients. The cumulative ranking curve (SUCRA) revealed that CT + CFT + EA was the most efficient intervention to improve (Mini-Mental State Examination, MMSE) efficiency, followed by CT + CFT + AP to improve (Montreal Cognitive Assessment, MoCA) efficiency, CT + CFT + ACU for improving (Activities of Daily Living scale, ADL) scores, and CT + CFT + EA to improve clinical efficiency. The results show that Different acupuncture methods can improve cognitive function and daily living ability in patients with PSCID. Network meta-analysis revealed that both CT + CFT + ACU and CT + CFT + EA appeared to be more beneficial for daily living activities, while CT + CFT + EA and CT + CFT + AP appeared to be more helpful for cognitive performance in patients with PSCID. Treatments including acupuncture are safer and have a reduced incidence of negative side effects.

A systematic analysis of neurologic manifestations of Long COVID in Nigeria.

Long COVID, also called post-acute sequelae of SARS-CoV-2 infection (PASC) affects millions of people in the world. The neurologic manifestations of PASC (Neuro-PASC) are among the most debilitating but they are largely unreported in Africa. We sought to compare the demographics, symptoms and cognitive profile of post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients in Nigeria. In this cross-sectional study performed at the Lagos University Teaching Hospital, 106/2319 (4.6%) SARS-CoV-2 positive individuals contacted via telephone reported Neuro-PASC symptoms with a higher frequency in PNP than in NNP individuals ((23/200 (11.5%) vs. 83/2119 (3.9%), p = < 0.0001). The predominant neurologic symptoms at any time during the disease course were difficulty remembering / brain fog (63/106; 59.4%), fatigue (59/106; 55.7%), sleep problems (34/106; 32%), headache (33/106; 31%), paresthesia (12/106; 11.3%), and myalgia (10/106; 9.4%). Of 66 participants with Neuro-PASC who underwent in-person neurological evaluation and cognitive screening, all had normal scores on the Intervention for Dementia in Elderly Africans cognition screen, while 11/65 (16.9%) that completed the Montreal Cognitive Assessment had results consistent with mild cognitive impairment (3/16 PNP (18.8%) and 8/49 NNP (16.3%); p = 1.0). Finally, 47/66 (71.2%) had digit span test scores consistent with mild cognitive dysfunction (12/16 PNP (75%) and 35/50 (70%) NNP; p = 1.0). Our findings reveal the previously unrecognized occurrence of Neuro-PASC among COVID-19 survivors in Nigeria and highlight the need for improved screening and diagnosis of Neuro-PASC in our population. Development of cognitive support services for persons suffering from Neuro-PASC in Nigeria is warranted.

Tong-Qiao-Huo-Xue Decoction promotes synaptic remodeling via cAMP/PKA/CREB pathway in vascular dementia rats

BackgroundTong-Qiao-Huo-Xue Decoction (TQHXD) is a traditional Chinese medicinal formula widely used in the treatment of vascular dementia (VD). Although it has demonstrated good clinical efficacy, the specific molecular mechanisms underlying its therapeutic effects on VD remain unclear. ObjectiveThis study aimed to elucidate the neuroprotective mechanisms of TQHXD to provide a scientific basis for the clinical treatment of VD. MethodsThe chemical components of TQHXD were qualitatively analyzed using ultra-performance liquid chromatography (UPLC) and gas chromatography (GC). Network pharmacology predicted the potential protective mechanisms of TQHXD against VD. A rat model of VD was established through bilateral vessel occlusion (2-VO), and an oxygen-glucose deprivation/reperfusion (OGD/R) model was used to induce damage to neuronal cells of the hippocampus. In vivo experiments assessed changes in cerebral blood flow, learning and memory capabilities, hippocampal neuronal morphology, dendritic length, dendritic spine density, and synapse number in rats. We examined the expression of synaptic remodeling-related proteins and pathway proteins in the hippocampal region. In vitro assays evaluated cell viability, apoptosis, reactive oxygen species (ROS) levels, and expression of synaptic remodeling-related proteins and signaling pathway. ResultsMultiple active components were identified in TQHXD. KEGG enrichment analysis suggested that the therapeutic effects of TQHXD on VD may be related to the cAMP signaling pathway. Treatment with TQHXD significantly improved learning and memory performance in VD rats, improved hippocampus morphology, and increased dendritic length, dendritic spine density, and number of synapses. Furthermore, TQHXD improved cell viability, reduced apoptosis, and decreased intracellular ROS levels in vitro. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay results collectively demonstrated that TQHXD upregulated the expression of synaptic remodeling-related proteins and pathway-related proteins both in vivo and in vitro. ConclusionsTQHXD treated VD by promoting synaptic remodeling in hippocampal neurons, likely through activation of the cAMP/PKA/CREB pathway.

CMS121, a Novel Drug Candidate for the Treatment of Alzheimer's Disease and Age-Related Dementia.

Old age is the major risk factor for sporadic Alzheimer's disease (AD). However, old age-related changes in brain physiology have generally not been taken into consideration in developing drug candidates for the treatment of AD. This is at least partly because the role of these age-related processes in the development and progression of AD are still not well understood. Nevertheless, we and others have described an association between the oxytosis/ferroptosis non-apoptotic regulated cell death pathway and aging. Based on this association, we incorporated protection against this pathway as part of a cell-based phenotypic screening approach to identify novel drug candidates for the treatment of AD. Using this approach, we identified the fisetin derivative CMS121 as a potent neuroprotective molecule that is able to maintain cognitive function in multiple pre-clinical models of AD. Furthermore, we identified a key target of CMS121 as fatty acid synthase, a protein which had not been previously considered in the context of AD. Herein, we provide a comprehensive description of the development of CMS121, its preclinical activities, and the results of the toxicology testing that led to its IND approval.

Pharmacodynamic and Clinical Effects of Ginkgo Biloba Extract EGb 761 and Its Phytochemical Components in Alzheimer's Disease.

Extracts made from plants are complex mixtures of substances with varying compositions depending on the plant material and method of manufacture. This complexity makes it difficult for scientists and clinicians to interpret findings from pharmacological and clinical research. We performed a narrative review summarizing information on ginkgo biloba leaf extract, its composition, pharmacological data and clinical evidence supporting its administration for the treatment of Alzheimer's disease (AD). Medicinal products containing ginkgo biloba leaf extract which are manufactured in compliance with the requirements of the European Pharmacopoeia are approved as medicinal products for the treatment of dementia and related conditions by drug regulatory agencies in Europe, Asia and South America. As multicomponent mixtures, they may affect various targets in the pathogenesis of AD, the most common form of dementia. Pharmacodynamic studies demonstrate the effects of EGb 761 and individual constituents on various pathophysiological features of experimentally induced cognitive impairment and neurodegeneration that could contribute to its clinical efficacy. The safety and efficacy in the treatment of AD and cognitive decline has been studied in randomized, placebo-controlled clinical trials. Most of the studies that investigate the effects of ginkgo biloba extract (GbE) used the special extract EGb 761, which makes it the best-researched plant preparation worldwide. It is therefore the only herbal alternative to standard-of-care anti-dementia drugs. However, the mechanism of action has not been fully elucidated yet, and the clinical studies in AD show heterogeneity.

Life-Course Multidisciplinary Psychosocial Predictors of Dementia Among Older Adults: Results From the Health and Retirement Study

Abstract Background and Objectives Identifying predictors of dementia may help improve risk assessments, increase awareness for risk reduction, and identify potential targets for interventions. We use a life-course psychosocial multidisciplinary modeling framework to examine leading predictors of dementia incidence. Research Design and Methods We use data from the Health and Retirement Study to measure 57 psychosocial factors across 7 different domains: (i) demographics, (ii) childhood experiences, (iii) socioeconomic conditions, (iv) health behaviors, (v) social connections, (vi) psychological characteristics, and (vii) adverse adulthood experiences. Our outcome is dementia incidence (over 8 years) operationalized using Langa–Weir classification for adults aged 65+ years who meet criteria for normal cognition at the baseline when all psychosocial factors are measured (N = 1 784 in training set and N = 1 611 in testing set). We compare the standard statistical method (Logistic regression) with machine learning (ML) method (Random Forest) in identifying predictors across the disciplines of interest. Results Standard and ML methods identified predictors that spanned multiple disciplines. The standard statistical methods identified lower education and childhood financial duress as among the leading predictors of dementia incidence. The ML method differed in their identification of predictors. Discussion and Implications The findings emphasize the importance of upstream risk and protective factors and the long-reaching impact of childhood experiences on cognitive health. The ML approach highlights the importance of life-course multidisciplinary frameworks for improving evidence-based interventions for dementia. Further investigations are needed to identify how complex interactions of life-course factors can be addressed through interventions.

Preventing risk of placement breakdown and hospital admission in the management of distressed behaviour in dementia care: A qualitative case study with family and care-home staff.

Objectives: Behaviours such as hitting-out and declining personal care are commonly exhibited by people living with dementia and are associated with care-giver stress and anxiety and care home placement breakdowns. Traditionally, pharmacological approaches have been used to manage behaviour; however, research indicates limited effectiveness. National guidelines recommend use of non-pharmacological interventions as first line treatment for distress, but further research is required to elucidate the components that lead to improved care for people living with dementia. This study aims to explore what works, examining case studies in which a non-pharmacological clinical intervention, the Newcastle Model, was used to understand and manage distressed behaviour in dementia care within care home settings. Method: A qualitative case study design was used. Three cases were selected from the Edinburgh Behaviour Support Service for their success in preventing care home placement breakdown during a distressed behaviour intervention in NHS Scotland. Family members and staff involved in the interventions within these cases were interviewed (N = 6). Thematic analysis was used to analyse data. Findings: All participants reported positive outcomes from the intervention. Three key themes were identified, each with subthemes. Participants described a supportive, non-judgmental environment which allowed them to integrate knowledge about dementia and tailor interventions to the specific needs of the individual living with dementia. There was also a sense of family and staff coming together to unite with shared goals. A preliminary model of all of themes and their interactions is presented. Conclusion: The study supports use of biopsychosocial, formulation-led approaches in the understanding and treatment of complex behavioural presentations in community care settings. It suggests that clinicians should endeavour to facilitate safe and open environments for care home staff and family members, in order to promote attribution change and person-centered care, and to help mediate differences and conflict between staff and family members.

Association between preventive treatment for unruptured intracranial aneurysms and incident dementia: a nationwide population-based cohort study

Preventive treatments for unruptured intracranial aneurysms (UIAs) are used worldwide. However, the long-term effects to cognition have been underestimated. Using representative sample data from the National Health Insurance Service-Senior Cohort database, we compared cumulative risk of incident dementia between two groups: (1) treatment versus observation group, and (2) within the treatment group (surgical versus endovascular treatment). Cox proportional hazard ratios were estimated after applying one-to-one propensity score matching. Subgroup analyses were conducted to investigate interactions between treatment effects and sex, age and history of stroke, respectively. After matching, 3,763 participants were included in each group. The 10-year incidence rates of dementia were 9.82 and 8.68 per 1,000 person-years in the treatment and observation groups, respectively (HR: 1.11, 95% CI: 0.90–1.38, P = 0.33). Furthermore, the risk of incident dementia was not different between the surgical and endovascular treatment groups (HR: 0.98, 95% CI: 0.70–1.37, P = 0.91). In the subgroup analysis, surgical treatment was associated with an increased risk of developing dementia, particularly among male patient (HR: 2.34, 95% CI: 1.04–5.28). Preventive treatment of UIAs appears acceptable in terms of long-term effects to cognition. However, further researches are strongly required to identify the high risk patients of development of dementia.