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Background: Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer's disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD., Methods: The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models., Results: The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period., Conclusions: The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling., (© 2024. The Author(s).)

Background: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity., Objectives: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias., Methods: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m 2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models., Results: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years)., Conclusion: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate., Design: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori., Setting: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial., Participants: Alzheimer's disease patients with clinically significant apathy., Measurements: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A)., Results: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale., Conclusion: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer's disease [AD], Huntington's disease [HD] and Parkinson's disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics-such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)-that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

Background and Purpose: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression., Methods: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003-2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke., Results: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X 2 =5.4; P =0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHR Depression =1.57 [1.24-1.98]) and incident dementia (aHR Depression =1.85 [1.40-2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHR Diabetes =1.20 [1.12-1.29]; aHR Depression =1.19 [1.04-1.37]), incident dementia (aHR Diabetes =1.14 [1.06-1.23]; aHR Depression =1.27 [1.08-1.49]), stroke/transient ischemic attack readmission (aHR Diabetes =1.18 [1.10-1.26]; aHR Depression =1.24 [1.07-1.42]), and all-cause mortality (aHR Diabetes =1.29 [1.23-1.36]; aHR Depression =1.16 [1.05-1.29])., Conclusions: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

Background: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice., Objective: To establish research criteria for the diagnosis of psychosis in AD., Methods: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria., Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers., Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Behavioral and psychological symptoms associated with dementia are highly prevalent and are associated with an increased risk of institutionalization and mortality. Current pharmacological treatments for these symptoms include cholinesterase inhibitors, antipsychotics, and selective serotonin reuptake inhibitors. When used for treating behavioral and psychological symptoms associated with dementia, they are associated with limited efficacy and/or serious adverse events. As such, there has been extensive research into novel agents with varying mechanisms of action targeting behavioral and psychological symptoms associated with dementia. In this article, we present the results of a comprehensive literature search and review that evaluates current agents that have completed or are currently in clinical trials for treating behavioral and psychological symptoms associated with dementia as a primary outcome. We highlight novel agents from miscellaneous drug classes, such as dextromethorphan/quinidine, bupropion/dextromethorphan, lumateperone, deudextromethorphan/quinidine, methylphenidate and scyllo-inositol, and drugs from various therapeutic classes (including atypical antipsychotics, selective serotonin reuptake inhibitors, and cannabinoids) that have demonstrated promising results and were generally well tolerated. Future research with large appropriately powered studies using validated outcome measures for behavioral and psychological symptoms associated with dementia should be conducted to further establish the clinical utility of these agents.

Purpose of Review: The purpose of this study was to update a national guideline on assessing drivers with dementia, addressing limitations of previous versions which included a lack of developmental rigor and stakeholder involvement., Methods: An international multidisciplinary team reviewed 104 different recommendations from 12 previous guidelines on assessing drivers with dementia in light of a recent review of the literature. Revised guideline recommendations were drafted by consensus. A preliminary draft was sent to specialist physician and occupational therapy groups for feedback, using an a priori definition of 90% agreement as consensus., Recent Findings: The research team drafted 23 guideline recommendations, and responses were received from 145 stakeholders. No recommendation was endorsed by less than 80% of respondents, and 14 (61%) of the recommendations were endorsed by more than 90%.The recommendations are presented in the manuscript. The revised guideline incorporates the perspectives of consensus of an expert group as well as front-line clinicians who regularly assess drivers with dementia. The majority of the recommendations were based on evidence at the level of expert opinion, revealing gaps in the evidence and future directions for research.

Purpose of Review: Efficacious treatment for neuropsychiatric symptoms (NPS), pain and weight loss for dementia patients is desperately needed. This review presents an up-to-date look at the literature investigating the use of cannabinoid for these symptoms in dementia., Recent Findings: We searched electronically for publications regarding cannabinoid use in dementia, with a focus on Alzheimer's disease. Seven studies and one case report have been conducted to examine the use of cannabinoids for the treatment of NPS of dementia, and three of these trials reported on the effect of cannabinoids on weight. Five studies reported decreased agitation or improvements in sleep with cannabinoid use. One crossover trial found that cannabinoids positively impacted weight, whereas a chart review study found no impact on weight with cannabinoids, but an increase in food intake. There were no trials examining the use of cannabinoids for pain in dementia., Summary: Findings from trials with small sample sizes and various clinical populations suggest that cannabinoid use may be well tolerated and effective for treatment of NPS such as agitation as well as weight and pain management in patients with dementia. Additional studies are necessary to further elucidate the relative risks and benefits of this treatment.

Background: Apathy, characterized by diminished motivation, is a highly prevalent neuropsychiatric symptom in dementia. However, there is a substantial knowledge gap with regard to prevalence rates, neurobiological underpinnings, and effective treatments for apathy in pre-dementia states, including mild cognitive impairment (MCI) and mild behavioral impairment (MBI)., Methods: We conducted a comprehensive literature search using MEDLINE, Embase, and PsycINFO databases to identify available research on apathy in prodromal dementia., Results: Apathy has consistently been detected in individuals with MCI with varying prevalence rates, and only recently has literature discussed the prevalence of apathy in MBI. Few pharmacological treatments have been utilized for apathy, with galantamine and risperidone showing mild reductions in apathetic behaviors. Non-pharmacological interventions in prodromal dementia are beginning to be explored and show promise, but few studies have replicated those results., Discussion: More comprehensive guidelines for diagnosing apathy and further research investigating neurobiological mechanisms of apathy in MCI and MBI are required in order to effectively treat apathetic patients in prodromal dementia.

Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.

Guidelines that physicians use to assess fitness to drive for dementia are limited in their currency, applicability, and rigor of development. Therefore, we performed a systematic review to determine the risk of motor vehicle collisions (MVCs) or driving impairment caused by dementia, in order to update international guidelines on driving with dementia. Seven literature databases (MEDLINE, CINAHL, Embase, etc.) were searched for all research studies published after 2004 containing participants with mild, moderate, or severe dementia. From the retrieved 12,860 search results, we included nine studies in this analysis, involving 378 participants with dementia and 416 healthy controls. Two studies reported on self-/informant-reported MVC risk, one revealing a four-fold increase in MVCs per 1,000 miles driven per week in 3 years prior, and the other showing no statistically significant increase over the same time span. We found medium to large effects of dementia on driving abilities in six of the seven recent studies that examined driving impairment. We also found that persons with dementia were much more likely to fail a road test than healthy controls (RR: 10.77, 95% CI: 3.00-38.62, z = 3.65, p < 0.001), with no significant heterogeneity (χ 2  = 1.50, p = 0.68, I 2  = 0%) in a pooled analysis of four studies. Although the limited data regarding MVCs are equivocal, even mild stages of dementia place patients at a substantially higher risk of failing a performance-based road test and of demonstrating impaired driving abilities on the road., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Research on efficacious treatments for apathy in Alzheimer disease has been hindered by a lack of consensus diagnosis, difficulties in measurement, and studies with small sample sizes., Methods: In designing the Apathy in Dementia Methylphenidate Trial (ADMET), a trial to evaluate the efficacy and safety of methylphenidate for the treatment of apathy in Alzheimer disease, we encountered the following issues: defining and measuring apathy, distinguishing apathy and depression, determining an appropriate test treatment, selecting relevant secondary outcomes, recruiting participants, and deciding on a suitable method for treatment unmasking. ADMET is a 6-week randomized, double-masked, placebo-controlled multicenter clinical trial with two parallel treatment groups assigned in a 1:1 ratio with randomization stratified by clinical center. The recruitment goal is 60 randomized participants over 2 years. The primary outcomes are change in apathy severity as measured by the Apathy Evaluation Scale and the Alzheimer Disease Cooperative Study-Clinical Global Impression of Change., Conclusion: The design decisions made for ADMET are important elements to be considered in trials assessing the safety and efficacy of medications for clinically significant apathy in Alzheimer disease., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Although recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies., Methods: A MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers β-amyloid, tau, positron emission tomography ((18)F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline., Results: Of the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds., Conclusions: The body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Behavioral and psychological symptoms of dementia (BPSD) include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite impairment. These symptoms have adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, worsening quality of life and earlier institutionalization. While the etiology of BPSD has not been clearly delineated, studies assessing the benefits of acetylcholinesterase inhibitors on BPSD suggest that some of the neuropsychiatric symptoms of dementia such as agitation, apathy and psychosis may represent a specific central cholinergic deficiency syndrome. Biochemical and neuroimaging studies of BPSD in Alzheimer's patients support these pharmacological data. This review discusses the literature describing the association between cholinergic deficiency and manifestations of BPSD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Cholinesterase inhibitors (ChEIs) are being used for increasingly long periods of time, even in patients with severe Alzheimer's disease. Because there is little data to help clinicians to decide on when it is safe and appropriate to discontinue ChEIs after long-term use, practices may vary widely., Methods: An internet-based survey was undertaken of Canadian dementia experts (geriatric psychiatrists, neurologists, geriatricians) involved in clinical trial research. Recommendations for ChEI discontinuation were determined based on responses to questions dealing with patient/caregiver preference, administrative considerations, effectiveness, and adverse events., Results: There was reasonable consensus that ChEIs should be discontinued based on patient and caregiver preference, and in the presence of severe bothersome adverse events. There was much less consensus on issues related to effectiveness - in particular, what constitutes greater than expected decline. There was a general reluctance to rely on any single measure of cognition, function and/or behavior, and in particular, the MMSE was seen as unhelpful for making decisions about discontinuation., Conclusion: Recommendations for discontinuing ChEIs after long-term use from a survey of dementia experts are presented. Ideally, clinical practice guidelines based on controlled discontinuation trials are needed.

Using PET neuroimaging, we demonstrated that four frontotemporal lobar dementia (FTLD) patients had significantly decreased serotonin 5-HT(1A) binding potential (BP) compared with controls in all 10 brain regions examined. These pilot data suggest that profound 5-HT(1A) BP losses may be present and contribute to symptomatology and treatment response in FTLD.

Objective: To estimate the contribution of behavioral and psychological symptoms of dementia (BPSD) to the costs of care., Method: A one-year prospective study of resource utilization recorded monthly by 500 caregivers of community dwelling patients with dementia. The effect of behavior on total, direct and indirect costs of care was examined., Results: The total cost of care was $1,298 per month and there was a significant independent relationship between costs and BPSD. The incremental cost of a one point increase in Neuropsychiatric Inventory score was $30 per month (95% CI: $19-$41)., Conclusion: BPSD contribute significantly to the overall costs of dementia care. Interventions targeted at BPSD may help to reduce the staggering societal costs of this illness., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Recent concerns regarding the use of atypical antipsychotics when used for the treatment of neuropsychiatric symptoms in dementia have led to a flurry of studies attempting to re-evaluate their place in therapy. We critically review current evidence on the safety profiles of these agents in patients with behavioural and psychological symptoms of dementia (BPSD) and provide recommendations to guide the clinician. Potential risks with this class of medications include extrapyramidal symptoms (EPS), weight gain, diabetes mellitus, cardiac conduction abnormalities (e.g. corrected QT [QTc] interval prolongation), cerebrovascular adverse events and mortality. Compared with placebo, treatment of BPSD with atypical antipsychotics leads to little or no increase in EPS and no significant weight change. Compared with typical antipsychotics, treatment of BPSD with atypical antipsychotics leads to a reduced risk of EPS, lower incidences of tardive dyskinesias and no significant weight gain. Atypical antipsychotics have not been associated with glucose intolerance, diabetes or hyperlipidaemia in elderly dementia patients. Both typical and atypical antipsychotics have been associated with cardiac conduction abnormalities, with the magnitude of QTc prolongation being slightly smaller with atypical antipsychotics. Randomised controlled trials suggest that atypical antipsychotics are associated with an increased risk of cerebrovascular adverse events, such as stroke, and an increased mortality compared with placebo. However, it appears that typical antipsychotics have similar risks of cerebrovascular adverse events and death. An increased risk of anticholinergic adverse effects and falls must also be considered with both typical and atypical antipsychotics. In summary, atypical antipsychotics are associated with potentially serious adverse events. Before prescribing these medications in elderly dementia patients, baseline EPS, ECG abnormalities and concomitant medications should be assessed, and the presence of cardiovascular, cerebrovascular and metabolic risk factors should be taken into consideration when benefits and risks are being weighed.

The behavioral and psychological symptoms of dementia (BPSD) are common serious problems that are a major contributor to caregiver burden. Despite their significance, the underlying neurobiology of these disturbances is still unclear. This review examines the role of norepinephrine (NE) on BPSD, including depression, aggression, agitation and psychosis. A number of lines of evidence suggest that NE dysfunction leading to BPSD may result from increased NE activity and/or hypersensitive adrenoreceptors compensating for loss of NE neurons with progression of Alzheimer's disease (AD). With greater appreciation of the underlying neurobiology of behavioral and psychological symptoms of dementia (BPSD) more effective, rational, targeted pharmacotherapy will hopefully emerge.

Objective: This study aimed to measure the economic value of cholinesterase inhibitors when used to treat Alzheimer's disease using the willingness-to-pay (WTP) approach and the framework of cost-benefit analysis., Methods and Study Design: A cost-benefit analysis using the WTP approach was employed. The study sample consisted of 28 nonprofessional caregivers of outpatients with mild to moderate dementia from Toronto, ON, Canada. The caregivers were presented with four scenarios. In the first scenario, scenario A, a hypothetical patient with mild dementia was stabilised with a cholinesterase inhibitor. In the second scenario, scenario A with adverse effects, the above patient (A) experienced adverse effects caused by the drug. In the third scenario, scenario B, the patient exhibited behavioural symptoms in addition to mild dementia, and both were stabilised with the drug. In the fourth scenario, scenario B with adverse effects, the above patient (B) experienced adverse effects caused by the drug. The caregivers were then asked what amount they would pay, in Canadian dollars, each year to buy the medication, assuming that they were the caregivers of the patient described. A multivariate regression analysis was performed to assess the relationship between the demographic data (including the caregiver's yearly income) and the WTP. The average WTP was also predicted for the general population and the elderly population of Canada using data from Statistics Canada, and these values were compared with the cost of the medication., Study Perspective: Nonprofessional caregiver perspective. All monetary values are 1999 values unless otherwise specified., Results: The mean yearly WTP was $Can4540 (95% CI 2334-6746) for scenario A, $Can3686 (95% CI 1530-5842) for scenario A with adverse effects, $Can5003 (95% CI 2661-7345) for scenario B and $Can4486 (95% CI 2222-6750) for scenario B with adverse effects. The WTP decreased when drug adverse effects were present (significantly in scenario A; p = 0.04), but did not significantly increase when behavioural symptoms were present and stabilised. In all scenarios, caregiver yearly income was the only significant predictor of WTP, in the direction expected. For all scenarios, the calculated WTPs from the regression analysis using our sample mean, the average Canadian population data and the elderly population data were all higher than the yearly cost of the cholinesterase inhibitors, with the net benefit ranging from $Can1723 to $Can4508., Conclusions: The results of the study, from a small sample of nonprofessional caregivers, revealed that the caregivers are willing to pay more for cholinesterase inhibitors than the drugs cost, even when the adverse effects of the drugs are taken into consideration. This indicates a net benefit for cholinesterase inhibitors in the treatment of mild to moderate dementia from a consumer's point of view.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

The common requirement to set the time to "10 past 11" on the Clock Drawing Test is intended to elicit a stimulus bound response (SBR), in which the responder is "pulled" to the salient stimulus "10," resulting in hands set at "10 before 11." SBRs are considered markers of executive dysfunction, although this assumption has not yet been validated. We compared SBR and other time-setting errors on inhibitory control tests, hypothesizing that they represent related constructs. The role of semantic dysfunction in the formation of those errors was also investigated. We examined baseline test performance of participants with Mild Cognitive Impairment or a history of depression, and control participants, enrolled in a dementia prevention study. Among 258 participants, we identified clocks with SBRs (n = 16), other time errors (n = 22), or no errors at all (n = 42). Performance between the groups with SBRs and other time-setting errors did not differ on any of the executive tests, and both error groups performed significantly worse than the No Error group on the semantic tests. Control for covariates further supported semantic and executive components in time-setting errors. Both semantic and inhibitory control deficits may underlie time representation errors in general. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

Background: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. Objectives: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. Design, Setting and Participants: We conducted a cohort analysis of participants in the COMPASS‐ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. Measurements: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. Results: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312) = −2.4, p = 0.02 and t(328) = −3.8, p = 0.001, respectively) and visuospatial reasoning (t(301) = −2.3, p = 0.02 and t(321) = −2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex‐stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166) = 2.4, p = 0.01) and verbal learning (t(167) = −4.3, p = 0.001) compared to the female neither group. Conclusions: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. Key points: Apathy and depression are common symptoms that patients with dementia face during the course of illness, and these symptoms are associated with impairments in several cognitive domains.We examined differences in cognitive performance between patients with either apathy alone, depression alone, both, or neither across a combined cohort with mild or major neurodegenerative disorders. Further, we evaluated this relationship within each sex.Among males, apathy with or without depression was associated with broad cognitive deficits. In females, depression was associated with deficits in executive function and verbal learning.These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI‐Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS: We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR‐global. RESULTS: Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI‐Q scores increased steeply with MCI (NPI‐Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI‐Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). DISCUSSION: CDR‐global staged AD by capturing differences in relevant outcomes along AD progression. Highlights: There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F (2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F (2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F (2,330) = 7.525, ηp2 = 0.044, p < 0.001). Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system. [ABSTRACT FROM AUTHOR]

Background: Sulfonylureas are oral glucose‐lowering medications positioned as a second‐line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase‐4 (DPP4) inhibitor use. Methods: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population‐based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity‐score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention‐to‐treat exposure definition. A separate propensity‐score weighted analysis was conducted to explore within‐class differences in dementia risk among sulfonylurea new users selected from the primary cohort. Results: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person‐years; aHR [95% CI] = 1.09 [1.04–1.15]) over a mean follow‐up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03–1.32]). Conclusion: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes. See related Editorial by Lee et al. in this issue. [ABSTRACT FROM AUTHOR]

Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent.Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC).Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models.Results: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy.Conclusion: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD. [ABSTRACT FROM AUTHOR]

Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed. Setting: Community-based multi-centered study based in Toronto across 5 academic sites. Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls. Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores. Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p <.05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p >.05). A history of hypertension was associated with lower performance in composite executive function (p <.05) and overall composite neuropsychological test score (p <.05) among a pooled cohort with MCI or MDD. Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions. [ABSTRACT FROM AUTHOR]

Introduction: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status. Methods: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory. Results: Compared to PPI, H2RAuse was associated with earlier progression fromMCI to dementia (HR = 1.40 [1.09-1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio=0.76 [0.64-0.92]; n=628), but not with progression from normal cognition toMCI (HR = 0.94 [0.71-1.24]; n = 2784). Discussion: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress.Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory.Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks.Results: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (β= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005).Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness. [ABSTRACT FROM AUTHOR]

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver.Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored.Methods: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation.Results: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%).Conclusion: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD).Design: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases.Setting: Patients were recruited from a long-term care facility and geriatric psychiatry clinics.Participants: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3).Intervention: Nabilone (target 1-2 mg) versus placebo.Measurements: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events.Results: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22).Conclusions: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored. [ABSTRACT FROM AUTHOR]

This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population. [ABSTRACT FROM AUTHOR]

Background: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described.Objective: To develop an instrument based on ISTAART-AA MBI criteria.Methods: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults.Results: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician.Conclusion: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes. [ABSTRACT FROM AUTHOR]

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Post hoc analyses of pooled results from 11 randomised controlled trials of risperidone and olanzapine in elderly dementia subjects revealed an increased incidence of cerebrovascular adverse events compared with placebo. Reanalysis of the risperidone trials suggests that some of the increased incidence may be accounted for by nonspecific events that were not strokes. Large observational administrative health database studies appear to confirm that risperidone and olanzapine are not associated with an increased risk of stroke in elderly patients compared with typical antipsychotics or untreated dementia patients. A larger number of subjects with vascular and mixed dementias were included in the risperidone studies compared with the olanzapine studies, which likely accounts for the increased incidence of cerebrovascular adverse events in the risperidone trials compared with the olanzapine studies. Potential mechanisms proposed to explain an association between atypical antipsychotics and cerebrovascular adverse events include thromboembolic effects, cardiovascular effects (e.g. orthostatic hypotension, arrhythmias), excessive sedation resulting in dehydration and haemoconcentration, and hyperprolactinaemia. However, there is little evidence to support these hypothesised mechanisms at present. The association between atypical antipsychotics and cerebrovascular adverse events requires further clarification. At the present time, this association is another factor that clinicians should consider when weighing the risks and benefits of treating behavioural and psychological disturbances in elderly dementia patients. [ABSTRACT FROM AUTHOR]

Background This study aimed to determine whether the Quality of Life in Late-Stage Dementia (QUALID) scale is responsive to changes in behaviour due to therapeutic intervention. Method 31 long-term care residents with moderate to severe AD and agitation/aggression entered a three-month, open-label trial of memantine 10 mg BID. The relationships between the QUALID and BPSD, global improvement, and cognition at baseline and endpoint, as well as the changes in these scales as a result of treatment, were examined. Results Despite a significant improvement in agitation and aggression (NPI agitation, F3,90 = 3.721, p =.014; CMAI total, F3,90 = 6.301, p =.001) and overall behaviour (NPI total, F3,90 = 4.035, p =.010), there was no significant change in QUALID score (t30 =-0.278, p =.783). The QUALID was correlated with NPI at baseline (τ = 0.270, p =.037) and endpoint (τ = 0.404, p =.002), but change scores were not correlated (τ = 0.107, p =.412). Conclusion While the QUALID correlates with behavioural measures at single time points, it does not appear to correlate with changes longitudinally associated with treatment. [ABSTRACT FROM AUTHOR]

Abstract: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. [Copyright &y& Elsevier]

SUMMARY Background: Alzheimer's disease (AD) is characterized by a number of serious and debilitating behavioral and psychological symptoms of dementia (BPSD). The most common of these BPSD is apathy, which represents a major source of morbidity and premature institutionalization in the AD population. Many studies have identified discrete changes to the dopaminergic (DAergic) system in patients with AD. The DAergic system is closely related to the brain reward system (BRS) and some studies have suggested that dysfunction in the DAergic system may account for symptoms of apathy in the AD population. Method: Changes to the dopamine (DA) system in AD will be reviewed, and evidence supporting the involvement of the DAergic system in the development of apathy will be examined. Additionally, some pharmacological interventions with DA activity have been identified. The utility of these treatments in the AD population will be reviewed, with a focus on apathy as an outcome. Results: Evidence presented in this review suggests that DA dysfunction in discrete brain areas is an important correlate of apathy in AD and that the DAergic system may be a rational target for pharmacological treatment of apathy. [ABSTRACT FROM AUTHOR]

Background/Aims: Adverse drug events (ADEs) are a frequent problem encountered in the elderly. The aim of this study was to elucidate the factors that influence ADEs in an elderly population with cognitive impairment. Methods: 242 patients were recruited from dementia clinics and assessed after 6 months for ADEs. The use of natural health products (NHPs) was also documented. Results: Backward logistic regression found that higher age (OR = 1.06; 95% CI 1.01–1.12), and greater cognitive impairment (OR = 0.94; 95% CI 0.90–0.98) were associated with an increased risk of developing an ADE while the use of NHPs (OR = 0.32; 95% CI 0.13–0.79) was associated with a decreased risk (χ2 = 27.6, p < 0.001). Conclusion: Risk of ADEs increased with greater age and cognitive impairment but decreased with the use of NHPs. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study compared patient and caregiver perceptions of natural health products (NHPs) and conventional medications in a memory clinic population. A total of 620 mildly cognitively impaired patients and their caregivers participated in interviews enquiring about their perceptions of NHPs in 4 areas: (1) disclosure of NHP usage information to health care professionals, (2) safety and benefits of NHPs, (3) safety and benefits of conventional medications, and (4) physician knowledge about NHPs. Differences in responses between NHP users and nonusers and between patients and caregivers were examined. A total of 51,8% of subjects were current NHP users, with vitamin E, ginkgo biloba, and glucosamine being the most commonly used products. Multivariate analysis of variance showed that NHP use significantly influenced participant interview responses (Pillai's trace, F[4, 613] = 3.488, P = .008), while interviewee (patient or caregiver; Pillai's trace, F[8, 1228] = 1.499, P = .153) and gender (Pillai's trace, F[4, 615] = 0.528, P = .715) did not. Subsequent univariate tests showed that NHP users were significantly more likely to endorse the effectiveness and safety of NHPs compared with nonusers (F[1, 616] = 7.826, P = .005). Careful questioning during visits with health care providers and better counseling may be necessary to reduce the potential for adverse events and NHP-drug interactions. [ABSTRACT FROM AUTHOR]

Background It is not understood why some patients with Alzheimer disease (AD) display aggression and others do not. Objective To examine the relation between regional brain perfusion and aggression in AD. Design Single-photon emission computed tomographic scans were coregistered to a standardized template in Talairach space, generating mean ratios of uptake referenced to the cerebellum. Participants Forty-nine outpatients (25 men and 24 women; mean ± SD age, 74 ± 11 years) with probable AD (Mini-Mental State Examination score, 17.7 ± 5.0; 30 aggressive and 19 nonaggressive), comparable in age, sex, and severity of cognitive impairment. Main Outcome Measures Regional perfusion ratios were determined for 5 bilateral regions of interest: orbitofrontal, middle medial temporal, inferior medial temporal, hypothalamus/thalamus, and anterior cingulate. Results Compared with nonaggressive patients, aggressive ones displayed hypoperfusion in the right and left middle medial temporal regions of interest (P = .02 for both), but not the others (all (t tests, unpaired, 2-tailed). On regression analyses, right middle temporal hypoperfusion (P = .001), younger age (P = .002), greater activity disturbances (P = .004), and higher Mini-Mental StateExamination scores (P = .04) independently predicted aggression, accounting for 44% of the total variance (F = 8.7; P<.001). Statistical parametric mapping analyses supported right middle medial temporal hypoperfusion in the aggressive group (P = .008). Conclusion In this sample of patients with AD, the right middle medial temporal region emerged as an important neural correlate of aggression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by disruptions in multiple major neurotransmitters. While many studies have attempted to establish whether GABA is disrupted in AD patients, findings have varied. We review evidence for disruptions in GABA among patients with AD and suggest that the variable findings reflect subtypes of the disease that are possibly manifested clinically by differing behavioural symptoms. GABA, the major inhibitory neurotransmitter, has long been a target for anxiolytics, hypnotic sedatives, and anticonvulsants. We review the clinical use of GABAergic agents in treating persons with AD symptoms. While newer generation GABAergic medications are now available, they have yet to be evaluated among patients with AD. [ABSTRACT FROM AUTHOR]

Background Indications for serotonergic medications in the treatment of behavioral disorders associated with Alzheimer's disease (AD) remain to be established. Method Sertraline (100 mg OD) was evaluated in a double-blind, randomized, placebo-controlled cross-over study in 22 nondepressed patients with severe probable AD and significant behavioral disturbance. Each subject was given a fenfluramine challenge to evaluate central serotonergic tone. Results Eight of 21 (38%) completers responded to sertraline. Drug responsive behaviors included aggression/agitation, irritability and aberrant motor behavior. Low aggression, female gender and large prolactin increase were associated with a better response. There was a trend for decreased aggression during sertraline versus placebo (p = 0.08). Conclusion Aggression, gender and serotonergic function were associated with sertraline response. Larger randomized controlled trials are needed to clarify the profile of responders. Copyright © 2002 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) has been associated with important behavioural disturbances, such as psychotic symptoms. Unfortunately, neuroleptic sensitivity in these patients limits effective pharmacological management of these symptoms. Seven patients, five male and two female (mean age 75.3±4.7 years, range 68–81), diagnosed with DLB were treated with the acetylcholinesterase inhibitor donepezil (5–10 mg once daily) to determine its effect on treating behavioural disorders. Although the intended length of treatment was a minimum of 8 weeks, only three patients completed 8 weeks of therapy, one patient completed 6 weeks, two patients completed 4 weeks and one patient was discontinued after 5 days. The primary outcome (behavioural disturbances) was measured prospectively by the Neuropsychiatric Inventory (NPI), while other outcomes included cognition (Mini-Mental State Examination (MMSE)) and Clinical Global Impression. Three of the seven subjects showed marked improvement in behaviour, with NPI scores dropping significantly over time. Donepezil therapy was discontinued prematurely in three of the cases due to insufficient response and/or adverse events. Overall, five of the seven patients were rated at least minimally improved in behavioural symptoms. Our experience with donepezil in this group of patients shows promise. Given the limited experience with this agent in treating behavioural disorders associated with DLB, further studies are warranted. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]