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BackgroundPsychotic 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.ObjectiveTo establish research criteria for the diagnosis of psychosis in AD.MethodsThe 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.ResultsConsensus 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.ConclusionWe 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.

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.

Objectives: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo‐controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. Results: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6‐month follow‐up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow‐up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post‐baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. Conclusions: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment. Key points: Methylphenidate (MPH) use in Alzheimer's Disease (AD) patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population.The ADMET2 trial found that participants with AD treated with MPH for apathy experienced a modest but statistically significant greater weight loss compared to placebo group over 6 months, emphasizing the need for clinicians to monitor weight change during treatment. [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.

INTRODUCTION: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes. METHODS: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM‐), or (3) neither (HTN‐/DM‐). AD risk in HTN+/DM+ and HTN+/DM‐ was compared to HTN‐/DM‐. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN‐/DM+ was compared to HTN‐/DM‐. RESULTS: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19–1.44]) and HTN+/DM‐ (HR = 1.24 [1.17–1.32]) increased AD risk compared to HTN‐/DM‐. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16–3.79]) and CAA (HR = 1.52 [1.09–2.12]), and in HTN+/DM‐ with CVNP (HR = 1.54 [1.17–2.03]). HTN‐/DM+ also increased AD risk (HR = 1.88 [1.30–2.72]) compared to HTN‐/DM‐. DISCUSSION: HTN+/DM+ and HTN+/DM‐ increased AD risk compared to HTN‐/DM‐, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles. Highlights: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/‐).HTN+/DM+ and HTN+/DM‐ both had an increased risk of AD compared to HTN‐/DM‐.Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM‐.In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA.In HTN+/DM‐, AD risk was greater in those with cerebrovascular neuropathology. [ABSTRACT FROM AUTHOR]

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]

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 m2 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. [ABSTRACT FROM AUTHOR]

Background: Many individuals with Alzheimer's disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments. Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD. Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD. Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost. Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions. [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: 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]

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6‐month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms. [ABSTRACT FROM AUTHOR]

Background: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. Objective: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. Methods: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating–Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. Results: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. Conclusion: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). Methods: A latent state–trait model with autoregressive effects was used to determine how much of the ADAS‐Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Results: Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS‐Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion‐specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Conclusions: Although the ADAS‐Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion‐specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS‐Cog item measures. Highlights: Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS‐Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state–trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion‐specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually. [ABSTRACT FROM AUTHOR]

Introduction: Mild behavioral impairment (MBI) is characterized by later‐life emergence of neuropsychiatric symptoms. Investigating its relationship with progression to Alzheimer's disease (AD) would provide insight on its importance as a predictor of AD. Methods: Cognitively normal participants (N = 11,372) from the National Alzheimer's Coordinating Center were stratified by MBI status, using the Neuropsychiatric Inventory‐Questionnaire. We investigated whether MBI and its domains were predictors of progression to clinically‐diagnosed AD. MBI as a predictor of progression to neuropathology‐confirmed AD was also investigated in those with neuropathological data. Results: Six percent (N = 671) of participants progressed to AD. MBI (N = 2765) was a significant predictor of progression to clinically‐diagnosed (hazard ratio [HR] = 1.75) and neuropathology‐confirmed AD (HR = 1.59). MBI domains were also associated with clinically‐diagnosed AD, with psychosis having the greatest effect (HR = 6.49). Discussion: These findings support the biological underpinnings of MBI, emphasizing the importance of later life behavioral changes in dementia detection and prognostication. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies regarding the relationship between depression and Alzheimer's neuropathology in older adults without dementia have reported conflicting findings. This study examined whether depression is associated with Alzheimer's neuropathology and whether sex moderates these relationships.Methods: This is a cross-sectional study of older adults without dementia (normal cognition or mild cognitive impairment, age 50+; CDR ≤ 0.5) who had autopsy within 1 year of their last clinic visit in the National Alzheimer's Coordinating Center database (2005-2020). Logistic regression models were fitted to determine if a recent or remote history of depression was associated with amyloid spread beyond the neocortex measured by modified Thal phase score, density of amyloid plaques measured by CERAD score or tau neuropathology measured by modified Braak score. A moderator analysis was performed to determine if any of these associations were moderated by sex.Results: This study included 407 participants (96 Thal, 405 Braak, and 406 CERAD). Those who had recently active depression (within previous 2 years) but not remote depression only were more likely to have higher Thal phase score compared to those without a history of depression (OR = 3.74; 95% CI, 1.15-12.17; p = 0.028). Sex did not moderate this association. No significant associations between recent depression and Braak or CERAD scores were observed.Conclusion: Our findings indicate that the association between late life depression and Alzheimer's neuropathology is associated with spread of amyloid pathology beyond the neocortex to include allocortical and subcortical regions critical for regulation of mood and motivated behavior. [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]

Background: Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease. Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. Method: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947–June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger's test were used to assess heterogeneity and risk of publication bias, respectively. Results: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] −1.45 [−1.83, −1.06], p<0.001) and MCI (−1.15 [−1.71, −0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (−0.87 [−1. 30, −0.44], z=3.96, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (−0.66 [−1.11, −0.21], p=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger's test indicated risk of publication bias. Conclusion: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity. [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]

Longitudinal invariance indicates that a construct is measured over time in the same way, and this fundamental scale property is a sine qua non to track change over time using ordinary mean comparisons. The Alzheimer's Disease Assessment Scale–cognitive (ADAS-Cog) and its subscale scores are often used to monitor the progression of Alzheimer's disease, but longitudinal invariance has not been formally evaluated. A configural invariance model was used to evaluate ADAS-Cog data as a three correlated factors structure for two visits over 6 months, and four visits over 2 years (baseline, 6, 12, and 24 months) among 341 participants with Alzheimer's disease. We also attempted to model ADAS-Cog subscales individually, and furthermore added item-specific latent variables. Neither the three-correlated factors ADAS-Cog model, nor its subscales viewed unidimensionally, achieved longitudinal configural invariance under a traditional modeling approach. No subscale achieved scalar invariance when considered unidimensional across 6 months or 2 years of assessment. In models accounting for item-specific effects, configural and metric invariance were achieved for language and memory subscales. Although some of the ADAS-Cog individual items were reliable, comparisons of summed ADAS-Cog scores and subscale scores over time may not be meaningful due to a lack of longitudinal invariance. [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]

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits. [ABSTRACT FROM AUTHOR]

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Background: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD.Methods: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1β), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year.Results: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1β (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (β = - 0.152, p = 0.015) but not memory (β = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance.Conclusions: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD. [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]

Background: Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1.Objective: To assess whether 24S-OHC was associated with agitation severity and response to nabilone.Methods: 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression).Results: 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03).Conclusion: 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Agitation is one of the most challenging neuropsychiatric symptoms to treat in Alzheimer's disease and has significant implications for patient and caregiver. A major source of difficulty in identifying safe and effective treatments for agitation is the lack of validated biomarkers. As such, patients may not be appropriately targeted, and biological response to pharmacotherapy cannot be adequately monitored. Methods: This systematic review aimed to summarize evidence on the association between biomarkers and agitation/aggression in patients with Alzheimer's disease, utilizing the National Institute on Aging–Alzheimer's Association Research Framework and the Biomarkers, EndpointS, and other Tools Resource of the Food and Drug Association‐National Institutes of Health Biomarker Working Group. Results: This review identified six classes of biomarkers (neuropathological, neurotransmitter, neuroimaging, apolipoprotein E (APOE) genotype, inflammatory, and clusterin) associated with agitation/aggression, which were mostly diagnostic in nature. Discussion: Future studies should investigate the predictive, prognostic, and monitoring capacity of biomarkers to provide insight into the longitudinal course of agitation/aggression, as well as predict and monitor biological response to a pharmacological intervention. [ABSTRACT FROM AUTHOR]

Background The purpose of this pilot study was to explore the potential of eye-tracking technology in monitoring symptoms and predicting outcomes in apathetic Alzheimer's disease (AD) patients treated with methylphenidate (MTP). Methods Neuropsychological tests and eye-tracking measurements were completed at baseline and following at least four weeks of treatment with MTP (5-10 mg BID). Eye-movements were measured while patients viewed novel and social stimuli. Cognition, behavior, and apathy were assessed using the Standardized Mini-Mental State Exam (sMMSE), Neuropsychiatric Inventory, and Apathy Evaluation Scale (AES), respectively. Results Nine patients were included in the analysis (age: median=75, interquartile range=8; sMMSE: median=22, interquartile range=14). Spearman correlations showed that improvement on the AES was associated with increased visual attention towards novel stimuli (ρ7=-0.809, p=.008). Additionally, lower baseline attention towards social images was associated with improvement on the AES (ρ7=0.905, p=.001). Conclusions Eye-tracking techniques can be developed as an objective and nonverbal method of monitoring symptoms and treatment outcomes in AD patients. [ABSTRACT FROM AUTHOR]

Objectives: Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC).Methods: Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type.Results: A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores.Conclusions: These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression.Objective: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients.Methods: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners' Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years.Results: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t = 2.78, p = 0.010) was also associated with greater decline in sMMSE scores (R2 = 0.41, Adjusted R2 = 0.35, F3,28 = 6.51, p = 0.002), adjusting for attention and baseline sMMSE.Conclusion: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired. [ABSTRACT FROM AUTHOR]

Background: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD).Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS).Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline.Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased.Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD. [ABSTRACT FROM AUTHOR]

Objective: To systematically review published clinical trials of the pharmacotherapy of neuropsychiatric symptoms of Alzheimer disease (AD).Method: We searched MEDLINE and EMBASE for published English-language medical literature. Our review focused on randomized controlled trials (RCTs) and corresponding metaanalyses.Results: The pharmacotherapy of neuropsychiatric symptoms of AD has been studied with numerous RCTs. The largest number of studies has focused on antipsychotics. Data are of reasonably high quality and indicate that risperidone and olanzapine are more effective than placebo for institutionalized patients with severe agitation, aggression, and psychosis. The efficacy of antipsychotics is counterbalanced by safety concerns that include cerebrovascular adverse events and mortality. Cholinesterase inhibitors and memantine appear to have modest benefits for patients with mildly to moderately severe symptoms. Antidepressants are effective for treating depression in AD, but more data are required to determine the efficacy of trazodone and citalopram for agitation and aggression. Carbamazepine appears to be efficacious, although side effects and concerns about drug-drug interactions limit its use. The data do not support the use of valproate. Benzodiazepines should only be used for short-term, as-needed use. There are insufficient data on other pharmacologic interventions, such as beta blockers, buspirone, and estrogen preparations.Conclusions: Although there have been numerous well-designed studies of the pharmacotherapy of neuropsychiatric symptoms in AD, safer and more effective treatments are urgently needed. [ABSTRACT FROM AUTHOR]

Objective: The important role of serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptors in cognition, behavior, and drug response is increasingly being recognized. Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD. Methods: The authors examined 5-HT(1A) receptors in 10 patients with mild to moderate AD and 10 healthy volunteers with the same sex and similar age using positron emission tomography imaging with the selective 5-HT(1A) receptor radioligand, [(11)C]WAY-100635. Regions of interest (ROIs) were manually drawn on coregistered magnetic resonance images for the frontal, lateral temporal, medial temporal (MTC), parietal, and cerebellar cortices. Using the simplified reference tissue model, 5-HT(1A) binding potentials (BPs) were calculated relative to the cerebellum. Results: After adjusting for partial volume effects, ROI analysis showed a significant group effect (AD versus comparison group) on BP. Analysis of between-subjects factors showed significantly decreased 5-HT(1A) BP in the right MTC, but not in the other ROIs. Conclusion: Given the strategic role of these receptors, loss of right medial temporal 5-HT(1A) receptors might play an important role in AD symptomatology. [ABSTRACT FROM AUTHOR]

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Background: Losses of gamma-aminobutyric acid (GABA) have been variably demonstrated in Alzheimer's disease (AD) and may be related to the presence of behavioral and psychological symptoms of dementia (BPSD) in AD. Our objective was to assess the relationship between plasma GABA (pGABA) levels and specific BPSD in patients with severe AD.Methods: pGABA levels and BPSD were measured in 14 institutionalized AD patients (8M/6F, mean age +/- S.D. = 85.6 +/- 4.5 years) with severe cognitive impairment (Mini-mental State Examination score = 4.5 +/- 4.6) and prominent behavioral disturbances (Neuropsychiatric Inventory (NPI) score = 33.4 +/- 23.6).Results: pGABA was positively correlated with depression and apathy scores on the NPI and negatively correlated with age. Apathy and age were independent predictors of pGABA levels.Conclusions: The final stages of AD are associated with GABAergic changes, which may contribute to depression and apathy in AD. [ABSTRACT FROM AUTHOR]

Background: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. Objective: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. Methods: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. Results: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023). Conclusion: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy. [ABSTRACT FROM AUTHOR]

Reports of elevated inflammatory markers in mild cognitive impairment (MCI) suggest that inflammation may be a potential early marker of the neurodegenerative cascade associated with Alzheimer's disease (AD). The aim of this study was to quantitatively summarize the data on peripheral blood concentrations of inflammatory factors in patients with MCI compared to controls. Mean (±SD) blood concentrations of inflammatory factors for MCI and control subjects were extracted from original English language peer-reviewed studies for meta-analysis. Twenty-two studies measuring concentrations of cytokines, chemokines, acute phase reactant proteins, immunoglobulins, intercellular adhesion molecules, and fibrinogen were included. No significant differences in inflammatory factors studied were found between subjects with MCI and healthy controls. These findings do not support the involvement of inflammatory markers at the MCI stage of cognitive decline although significant heterogeneity was observed in some comparisons. It remains to be established whether inflammation may predict increased rate of conversion to dementia. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives. Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS). The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD. [ABSTRACT FROM AUTHOR]