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Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer’s disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer’s disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer’s Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer’s disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer’s disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03–1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50–5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02–1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03–1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer’s disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02–1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01–1.10). There was higher discrimination accuracy for Alzheimer’s disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer’s disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer’s disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer’s disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer’s disease.

The present study investigated abbreviation methods for the Test of Memory Malingering (TOMM) in relation to traditional manual-based test cutoffs and independently derived more stringent cutoffs suggested by recent research (≤48 on Trial 2 or 3). Consecutively referred outpatient U.S. military veterans (

Introduction We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). Methods Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. Results Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. Discussion These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

A large proportion of adolescents experiencing depression never access treatment. To increase access to effective mental health care, it is critical to understand factors associated with increased versus decreased odds of adolescent treatment access. This study used individual depression symptoms and sociodemographic variables to predict whether and where adolescents with depression accessed mental health treatments. We performed a pre-registered, secondary analysis of data from the 2017 National Survey of Drug Use and Health (NSDUH), a nationally representative sample of non-institutionalized civilians in the United States. Using four cross-validated random forest models, we predicted whether adolescents with elevated past-year depressive symptoms (N = 1,671; ages 12–17 years) accessed specific mental health treatments in the previous 12 months (“yes/no” for inpatient, outpatient, school, any). 53.38% of adolescents with elevated depressive symptoms accessed treatment of any kind. Even with depressive symptoms and sociodemographic factors included as predictors, pre-registered random forests explained

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)(181) to detect cognitive impairment due to Alzheimer’s disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau(181) discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau(181) had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau(181) for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79]), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.

Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo response in randomized controlled trials has not been described.We conducted a search of the medical literature following the protocol outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement using MEDLINE, EMBASE and EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials for all drugs used for the treatment of CIC. Two independent reviewers performed eligibility assessment and data extraction. The mean response rate was examined for the following 2 responder endpoints: (i) greater than or equal to 3 complete spontaneous bowel movements (CSBMs)/wk (≥3 CSBMs/wk responders) and (ii) mean increase of ≥1 CSBM/wk compared with baseline (increase in ≥1 CSBM/wk responders).A total of 23 placebo-controlled trials met our inclusion criteria and were included in this meta-analysis. The placebo response in CIC trials ranged from 4% to 44%. The magnitude of the placebo response was 13% (95% confidence interval 11%-16%) with the ≥3 CSBM/wk responder endpoint and 28% (95% confidence interval 21%-30%) with the increase of ≥1 in the CSBM responder endpoint. Higher baseline CSBM, older age, and trials with more male participants were significantly associated with a stronger placebo response for both the ≥3 CSBMs/wk endpoint and increase in the ≥1 CSBM/wk endpoint. Trial characteristics such as location (Europe vs Asia/United States) and laxative class (prokinetic vs secretagogue) revealed key differences in the placebo response for both endpoints. The placebo response was not significantly affected by the number of study visits, study duration, year of publication, number of drop outs, or likelihood of receiving active drug.The placebo response in CIC trials ranges from 4% to 44% depending on the endpoint. Modifying factors of the placebo response include multiple subject and trial characteristics.

Previous studies have indicated that obsessive-compulsive disorder (OCD) might have a reduced placebo response compared to other anxiety-related disorders including generalized anxiety disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder. No previous analysis has directly compared antidepressant and placebo responses between OCD and these conditions.We analyzed pre-post change scores within drug and placebo groups as well as between-groups change scores (i.e., drug compared to placebo) for all FDA-approved antidepressants for the treatment of these five anxiety-related disorders. Antidepressants included duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. Random effects meta-analysis was used to examine all trials submitted to the FDA, plus additional post-approval trials available from manufacturer-sponsored clinical trial registers. Clinician-rated symptom inventories were the outcome measures for all conditions to facilitate comparisons across diagnoses.Fifty-six trials met inclusion criteria. OCD had significantly lower pre-post effect sizes (ps0.003) for both placebo (Hedges' g=0.49) and antidepressants (g=0.84) compared to the other four conditions (gs between 0.70 and 1.10 for placebo and 1.11 and 1.40 for antidepressants). However, the drug-placebo effect sizes did not significantly differ across diagnoses (Q(4)=6.09, p=0.193, IOverall pre-post change scores were smaller for OCD compared to other anxiety disorders for both antidepressants and placebo, although drug-placebo effects sizes did not significantly differ across disorders. Theoretical and clinical implications for the understanding and treatment of OCD are discussed.

Objective: A majority of adolescents experiencing depression never access treatment. To increase access to effective mental health care, it is critical to understand factors associated with increased versus decreased odds of adolescent treatment access. This study investigated the relative importance of individual depression symptoms and sociodemographic variables in predicting whether and where adolescents with depression accessed mental health treatments. Method: We performed a pre-registered, secondary analysis of data from the 2017 National Survey of Drug Use and Health (NSDUH), a nationally representative sample of non-institutionalized civilians in the United States. Using four cross-validated random forest models, we predicted whether high-symptom adolescents (N = 1,671; ages 12-17 years) accessed specific mental health treatments in the previous 12 months (“yes/no” for inpatient, outpatient, school, any). Results: 53.38% of adolescents with elevated depressive symptoms accessed treatment of any kind. Even with depressive symptoms and sociodemographic factors included as predictors, pre-registered random forests explained < 0.00% of pseudo out-of-sample deviance in adolescent access to inpatient, outpatient, school, or overall treatments. Exploratory elastic net models explained 0.80 - 2.50% of pseudo out-of-sample deviance in adolescent treatment access across all four treatment types. Conclusions: Neither individual depressive symptoms nor any socioeconomic variables meaningfully predicted specific or overall mental health treatment access in high-symptom adolescents. This study highlights substantial limitations in our capacity to predict whether and where high-symptom adolescents access mental health treatment and underscores the broader need for more accessible, scalable adolescent depression treatments.

Background Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer’s disease, particularly in the early disease stages. This study leveraged the National Alzheimer’s Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition. Methods The sample included 465 participants from the National Alzheimer’s Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer’s Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer’s disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD. Results Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p

Community health workers (CHWs) are frontline public health workers who are becoming increasingly integrated into medical settings for the prevention, treatment, and control of chronic disease. In particular, they have demonstrated the ability to improve medication adherence in underserved populations. One overlooked population that could benefit from CHW intervention is individuals with severe mental illnesses such as schizophrenia and bipolar disorder. These conditions are disproportionally weighted to economically disadvantaged communities and people of color, and are typically treated using antipsychotic medications. A number of factors, including social disadvantage, contribute to antipsychotic non-adherence, which is highly prevalent and drastically increases the burden of illness and economic impact of these conditions. This commentary examines the ways in which CHWs may be able to best serve individuals with severe mental illness, and proposes methods for facilitating this expanded scope of work.

Objective: Forced-choice (FC) recognition memory is a common performance validity assessment methodology. This study introduces and evaluates the classification accuracy of a FC recognition trial for the Rey Auditory Verbal Learning Test (RAVLT). Method: The present sample of 122 military veterans (Mean age = 35.4, SD = 9.3) were all administered the RAVLT along with the FC procedure as part of a full neuropsychological protocol. Veterans were assigned to valid (n = 94) or invalid (n = 28) groups based on outcomes of performance validity measures. Results: The FC procedure was found to have strong sensitivity (67.9%) and specificity (92.6%) in predicting validity group status based on a cutoff score of ≤ 13. The FC trial outperformed RAVLT recognition hits (sensitivity = 46.4%, specificity = 91.5%) as a predictor of invalid performance. Conclusions: The RAVLT FC is demonstrated to be an effective measure of performance validity and is recommended for use as an adjunctive trial for the RAVLT.

BACKGROUND White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. OBJECTIVE This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. METHODS The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. RESULTS 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps

We conducted a randomized controlled trial of the Aging Well through Interaction and Scientific Education (AgeWISE) program, a 12-week manualized cognitive rehabilitation program designed to provide psychoeducation to older adults about the aging brain, lifestyle factors associated with successful brain aging, and strategies to compensate for age related cognitive decline.Forty-nine cognitively intact participants ≥ 60 years old were randomly assigned to the AgeWISE program (n = 25) or a no-treatment control group (n = 24). Questionnaire data were collected prior to group assignment and post intervention. Two-factor repeated-measures analyses of covariance (ANCOVAs) were used to compare group outcomes.Upon completion, participants in the AgeWISE program reported increases in memory contentment and their sense of control in improving memory; no significant changes were observed in the control group. Surprisingly, participation in the group was not associated with significant changes in knowledge of memory aging, perception of memory ability, or greater use of strategies.The AgeWISE program was successfully implemented and increased participants' memory contentment and their sense of control in improving memory in advancing age.This study supports the use of AgeWISE to improve perspectives on healthy cognitive aging.

The purpose of this study was to determine how well scores from the Rey Complex Figure Test (RCFT) could serve as embedded measures of performance validity in a large, heterogeneous clinical sample at an urban-based Veterans' Affairs hospital. Participants were divided into credible performance (n = 244) and noncredible performance (n = 87) groups based on common performance validity tests during their respective clinical evaluations. We evaluated how well preselected RCFT scores could discriminate between the 2 groups using cut scores from single indexes as well as multivariate logistic regression prediction models. Additionally, we evaluated how well memory error patterns (MEPs) could discriminate between the 2 groups. Optimal discrimination occurred when indexes from the Copy and Recognition trials were simultaneous predictors in logistic regression models, with 91% specificity and at least 53% sensitivity. Logistic regression yielded superior discrimination compared with individual indexes and compared with the use of MEPs. Specific scores on the RCFT, including the Copy and Recognition trials, can serve as adequate indexes of performance validity, when using both cut scores and logistic regression prediction models. We provide logistic regression equations that can be applied in similar clinical settings to assist in determining performance validity.

Background & Aims Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non–cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine). Methods We conducted a search of the medical literature following the protocol outlined in the Cochrane Handbook for systematic review. We searched MEDLINE, EMBASE, EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials until March 2017 to identify randomized controlled trials of peripheral μ-opioid–receptor antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine), lubiprostone, or prucalopride. Response to therapy was extracted in a dichotomous assessment as an overall response to therapy. The effect of pharmacologic therapies was pooled and reported as a relative risk (RR) of failure to respond to the treatment drug, with 95% CIs. Results We included 27 placebo-controlled trials in our meta-analysis (23 trials evaluated μ-opioid–receptor antagonists, 3 trials evaluated lubiprostone, and 1 trial evaluated prucalopride). In these trials, 5390 patients received a drug and 3491 received a placebo. Overall, μ-opioid–receptor antagonists, lubiprostone, and prucalopride were superior to placebo for the treatment of OIC, with a RR of failure to respond to therapy of 0.70 (95% CI, 0.64–0.75) and an overall number needed to treat of 5 (95% CI, 4–7). When restricted to only Food and Drug Administration–approved medications for OIC, the RR of failure to respond to therapy was 0.69 (95% CI, 0.62-0.77), with a number needed to treat of 5 (95% CI, 4–7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed that treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. Study duration and prespecified primary outcome did not affect the RR of failure. Participants who received μ-opioid–receptor antagonists were significantly more likely to have diarrhea, abdominal pain, nausea, or vomiting than patients who received placebo. Conclusions In a systematic review and meta-analysis, we found μ-opioid–receptor antagonists to be safe and effective for the treatment of OIC. Prescription-strength laxatives (prucalopride, lubiprostone) are slightly better than placebo in reducing OIC.

While recognition memory has been the primary tool for the assessment of performance validity in neuropsychological evaluations, some consideration has also been given to embedded measures from other cognitive domains, including processing speed. The present study evaluated the classification accuracy of several speed-based measures in a Veterans Affairs Medical Center Polytrauma sample.The present sample consisted of 114 military veterans (Mean age = 35.5, SD = 9.4) referred for a suspected history of mild traumatic brain injury who were administered a full neuropsychological protocol that included several validity checks. Veterans were assigned to Valid (n = 80) or Invalid (n = 34) groups based on outcomes of performance validity measures (PVMs).Several processing speed measures yielded acceptable or excellent classification accuracy; sensitivity values ranged from 29 to 53% with specificity values above 90%. Efforts to identify an improved algorithm that would collapse across multiple processing speed PVMs were unsuccessful compared to classification based on single measures.Processing speed measures can serve as efficient performance validity assessment tools.

Background The goal of the current study was to determine if the Dementia Rating Scale-2 (DRS-2) is an appropriate tool for evaluating cognitive abilities in adults with Prader–Willi syndrome (PWS). The DRS-2 is a screening measure previously utilised in low-functioning populations with and without dementia, including individuals with intellectual disability.Method Thirteen adults with PWS between 21 and 59 years old were administered the DRS-2.Results Participants demonstrated impairment on all 5 subscales, with the largest impairments observed on the Initiation/Perseveration and Construction subscales. No significant floor or ceiling effects were observed. No correlations were observed between age and any subscale score.Conclusion The DRS-2 may be a valid assessment tool for capturing the full spectrum of cognitive functioning in adults with PWS. The largest impairments were observed on items requiring verbal and motor fluency and visuo-spatial processing. Future directions for the use of the DR...

Deciding on the optimal treatment plan is crucial for individuals with depressive disorders. Specifically, pharmacotherapy (most commonly with antidepressant medications) and psychotherapy are far ...

Cognitive assessment with virtual reality (VR) may have superior ecological validity for older adults compared to traditional pencil-and-paper cognitive assessment. However, few studies have reported the development of VR tasks. The aim of this study was to present the development, feasibility, content validity, and preliminary evidence of construct validity of an ecological task of cognitive assessment for older adults in VR (ECO-VR). The tasks were prepared based on theoretical and clinical backgrounds. We had 29 non-expert judges identify virtual visual stimuli and three-dimensional scenarios, and five expert judges assisted with content analysis and developing instructions. Finally, six older persons participated in three pilot studies and thirty older persons participated in the preliminary study to identify construct validity evidence. Data were analyzed by descriptive statistics and partial correlation. Target stimuli and three-dimensional scenarios were judged adequate and the content analysis demonstrated that ECO-VR evaluates temporo-spatial orientation, memory, language and executive functioning. We made significant changes to the instructions after the pilot studies to increase comprehensibility and reduce the completion time. The total score of ECO-VR was positively correlated mainly with performance in executive function (r = .172, p < .05) and memory tests (r = .488, p ≤ .01). The ECO-VR demonstrated feasibility for cognitive assessment in older adults, as well as content and construct validity evidences.

Background: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ?4 allele could moderate the effect of PA or CA on hippocampal structure or function. Methods: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. Results: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. Conclusions: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Using cross sectional data Psychological vulnerability was identified as a correlate of older adult's being defrauded. We extend that research by examining fraud prevalence using longitudinal data from the Health and Retirement Study, and to identify the best predictors of fraud longitudinally across a 4-year time frame. Whereas reported fraud prevalence was 5.0% in a 5-year look-back period in 2008, it increased to 6.1% in 2012. The rate of new-incident fraud across only a 4-year look-back was 4.3%. Being younger-old, having a higher level of education, and having more depression significantly predicted the new cases of fraud reported in 2012. Psychological vulnerability was a potent longitudinal predictor of fraud, with the most vulnerable individuals being more than twice as likely to be defrauded. Results indicate that fraud victimization among older adults is rising, and that vulnerability variables, along with some demographic variables, predict new cases of fraud.

Inclusion body myositis (IBM) is the most common age-related degenerative skeletal muscle disorder. The aberrant intracellular accumulation of the beta-amyloid (Abeta) peptide within skeletal muscle is a pathological hallmark of IBM. Skeletal muscle is comprised of both slow and fast twitch fibers, which are present in different proportions in various muscles. It remains unclear if fast and/or slow twitch fibers are differentially involved in IBM pathogenesis. To better understand the molecular pathogenesis of IBM, we analyzed human IBM muscle biopsies and muscle from a transgenic mouse model of IBM (MCK-betaAPP). Here we report that the majority of histopathologically-affected fibers in human IBM biopsies were type II fast fibers. Skeletal muscle from MCK-betaAPP mice exhibited higher transgene expression and steady-state levels of human betaAPP in fast type IIB fibers compared to slow type I fibers. These findings indicate that fast twitch fibers may selectively accumulate and be more vulnerable to betaAPP- and Abeta-mediated damage in IBM. These findings also highlight parallels between the MCK-betaAPP mice and the human IBM condition.

Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between production and degradation. Although the proteolytic processes leading to Abeta formation have been extensively studied, less is known about the proteases that degrade Abeta, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Abeta accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.

OBJECTIVE To determine whether scores from 2 commonly used cognitive screening tests can help predict general intellectual functioning in older adults. BACKGROUND Cutoff scores for determining cognitive impairment have been validated for both the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). However, less is known about how the 2 measures relate to general intellectual functioning as measured by the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). METHODS A sample of 186 older adults referred for neuropsychological assessment completed the MoCA, MMSE, and WAIS-IV. Regression equations determined how accurately the screening measures could predict the WAIS-IV Full Scale Intelligence Quotient (FSIQ). We also determined how predictive the MoCA and MMSE were when combined with 2 premorbid estimates of FSIQ: the Test of Premorbid Functioning (TOPF) (a reading test of phonetically irregular words) and a predicted TOPF score based on demographic variables. RESULTS MoCA and MMSE both correlated moderately with WAIS-IV FSIQ. Hierarchical regression models containing the MoCA or MMSE combined with TOPF scores accounted for 58% and 49%, respectively, of the variance in obtained FSIQ. Both regression equations accurately estimated FSIQ to within 10 points in >75% of the sample. CONCLUSIONS Both the MoCA and MMSE provide reasonable estimates of FSIQ. Prediction improves when these measures are combined with other estimates of FSIQ. We provide 4 equations designed to help clinicians interpret these screening measures.

The objective of this study was to determine to what extent verbal fluency measures can be used as performance validity indicators during neuropsychological evaluation. Participants were clinically referred for neuropsychological evaluation in an urban-based Veteran's Affairs hospital. Participants were placed into 2 groups based on their objectively evaluated effort on performance validity tests (PVTs). Individuals who exhibited credible performance (n = 431) failed 0 PVTs, and those with poor effort (n = 192) failed 2 or more PVTs. All participants completed the Controlled Oral Word Association Test (COWAT) and Animals verbal fluency measures. We evaluated how well verbal fluency scores could discriminate between the 2 groups. Raw scores and T scores for Animals discriminated between the credible performance and poor-effort groups with 90% specificity and greater than 40% sensitivity. COWAT scores had lower sensitivity for detecting poor effort. A combination of FAS and Animals scores into logistic regression models yielded acceptable group classification, with 90% specificity and greater than 44% sensitivity. Verbal fluency measures can yield adequate detection of poor effort during neuropsychological evaluation. We provide suggested cut points and logistic regression models for predicting the probability of poor effort in our clinical setting and offer suggested cutoff scores to optimize sensitivity and specificity.

Interferon-gamma (IFN-gamma), traditionally associated with a variety of physiological and pathological processes of the immune system, manifests an array of biological effects on cells of the nervous system. Clinical and in vitro studies support a key role for IFN-gamma in the pathogenesis of immune-mediated demyelinating disorders such as multiple sclerosis (MS). To investigate the role of this cytokine within the central nervous system (CNS), transgenic mice were derived in which IFN-gamma transgene expression was selectively targeted to astrocytes, a potentially important cellular source of this cytokine. Here we report that astrocyte-directed expression of IFN-gamma results in regional hypomyelination and selective disruption of brain histogenesis, which included severe cerebellar and hippocampal dysplasia. Transgenic mice were markedly ataxic and the majority died prior to reaching sexual maturity. This study demonstrates that astrocyte-directed expression of IFN-gamma profoundly affects the differentiation and morphogenesis of the brain and provides additional evidence that this cytokine has deleterious consequences on myelin-producing cells, independent of the cellular source.

Interest in the possible role of herpes simplex virus type 1 (HSV1) as a cofactor in the pathogenesis of Alzheimer's disease (AD) has re-emerged following the detection of viral DNA sequences in the central nervous system (CNS). Evidence from 2 independent laboratories indicates that HSV1 may interact with a host-specific factor, the apolipoprotein E epsilon 4 allele, to further augment the risk for AD. In this review, we consider the arguments implicating HSV1 in the pathogenesis of AD. Although further studies are required to confirm a role for HSV1 in AD and to elucidate its underlying molecular basis, implicating a virus in the pathogenesis of this insidious disease clearly offers novel potential treatments.

Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively “Stable” or “Declining” based on ≥1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R2 = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R2 = .285; C index = .787), whereas the addition of EM did not (R2 = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer's disease. (JINS, 2012, 18, 1–11)

There is now a substantial body of work demonstrating that action video game experience results in enhancements in a wide variety of perceptual skills. More recently, several groups have also demonstrated improvements in abilities that are more cognitive in nature, in particular, the ability to efficiently switch between tasks. In a series of four experiments, we add to this body of work, demonstrating that the action video game player advantage is not exclusively due to an ability to map manual responses onto arbitrary buttons, but rather generalizes to vocal responses, is not restricted to tasks that are perceptual in nature (e.g. respond to a physical dimension of the stimulus such as its color), but generalizes to more cognitive tasks (e.g. is a number odd or even), and is present whether the switch requires a goal-switch or only a motor switch. Finally, a training study establishes that the relationship between the reduction in switch cost and action game playing is causal.

Functional magnetic resonance imaging (fMRI) allows for dynamic observation of the neural substrates of cognitive processing, which makes it a valuable tool for studying brain changes that may occur with both normal and pathological aging. fMRI studies have revealed that older adults frequently exhibit a greater magnitude and extent activation of the blood-oxygen-level-dependent signal compared to younger adults. This additional activation may reflect compensatory recruitment associated with functional and structural deterioration of neural resources. Increased activation has also been associated with several risk factors for Alzheimer's disease (AD), including the apolipoprotein ε4 allele. Longitudinal studies have also demonstrated that fMRI may have predictive utility in determining which individuals are at the greatest risk of developing cognitive decline. This chapter will review the results of a number of task-activated fMRI studies of older adults, focusing on both healthy aging and neuropathology associated with AD. We also discuss models that account for cognitive aging processes, including the hemispheric asymmetry reduction in older adults (HAROLD) and scaffolding theory of aging and cognition (STAC) models. Finally, we discuss methodological issues commonly associated with fMRI research in older adults.

Many previous studies have shown that the speed of processing in attentionally demanding tasks seems enhanced following habitual action videogame play. However, using one of the diagnostic tasks for efficiency of attentional processing, a visual search task, Castel and collaborators (Castel, Pratt, & Drummond, Acta Psychologica 1119:217–230, 2005) reported no difference in visual search rates, instead proposing that action gaming may change response execution time rather than the efficiency of visual selective attention per se. Here we used two hard visual search tasks, one measuring reaction time and the other accuracy, to test whether visual search rate may be changed by action videogame play. We found greater search rates in the gamer group than in the nongamer controls, consistent with increased efficiency in visual selective attention. We then asked how general the change in attentional throughput noted so far in gamers might be by testing whether exogenous attentional cues would lead to a disproportional enhancement in throughput in gamers as compared to nongamers. Interestingly, exogenous cues were found to enhance throughput equivalently between gamers and nongamers, suggesting that not all mechanisms known to enhance throughput are similarly enhanced in action videogamers.

Presenilins mediate an unusual intramembranous proteolytic activity known as γ-secretase, two substrates of which are the Notch receptor (Notch) and the β-amyloid precursor protein (APP). γ-Secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [ A PP i ntra c ellular d omain (AICD)] that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of γ-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and—notably—these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a γ-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.

A study was conducted with Community and Technical College students enrolled at the University of Akron, a major urban university, during the 1978–1979 academic year. Students were divided into traditional and nontraditional persisters and nonpersisters, and if they were placed on academic probation, they were removed from the study. These students were given modified National Center for Higher Education Management Systems (NCHEMS) questionnaires for program completers and noncompleters. The questions tested for varying degrees of satisfaction with the University and reasons for withdrawal concerning various academic, socioeconomic, and environmental press variables. In addition, selected demographic variables from the student masterfile were tested, along with the questionnaire responses in 99 research hypotheses using multiple linear regression and corrected for multiple comparisons. Results indicate that 13 hypotheses were found to significantly discriminate between traditional and nontraditional community college students. The persisting nontraditional students appeared to be more satisfied with the University concerning a few variables, greater proportion attended part-time, during the day, enrolled for less hours, and had a greater high school grade point average than their traditional counterparts. The nonpersisting, nontraditional students were similar to their persisting counterparts, except that traditional nonpersisting students had a higher high school grade point average, lived at greater distances from the school, and attended day time classes as compared to nontraditional students.

Children’s speech timing is often more variable than adults’. In the present study, two hypotheses that have been proposed to account for this observation are considered. One claims that children do not have neuromotor control capabilities comparable to adults. The other suggests that the greater variability is a statistical consequence of children’s longer segment durations. These two hypotheses were examined by having children and adults speak at both faster and slower rates than normal. Within‐group comparisons across different rates and between‐group comparisons for similar durational values were made from spectrographic measurements. Results indicate that both statistical and neuromotor factors seem to contribute to the greater variability commonly observed in children’s speech.