Screening and measurement of cognitive impairment in psychiatry.

A key message from the review of cognitive dysfunction in psychiatry published by Millan et al (2012) was not just that cognitive skills are often compromised in patients with psychiatric disorders, but that deficits in specific domains are common to a number of conditions. The review also highlighted that the magnitude of the observed deficits varied across disorders. A helpful element of the Millan et al study was the inclusion of a table in which the authors sought to convey the domains of cognition and a categorization of the magnitude of the observed deficits.In previous articles, we have considered best practice for the assessment of cognition. In these contributions, we have argued not for the use of specific tests, but instead for measures that meet acceptable standards of reliability, validity, and sensitivity. In the course of our discussions, we have included reference to test validity in the context of considering whether selected measures index appropriate domains of cognition. In this article, we begin with a brief discussion of the requirements for good test selection, especially with respect to issues of sensitivity, reliability, and validity. Thereafter the focus of this article is on the issue of domain validity. We will critically review the specification of the cognitive domains proposed by Millan et al, as well as those selected by authors of meta-analyses characterizing cognitive deficits in major depressive disorders. This focus is solely to make the discussion tractable, though we propose that the issues raised will be applicable across all psychiatric and neurological disorders.

No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data.

Aims: Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Methods and results: Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age. Conclusions: Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.

Which Cognitive Domains are Improved by Treatment with Vortioxetine?

BACKGROUND: These post hoc analyses evaluated vortioxetine efficacy on cognitive dysfunction in depression. Data were from a double-blind, randomized, fixed-dose, placebo-controlled, 8-week depression study in adults aged 18-65 years (n = 602) with DSM-IV-defined major depressive disorder (MDD). Subjects were randomized (1:1:1) to vortioxetine 10mg/day or 20mg/day or placebo. METHODS: Cognitive function was assessed at baseline, Week 1 (10mg/day only) and Week 8 using Digit Symbol Substitution Test (DSST) number of correct symbols, Rey Auditory Verbal Learning Test, Trail Making Test, Stroop test, Simple Reaction Time, and Choice Reaction Time tests. The cognition variables were standardized and used for constructing composite Z-scores for the cognitive domains of executive function, attention/speed of processing, and memory. RESULTS: At Week 1, vortioxetine 10mg/day separated from placebo for attention/speed of processing (standardized composite Z-score = 0.21; p = 0.0238) and DSST number of correct symbols (standardized effect size = 0.18; p = 0.0458) and for executive function (standardized composite Z-score = 0.20; p = 0.0274). At Week 8, vortioxetine 10mg/day and 20mg/day separated from placebo for executive function and attention/speed of processing, with standardized composite Z-scores ranging from 0.35 to 0.49 (all p < 0.01). Standardized composite Z-scores for memory were 0.31 ( p = 0.0036, 10mg/day) and 0.22 ( p = 0.0349, 20mg/day). Standardized effect sizes for DSST were 0.51 ( p < 0.0001, 10mg/day) and 0.52 ( p < 0.0001, 20mg/day). Results are limited by the post hoc nature of the analyses and the absence of an active reference in the original study. CONCLUSIONS: Vortioxetine (10 and 20mg/day) had a multi-domain beneficial effect on cognitive performance, as evidenced by improvements in measures of executive function, attention/speed of processing, and memory. The effect on the DSST may be due to improvements in several cognitive skills.

What's in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults.

OBJECTIVE: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. METHOD: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. RESULTS: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. CONCLUSIONS: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

BACKGROUND AND OBJECTIVES: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. METHODS: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (ßtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. RESULTS: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (ßtime range -0.30 to -0.71), followed by delayed word list recognition (ßtime range -0.18 to -0.50). Functional decline (ßtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (ßtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. DISCUSSION: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

Further validation of the THINC-it tool and extension of the normative data set in a study of n = 10.019 typical controls.

INTRODUCTION: We report further validation and normative data for the THINC-Integrated Tool (THINC-it), a measure of cognitive function designed for use with individuals living with Major Depressive Disorder, but which is finding use in further psychiatric and neurological diseases. THINC-it comprises four objective computerised cognitive tests based on traditional psychological paradigms and a version of the Perceived Deficits Questionnaire assessment. METHODS: Sample size of n = 10.019 typical control study participants were tested on one to two occasions to further validate the reliability of THINC-it. Temporal reliability was assessed across 120-180 days. RESULTS: Test-retest reliability correlations varied between r = 0.50 and 0.72 for the component measures and r = 0.75 (95% confidence intervals 0.74, 0.76) for the THINC-it composite score. Normative data categorised by Age, Sex and Years of Education were calculated and the effect on task performance was reported. DISCUSSION: Our analysis confirms previously reported levels of reliability and validates previously reported normative data values.

Asynchronous Remote Assessment for Cognitive Impairment: Reliability Verification of the Neurotrack Cognitive Battery.

BACKGROUND: As evidenced by the further reduction in access to testing during the COVID-19 pandemic, there is an urgent, growing need for remote cognitive assessment for individuals with cognitive impairment. The Neurotrack Cognitive Battery (NCB), our response to this need, was evaluated for its temporal reliability and stability as part of ongoing validation testing. OBJECTIVE: The aim of this study is to assess the temporal reliability of the NCB tests (5 total) across a 1-week period and to determine the temporal stability of these measures across 3 consecutive administrations in a single day. METHODS: For test-retest reliability, a range of 29-66 cognitively healthy participants (ages 18-68 years) completed each cognitive assessment twice, 1 week apart. In a separate study, temporal stability was assessed using data collected from 31 different cognitively healthy participants at 3 consecutive timepoints in a single day. RESULTS: Correlations for the assessments were between 0.72 and 0.83, exceeding the standard acceptable threshold of 0.70 for temporal reliability. Intraclass correlations ranged from 0.60 to 0.84, indicating moderate to good temporal stability. CONCLUSIONS: These results highlight the NCB as a brief, easy-to-administer, and reliable assessment for remote cognitive testing. Additional validation research is underway to determine the full magnitude of the clinical utility of the NCB.

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.

A validation study of appropriate phonological verbal fluency stimulus letters for use with croatian speaking individuals.

The aim of this study is to determine the word frequency for all thirty letters of the Croatian alphabet and to collect normative data for the letter fluency task in Croatian speakers. Ninety two healthy participants were given each of the Croatian letters, and asked to generate as many words as possible in 60 seconds for each letter Results suggested that participants generated most frequently words starting with the letters as follows: "K", "P", "S" and "M".

A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.

BACKGROUND: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aß) production and tau pathology. METHODS: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aß1-40, Aß1-42, neurogranin, and neurofilament light chain]. RESULTS: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS. CONCLUSIONS AND RELEVANCE: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

Commentary: Composite cognitive and functional measures for early stage Alzheimer's disease trials.

In this commentary I consider the issues raised in Schneider and Goldberg's review of composite cognitive and functional measures. I find much to agree with in their commentary and especially their concerns regarding satisfactory psychometric validation of composite measures. I endorse also their provision for analysis by cognitive domain, backed by the use of statistical methods for grouping test variables. The authors helpfully mention the possibility that treatment effects may be peculiar to specific domains of cognitive function. I develop this view and argue for exploratory studies of new therapeutic interventions to include broad assessments of the cognitive domains known to be compromised in early Alzheimer's disease. I suggest that the results of exploratory studies be used to help identify target domains for confirmatory studies. Finally, I note that computerized cognitive composite assessments have often been validated in the fashion that the authors recommend for composite measures.

Evaluation of Speech-Based Digital Biomarkers: Review and Recommendations.

Speech represents a promising novel biomarker by providing a window into brain health, as shown by its disruption in various neurological and psychiatric diseases. As with many novel digital biomarkers, however, rigorous evaluation is currently lacking and is required for these measures to be used effectively and safely. This paper outlines and provides examples from the literature of evaluation steps for speech-based digital biomarkers, based on the recent V3 framework (Goldsack et al., 2020). The V3 framework describes 3 components of evaluation for digital biomarkers: verification, analytical validation, and clinical validation. Verification includes assessing the quality of speech recordings and comparing the effects of hardware and recording conditions on the integrity of the recordings. Analytical validation includes checking the accuracy and reliability of data processing and computed measures, including understanding test-retest reliability, demographic variability, and comparing measures to reference standards. Clinical validity involves verifying the correspondence of a measure to clinical outcomes which can include diagnosis, disease progression, or response to treatment. For each of these sections, we provide recommendations for the types of evaluation necessary for speech-based biomarkers and review published examples. The examples in this paper focus on speech-based biomarkers, but they can be used as a template for digital biomarker development more generally.

Cognitive Functions as Predictors of Alzheimer's Disease Biomarker Status in the European Prevention of Alzheimer's Dementia Cohort.

Alterations in Alzheimer's disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer's Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-ß (Aß) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aß. While previous research has focused on the relationship between cognition and levels of Aß, our findings suggest that p-tau may potentially be a more significant correlate.

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: Longitudinal findings from the Catch-Cog study cohort.

INTRODUCTION: In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints. METHODS: This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment, or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6, and 12 months. Sensitivity to change was investigated using linear mixed models and r 2 effect sizes. RESULTS: CFC scores declined over time (ß = -.16, P < .001), with steepest decline observed in mild Alzheimer's dementia (ß = -.25, P < .001). The CFC showed medium-to-large effect sizes at succeeding follow-up points (r 2 = .08-.42), exhibiting greater change than the Clinical Dementia Rating scale (r 2 = .02-.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (ß = .38, P < .001). DISCUSSION: By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease.

BACKGROUND: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. CONCLUSION: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

FDA position statement "Early Alzheimer's disease: Developing drugs for treatment, Guidance for Industry".

Despite billions of dollars invested in clinical trials to develop novel therapeutics for Alzheimer's disease, no approved treatments have been developed in the past 15 years. In that span, new classes of drugs have been developed and tested, including monoclonal antibodies, γ-secretase modulators, γ-secretase inhibitors, BACE inhibitors, RAGE inhibitors, nicotinic agonists, 5HT6 antagonists, and others. The one constant for all of these clinical trials programs is the use of the ADAS-cog as the primary scale to determine efficacy. The question that needs to be considered is whether it is the target engagement of the drug or the clinical trial measure testing the efficacy. The FDA put out a new position statement in 2018 informing the field on possible considerations for demonstrating efficacy to open the path for approval. Here, we propose and comment on a variety of approaches that are alternatives to the ADAS for FDA-specified stage 3 and 4 Alzheimer's disease. These novel outcomes are being validated in current clinical trials and could be used as efficacy measures moving forward.

Assessing cognition and daily function in early dementia using the cognitive-functional composite: findings from the Catch-Cog study cohort.

BACKGROUND: The cognitive-functional composite (CFC) was designed to improve the measurement of clinically relevant changes in predementia and early dementia stages. We have previously demonstrated its good test-retest reliability and feasibility of use. The current study aimed to evaluate several quality aspects of the CFC, including construct validity, clinical relevance, and suitability for the target population. METHODS: Baseline data of the Capturing Changes in Cognition study was used: an international, prospective cohort study including participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia, and dementia with Lewy bodies (DLB). The CFC comprises seven existing cognitive tests focusing on memory and executive functions (EF) and the informant-based Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). Construct validity and clinical relevance were assessed by (1) confirmatory factor analyses (CFA) using all CFC subtests and (2) linear regression analyses relating the CFC score (independent) to reference measures of disease severity (dependent), correcting for age, sex, and education. To assess the suitability for the target population, we compared score distributions of the CFC to those of traditional tests (Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, and Clinical Dementia Rating scale). RESULTS: A total of 184 participants were included (age 71.8 ± 8.4; 42% female; n = 14 SCD, n = 80 MCI, n = 78 AD, and n = 12 DLB). CFA showed that the hypothesized three-factor model (memory, EF, and IADL) had adequate fit (CFI = .931, RMSEA = .091, SRMR = .06). Moreover, worse CFC performance was associated with more cognitive decline as reported by the informant (ß = .61, p < .001), poorer quality of life (ß = .51, p < .001), higher caregiver burden (ß = - .51, p < .001), more apathy (ß = - .36, p < .001), and less cortical volume (ß = .34, p = .02). Whilst correlations between the CFC and traditional measures were moderate to strong (ranging from - .65 to .83, all p < .001), histograms showed floor and ceiling effects for the traditional tests as compared to the CFC. CONCLUSIONS: Our findings illustrate that the CFC has good construct validity, captures clinically relevant aspects of disease severity, and shows no range restrictions in scoring. It therefore provides a more useful outcome measure than traditional tests to evaluate cognition and function in MCI and mild AD.

Cognition comes of age: comments on the new FDA draft guidance for early Alzheimer's disease.

BACKGROUND: The FDA have recently published draft guidance for the development of treatments for early Alzheimer's disease. Key features of this guidance are the advocacy of sensitive cognitive measures and a taxonomy of disease severity. Whilst desirable patterns of cognitive-functional improvement are included, specific measures, and the magnitude of required effects, are not described. MAIN SECTION: We describe key elements of the guidance content, especially with regard targeting key cognitive domains and the means by which they might be efficiently indexed in the disease stages included in the guidance. We discuss also the opportunities to assess cognitive performance in 'Stage 2' and 'Stage 3' patients, as well as the possibilities for effectively assessing function in the latter category. In this section we review candidate cognitive assessments that we judge are capable of delivering on the guidance specification for sensitive neuropsychological measures. This includes detailed consideration of the ADCS-PACC and Catch-Cog initiatives. With respect to the magnitude of effects, we propose that standardised effect sizes of 0.3 represent a reasonable level of efficacy based on the observation that already marketed drugs on average deliver this level of improvement. CONCLUSIONS: We propose the use of cognitive measures in stage 2 patients to index the cognitive skills known to be compromised early in the Alzheimer's disease process. We recommend extending the traditional interest in episodic memory to include sensitive, reliable and valid measures of attention, working memory and aspects of executive function. We propose a focus on these additional cognitive abilities based on evidence that performance on tests of these domains is moderately well related to functional skills.

Cognitive Impairment Associated with Cancer: A Brief Review.

This brief review explores the areas of cognitive impairment that have been observed in cancer patients and survivors, the cognitive assessment tools used, and the management of the observed cognitive changes. Cognitive changes and impairment observed in patients with cancer and those in remission can be related to the direct effects of cancer itself, nonspecific factors or comorbid conditions that are independent of the actual disease, and/or the treatments or combination of treatments administered. Attention, memory, and executive functioning are the most frequently identified cognitive domains impacted by cancer. However, the prevalence and extent of impairment remains largely unknown due to marked differences in methodology, definitions of cognitive impairment, and the assessment measures used. Assessment of cognitive functioning is an important and necessary part of a comprehensive oncological care plan. Research is needed to establish a better understanding of cognitive changes and impairments associated with cancer so that optimal patient outcomes can be achieved.

Stability, reliability, and validity of the THINC-it screening tool for cognitive impairment in depression: A psychometric exploration in healthy volunteers.

OBJECTIVES: There is a need for a brief, reliable, valid, and sensitive assessment tool for screening cognitive deficits in patients with Major Depressive Disorders. This paper examines the psychometric characteristics of THINC-it, a cognitive assessment tool composed of four objective measures of cognition and a self-rated assessment, in subjects without mental disorders. METHODS: N = 100 healthy controls with no current or past history of depression were tested on four sequential assessments to examine temporal stability, reliability, and convergent validity of the THINC-it tests. We examined temporal reliability across 1 week and stability via three consecutive assessments. Consistency of assessment by the study rater (intrarater reliability) was calculated using the data from the second and third of these consecutive assessments. RESULTS: Test-retest reliability correlations varied between Pearson's r = 0.75 and 0.8. Intrarater reliability between 0.7 and 0.93. Stability for the primary measure for each test yielded within-subject standard deviation values between 5.9 and 11.23 for accuracy measures and 0.735 and 17.3 seconds for latency measures. Convergent validity for three tasks was in the acceptable range, but low for the Symbol Check task. CONCLUSIONS: Analysis shows high levels of reliability and stability. Levels of convergent validity were modest but acceptable in the case of all but one test.