Reproducibility of quantitative (R)-[11C]verapamil studies

Background P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data. Methods Dynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures. Results Analysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data. Conclusion The model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model

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).</p

Neuropsychology/computerized neuropsychological assessment

AbstractBackgroundDifferential diagnostics in dementia is challenging. To date, the basic assessment still includes imaging of the brain and cognitive testing with pen and paper. Web‐based cognitive tests however hold potential for standardized and low‐cost screening in clinical workup. How they perform when combined with imaging of the brain is unknown. We therefore evaluated the accuracy of a new web‐based cognitive battery (Muistikko [1]) detecting different types of dementia, when combined with brain MRI, and compared this to traditional cognitive testing and MRI.MethodWe included 229 subjects from two memory clinic cohorts (PredictND and VPH‐DARE), consisting of 188 controls, 29 patients with Alzheimer's dementia (AD), 7 with frontotemporal dementia (FTD) and 5 with vascular dementia (VaD) (Table 1). All patients performed a traditional cognitive test battery (consisting of MMSE, RAVLT, TMT‐A and B, Animal Fluency), web‐based cognitive testing and had MRI of the brain. Although Muistikko is composed of seven subtasks, only global cognitive score (GCS) was used as defined in [1]. From MRI, multiple imaging biomarkers were defined [2]. Disease‐state index classifier was developed from the predictors [2]. Cross‐validation was used to calculate balanced accuracy (BACC; average of sensitivities for each diagnostic group). Given the class imbalance, we also calculated prevalence corrected accuracy (PACC).ResultBACC was 66 % and PACC 64% when using the traditional cognitive test battery + MRI. Both BACC and PAC were 69 % when using the web‐based cognitive testing + MRI (Table 2). Of note, since we compare four diagnostic groups, BACC by guessing would be 25%.ConclusionThis study shows that combining web‐based cognitive tests with MRI data results in high accuracy when separating different types of dementia. The results were comparable with the standard traditional work‐up. Web‐based cognitive testing is therefore a promising tool to support the clinician in the daily challenge of differential diagnostics, especially when combined with MRI data. References: [1] Paajanen, S. et al. Detecting cognitive disorders using Muistikko web‐based cognitive test battery. Alzheimer's & Dementia 13(7):Supplement,P234‐P235,2017 [2] Bruun, M. et al. Evaluating combinations of diagnostic tests to discriminate different dementia types. Alzheimers Dement 2018 Aug17;10:509‐51

Cross-cultural adaptation and validation of the Amsterdam Instrumental Activities of Daily Living questionnaire short version German for Switzerland

Background Instrumental Activities of Daily Living (IADL) limitations are associated with reduced health-related quality of life for people with mild cognitive impairment (MCI). For these people, the assessment of IADL is crucial to the diagnostic process, as well as for the evaluation of new interventions addressing MCI. The Amsterdam IADL Questionnaire Short Version (A-IADL-Q-SV) is an established assessment tool with good psychometric properties that has been shown to be robust to cultural differences in Western countries. The aims of this study were to: (1) cross-culturally adapt and validate the A-IADL-Q-SV for the German-speaking population of Switzerland; (2) investigate its cultural comparability; and (3) evaluate further psychometric properties. Methods The A-IADL-Q-SV German was pretested on clinicians and participants in a memory clinic setting. The psychometric properties and cultural comparability of the questionnaire were investigated in memory clinic settings including participants with MCI or mild dementia, as well as participants with normal cognition recruited from the community. Item response theory (IRT) was applied to investigate measurement invariance by means of differential item functioning to assess item bias. Additionally, the test–retest reliability on scale level, the construct validity through hypothesis testing and the discriminant validity of the A-IADL-Q-SV German were evaluated. Results Ninety-six informants of participants with normal cognition, MCI or mild dementia completed the A-IADL-Q-SV German. The basic assumptions for IRT scoring were met. No meaningful differential item functioning for culture was detected between the Swiss and Dutch reference samples. High test–retest reliability on scale level (ICC 0.93; 95% CI 0.9–0.96) was found. More than 75% of the observed correlations between the A-IADL-Q-SV German and clinical measures of cognition and functional status were found to be in the direction and of the magnitude hypothesized. The A-IADL-Q-SV German was shown to be able to discriminate between participants with normal cognition and MCI, as well as MCI and mild dementia. Conclusions The A-IADL-Q-SV German is a psychometrically robust measurement tool for a Swiss population with normal cognition, MCI and mild dementia. Thus, it provides a valuable tool to assess IADL functioning in clinical practices and research settings in Switzerland

Blood-based metabolic signatures in Alzheimer's disease

Introduction Identification of blood-based metabolic changes might provide early and easy-to-obtain biomarkers. Methods We included 127 Alzheimer's disease (AD) patients and 121 control subjects with cerebrospinal fluid biomarker-confirmed diagnosis (cutoff tau/amyloid β peptide 42: 0.52). Mass spectrometry platforms determined the concentrations of 53 amine compounds, 22 organic acid compounds, 120 lipid compounds, and 40 oxidative stress compounds. Multiple signatures were assessed: differential expression (nested linear models), classification (logistic regression), and regulatory (network extraction). Results Twenty-six metabolites were differentially expressed. Metabolites improved the classification performance of clinical variables from 74% to 79%. Network models identified five hubs of metabolic dysregulation: tyrosine, glycylglycine, glutamine, lysophosphatic acid C18:2, and platelet-activating factor C16:0. The metabolite network for apolipoprotein E (APOE) ε4 negative AD patients was less cohesive compared with the network for APOE ε4 positive AD patients. Discussion Multiple signatures point to various promising peripheral markers for further validation. The network differences in AD patients according to APOE genotype may reflect different pathways to AD

The influence of diversity on the measurement of functional impairment : An international validation of the Amsterdam IADL questionnaire in 8 countries

Peer reviewe

Linkage disequilibrium analysis to enable more efficient gene and QTL mapping in apple

BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia

© 2020 The Authors. Alzheimer\u27s & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer\u27s Association Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer\u27s disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at-risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies

Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis

IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION: Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. DATA EXTRACTION AND SYNTHESIS: Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method. RESULTS: The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. CONCLUSIONS AND RELEVANCE: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years