What the CERAD Battery Can Tell Us about Executive Function as a Higher-Order Cognitive Faculty

Executive function (EF) is believed to control or influence the integration and application of cognitive functions such as attention and memory and is an important area of research in cognitive aging. Recent studies and reviews have concluded that there is no single test for EF. Results from first-order latent variable modeling have suggested that little, if any, variability in cognitive performance can be directly (and uniquely) attributed to EF; so instead, we modeled EF, as it is conceptualized, as a higher-order function, using elements of the CERAD neuropsychological battery. Responses to subtests from two large, independent cohorts of nondemented elderly persons were modeled with three theoretically plausible structural models using confirmatory factor analysis. Robust fit statistics, generated for the two cohorts separately, were consistent and support the conceptualization of EF as a higher-order cognitive faculty. Although not specifically designed to assess EF, subtests of the CERAD battery provide theoretically and empirically robust evidence about the nature of EF in elderly adults

Using the Guttman Scale to Define and Estimate Measurement Error in Items over Time: The Case of Cognitive Decline and the Meaning of “Points Lost”

We used a Guttman model to represent responses to test items over time as an approximation of what is often referred to as “points lost” in studies of cognitive decline or interventions. To capture this meaning of “point loss”, over four successive assessments, we assumed that once an item is incorrect, it cannot be correct at a later visit. If the loss of a point represents actual decline, then failure of an item to fit the Guttman model over time can be considered measurement error. This representation and definition of measurement error also permits testing the hypotheses that measurement error is constant for items in a test, and that error is independent of “true score”, which are two key consequences of the definition of “measurement error” –and thereby, reliability- under Classical Test Theory. We tested the hypotheses by fitting our model to, and comparing our results from, four consecutive annual evaluations in three groups of elderly persons: a) cognitively normal (NC, N = 149); b) diagnosed with possible or probable AD (N = 78); and c) cognitively normal initially and a later diagnosis of AD (converters, N = 133). Of 16 items that converged, error-free measurement of “cognitive loss” was observed for 10 items in NC, eight in converters, and two in AD. We found that measurement error, as we defined it, was inconsistent over time and across cognitive functioning levels, violating the theory underlying reliability and other psychometric characteristics, and key regression assumptions

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No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50314/1/410190427_ftp.pd

What the CERAD Battery Can Tell Us about Executive Function as a Higher-Order Cognitive Faculty

Executive function (EF) is believed to control or influence the integration and application of cognitive functions such as attention and memory and is an important area of research in cognitive aging. Recent studies and reviews have concluded that there is no single test for EF. Results from first-order latent variable modeling have suggested that little, if any, variability in cognitive performance can be directly (and uniquely) attributed to EF; so instead, we modeled EF, as it is conceptualized, as a higher-order function, using elements of the CERAD neuropsychological battery. Responses to subtests from two large, independent cohorts of nondemented elderly persons were modeled with three theoretically plausible structural models using confirmatory factor analysis. Robust fit statistics, generated for the two cohorts separately, were consistent and support the conceptualization of EF as a higherorder cognitive faculty. Although not specifically designed to assess EF, subtests of the CERAD battery provide theoretically and empirically robust evidence about the nature of EF in elderly adults

The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go–no-go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention

Metabolic effects of adenosine on regional myocardial ischemia by phosphorus 31 nuclear magnetic resonance spectroscopy

The metabolic effects of adenosine on regionally ischemic myocardium were investigated in an open-chest rabbit model by means of phosphorus 31 nuclear magnetic resonance (NMR) spectroscopy. Sixteen anesthetized New Zealand white rabbits were subjected to thoracotomy; a reversible snare occluder was placed around a large branch of the left circumflex coronary artery, and an NMR surface coil was positioned adjacent to the myocardium perfused by this vessel. The animals were placed in a 2.0 T CSI spectrometer (GE Medical Systems, Fremont, Calif.), and baseline spectra were acquired. Eight animals were treated with intravenous adenosine (25 mg/kg), and eight rabbits served as control subjects. All animals were subjected to a 10-minute period of ischemia followed by a period of reperfusion. NMR spectra were acquired during both intervals. During the occlusion period, expected increases in inorganic phosphate levels and decreases in phosphocreatine levels were observed in both groups; however, inorganic phosphate increased less in adenosine-treated animals (adenosine: 33 +/- 2.8% total spectral area during occlusion vs control: 41+/-3.1%) and phosphocreatine diminished less with adenosine (adenosine: 26+/-3% vs control: 13+/-1.2%; p<0.002). No significant differences were seen in [beta]-adenosine triphosphate levels. In both groups the metabolite levels during reperfusion recovered to near baseline values, although phosphocreatine remained slightly higher in the treated group during early reperfusion. An apparent cardioprotective effect of adenosine on relative phosphocreatine and inorganic phosphate levels can be observed in intact rabbits by means of phosphorus 31 NMR spectroscopy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29773/1/0000112.pd

Detection and sizing of myocardial ischemia and infarction by nuclear magnetic resonance imaging in the canine heart

The usefulness of NMR imaging to size infarcted and hypoperfused, ischemic myocardium was assessed in 16 dogs which underwent coronary artery occlusion and reperfusion. During occlusion, technetium-99 microspheres were injected into the left atrium. Following death, the hearts were excised and underwent NMR imaging with a 0.35 tesla magnet, using multiple spin-echo pulse sequences. The epicardium of the heart was marked to indicate the level of the NMR cross-sectional tomographic image. The heart was subsequently breadloafed into 5 mm sections and the corresponding NMR cross-section was flagged for analysis. Autoradiography was performed to measure the hypoperfused, at-risk zone, and triphenyltetrazolium chloride staining was used to measure infarct size. For the flagged tomographic slice, the size of the NMR abnormality correlated well (r = 0.95), and was comparable to the actual hypoperfused, at-risk zone of the left ventricle. However, NMR estimates of infarct size correlated less well (r = 0.75) with the pathologic measure, and significantly overestimated actual infarct size (p 1 and T2 values were consistently increased (p < 0.0005) in both the hypoperfused and infarct zones, compared to normal myocardium. We conclude that NMR imaging can detect acute myocardial ischemia and infarction, but overestimates infarct size and corresponds better to the area of hypoperfused, ischemic myocardium. In this excised canine heart occlusion-reperfusion model, the NMR abnormality corresponded best to the area including both infarction and the surrounding ischemic region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25932/1/0000495.pd

Early Stages of Alzheimer\u27s Disease: Evolving the Care Team for Optimal Patient Management.

Alzheimer\u27s disease (AD) is a progressive, neurodegenerative disease that creates complex challenges and a significant burden for patients and caregivers. Although underlying pathological changes due to AD may be detected in research studies decades prior to symptom onset, many patients in the early stages of AD remain undiagnosed in clinical practice. Increasing evidence points to the importance of an early and accurate AD diagnosis to optimize outcomes for patients and their families, yet many barriers remain along the diagnostic journey. Through a series of international working group meetings, a diverse group of experts contributed their perspectives to create a blueprint for a patient-centered diagnostic journey for individuals in the early stages of AD and an evolving, transdisciplinary care team. Here, we discuss key learnings, implications, and recommendations

BRISC—An Open Source Pulmonary Nodule Image Retrieval Framework

We have created a content-based image retrieval framework for computed tomography images of pulmonary nodules. When presented with a nodule image, the system retrieves images of similar nodules from a collection prepared by the Lung Image Database Consortium (LIDC). The system (1) extracts images of individual nodules from the LIDC collection based on LIDC expert annotations, (2) stores the extracted data in a flat XML database, (3) calculates a set of quantitative descriptors for each nodule that provide a high-level characterization of its texture, and (4) uses various measures to determine the similarity of two nodules and perform queries on a selected query nodule. Using our framework, we compared three feature extraction methods: Haralick co-occurrence, Gabor filters, and Markov random fields. Gabor and Markov descriptors perform better at retrieving similar nodules than do Haralick co-occurrence techniques, with best retrieval precisions in excess of 88%. Because the software we have developed and the reference images are both open source and publicly available they may be incorporated into both commercial and academic imaging workstations and extended by others in their research

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease

Altres ajuts: NIH grants (ADNI U19 AG024904); UPenn (ADRC P30 AG010124); MJFox Foundation for Parkinson's Research (MJFF-005441); National Medical Research Council of Singapore; AMED grants (JP20dm0207073, JP20dm0107143); MHLW grants (19192257, 20316440); National Natural Science Foundation of China (81530036); the National Key Scientific Instrument and Equipment Development Project (31627803); Beijing Scholars Program; Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016, Z201100005520017); Project for Outstanding Doctor with Combined Ability of Western and Chinese Medicine; Beijing Municipal Commission of Health and Family Planning (PXM2019_026283_000003); National Key Research and Development Project grant (2017YFC1311100); Keep Memory Alive (KMA); National Institute of General Medical Sciences grant (P20GM109025); National Institute of Neurological Disorders and Stroke grant (U01NS093334); National Institute on Aging grant (R01AG053798); European Commission (Marie Curie International Training Network, Joint Programme - Neurodegenerative Disease); Health Holland; Dutch Research Council (ZonMw); the Selfridges Group Foundation; Alzheimer Netherlands; Alzheimer Association.Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD