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

Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer’s Disease

Abstract Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer’s disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. Methods: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. Conclusions: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process

Visualization of myocardial infarction and subsequent coronary reperfusion with MRI using a dog model

Twelve anesthetized mongrel dogs underwent left thoracotomy with placement of a removable ligature around the left circumflex coronary artery. Following a 3 to 6 hour delay, ECG-gated spin-echo MRI was performed. The ligature was then removed reperfusing the heart, and after a 10-15 min period, MRI repeated. Finally, post-sacrifice images were obtained, and the hearts chemically stained for infarct evaluation. The MR images were subjectively and quantitatively evaluated for visibility of the endocardial border and of the injured myocardium, and for changes after reperfusion. The injured tissue was variably visible in vivo, the major limitation a result of motion blurring and artifact. The abnormal tissue was easily visible on MRI in 11 animals, and not clearly visible in one. The endocardial border was easily seen in 10 animals. The variation of calculated relaxation times was high for both normal and ischemic/infarcted myocardium in the beating hearts (normal: T1 = 566 +/- 288, T2 = 38 +/- 6; injured myocardium: T1 = 637 +/- 250, T2 = 41 +/- 12) in contrast, relatively stationary skeletal muscle measured in the same images had narrower ranges (T1 = 532 +/- 199, T2 = 28 +/- 2). Changes with reperfusion were seen, but not reliably. The infarcted or ischemic zones were easily visible on post-sacrifice images in all animals imaged. Post-sacrifice relaxation times were T1 = 564 +/- 69 msec, T2 = 39 +/- 3 msec for normal heart muscle, and 725 +/- 114, T2 = 47 +/- 5 for ischemic/infarcted tissue. We conclude that acute myocardial infarction can usually be detected by MRI, given a prior knowledge of its location. However, the technique is at present likely to be of only limited value clinically in the prospective diagnosis of acute myocardial infarction, though this may improve as technology advances. Finally, signal changes following reperfusion may be visible in some cases, but not reliably so.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26951/1/0000517.pd

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

© 2019, The Author(s). The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer’s disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II–VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention

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

No Effect of One-Year Treatment with Indomethacin on Alzheimer's Disease Progression: A Randomized Controlled Trial

Contains fulltext : 71117.pdf (publisher's version ) (Open Access)BACKGROUND: The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD). METHODOLOGY/PRINCIPAL FINDINGS: This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8+/-7.6), than in the placebo group (9.3+/-10.0). This difference (1.5 points; CI -4.5-7.5) was not statistically significant, and neither were any of the secondary outcome measures. CONCLUSIONS/SIGNIFICANCE: The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD

Serial nuclear magnetic resonance imaging in acute myocardial infarction

Recent studies show that proton nuclear magnetic resonance (NMR) imaging can detect myocardial ischemia and acute myocardial infarction (AMI) in animal models1-3 and in humans.4-6 The area of AMI appears as increased signal intensity on the spin-echo NMR images and most likely reflects the regional edema associated with tissue necrosis.1 Thus, the time course of regional edema and the evolution of infarct healing may be revealed by serial NMR studies. In a recent canine study, Pflugfelder et al7 examined the time course of the increased NMR signal intensity associated with AMI. They found that the relative signal intensity increased between the day of AMI and 2 weeks after AMI and subsequently decreased by the 20th day. We examined the early time course of NMR changes in humans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26729/1/0000279.pd