Measuring cognition and function in the preclinical stage of Alzheimer\u27s disease

© 2018 The Authors The Alzheimer\u27s Association\u27s Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer\u27s disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer\u27s disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer\u27s Prevention Initiative Autosomal Dominant Alzheimer\u27s Disease Trial, the Alzheimer\u27s Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer\u27s to compare current approaches and tools that are being developed

Endpoints for Pre-Dementia AD Trials: A Report from the EU/US/CTAD Task Force

For Alzheimer's disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials

Association between an Alzheimer's Disease-Related Index and APOE ε4 Gene Dose.

<label>BACKGROUND</label>We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers.<label>METHODS</label>An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers.<label>RESULTS</label>These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001).<label>CONCLUSIONS</label>The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD

Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease

OBJECTIVE: To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε(4) allele, reflecting 3 levels of risk for late-onset Alzheimer disease. DESIGN: Cross-sectional comparison of measurements of cerebral glucose metabolism using (18)F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε(4) homozygotes, ε(4) heterozygotes, and noncarriers. SETTING: Academic medical center. PARTICIPANTS: A total of 31 ε(4) homozygotes, 42 ε(4) heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. MAIN OUTCOME MEASURES: The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. RESULTS: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ε(4) gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05, determined by use of pairwise Fisher z tests). CONCLUSIONS: Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease

Excessive iron storage in captive omnivores? The case of the coati (Nasua spp.)

We collated necropsy reports for 13 coatis (Nasua spp.), revealing four cases of moderate and six cases of massive iron deposition in liver tissue. This survey corroborates an earlier report that noted a high frequency of iron deposits in coatis at necropsy. A comparison of the reported natural diet of coatis and the usually fed captive diets revealed that whereas vertebrate products (dog/cat food, prey items) represent the staple diet items for captive individuals, free-ranging coatis only rarely consume vertebrate prey; their natural diet is dominated by wild fruits and invertebrates. This discrepancy should be reflected in high levels of readily available heme iron in captive diets, with little or no heme iron in the natural diets. Therefore, it could be hypothesized that the use of vertebrate products in animals not adapted to such high levels of readily available heme iron could be a cause for dietary iron overload. Further studies on the relevance of excessive iron storage in omnivores/insectivores, and their etiopathology, are indicated

HCI z-score maps of AD-associated hypometabolism in a APOE ε4 homozygote (A), a APOE ε4 heterozygote (B) and a APOE ε4 non-carrier (C) demonstrate differences in extent of hypometabolism proportional to APOE ε4 gene dose.

<p>HCI z-score maps of AD-associated hypometabolism in a APOE ε4 homozygote (A), a APOE ε4 heterozygote (B) and a APOE ε4 non-carrier (C) demonstrate differences in extent of hypometabolism proportional to APOE ε4 gene dose.</p