Cognitive and Brain Profiles Associated with Current Neuroimaging Biomarkers of Preclinical Alzheimer's Disease

Abstract

Neuroimaging biomarkers, namely hippocampal volume loss, temporoparietal hypometabolism, and neocortical ␤-amyloid (A␤) deposition, are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our aim was to characterize the cognitive and brain profiles of elders classified as positive or negative for each biomarker to further our understanding of their use in the preclinical diagnosis of AD. Fifty-four cognitively normal individuals (age ϭ 65.8 Ϯ 8.3 years) underwent neuropsychological tests (structural MRI, FDG-PET, and Florbetapir-PET) and were dichotomized into positive or negative independently for each neuroimaging biomarker. Demographic, neuropsychological, and neuroimaging data were compared between positive and negative subgroups. The MRI-positive subgroup had lower executive performances and mixed patterns of lower volume and metabolism in AD-characteristic regions and in the prefrontal cortex. The FDG-positive subgroup showed only hypometabolism, predominantly in AD-sensitive areas extending to the whole neocortex, compared with the FDG-negative subgroup. The amyloid-positive subgroup was older and included more APOE 4 carriers compared with the amyloidnegative subgroup. When considering MRI and/or FDG biomarkers together (i.e., the neurodegeneration-positive), there was a trend for an inverse relationship with A␤ deposition such that those with neurodegeneration tended to show less A␤ deposition and the reverse was true as well. Our findings suggest that: (1) MRI and FDG biomarkers provide complementary rather than redundant information and (2) relatively young cognitively normal elders tend to have either neurodegeneration or A␤ deposition, but not both, suggesting additive rather than sequential/causative links between AD neuroimaging biomarkers at this age. Key words: Alzheimer's disease; amyloid; biomarkers; FDG; MRI; PET Significance StatementNeuroimaging biomarkers are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our findings suggest that MRI and FDG-PET biomarkers should be used in combination, offering an additive contribution instead of reflecting the same process of neurodegeneration. Moreover, the present study also challenges the hierarchical use of the neuroimaging biomarkers in preclinical AD because it suggests that the neurodegeneration observed in this population is not due to ␤-amyloid deposition. Rather, our results suggest that ␤-amyloid-and tau-related pathological processes may interact but not necessarily appear in a systematic sequence.

Graph analysis of structural brain networks in Alzheimer’s disease: beyond small world properties

“…One useful source of information for early AD diagnosis is structural MRI, which can reveal abnormalities in a wide range of brain areas. Multiple studies have found structural MRI (sMRI), a useful diagnostic tool that can contribute to detecting AD-related modifications before the development of clinical symptoms (Raskin et al 2015;Xie et al 2015;Teipel et al 2015;Besson et al 2015;Goveas et al 2015). A different way in which sMRI can assist in early AD diagnosis is by providing data sets for a distinct group of recently developed analytical procedures involving advanced mathematical and statistical methods such as machine learning (Gorji and Haddadnia 2015;Klöppel et al 2008;Salvatore et al 2015;Zhan et al 2015) and graph theory, the formal study of networks (Supekar et al 2008;Stam et al 2009;He et al 2008).…”

Neurodegeneration and Alzheimer's disease (AD). What Can Proteomics Tell Us About the Alzheimer's Brain?

“…In contrast to most other neurodegenerative disorders, a set of brain biomarkers has been developed and validated for the different pathological processes in AD (17). These include positron emission tomography (PET), which is used to evaluate glucose metabolism and thus brain activity, magnetic resonance imaging (MRI), which reveals hippocampal and whole brain atrophy (20,21), and CSF analysis, which measures both increased levels of total tau protein, an indicator of the intensity of neuronal degeneration (22,23), and increased levels of phosphorylated tau (p-tau), an indicator of the presence of tangles (24,25). In addition, increased amyloid burden can be measured via specific PET assays using ligands that bind amyloid plaques (26).…”

“…In addition, increased amyloid burden can be measured via specific PET assays using ligands that bind amyloid plaques (26). PET assays are combined with neuroimaging (21) and the analysis of A␤(1-42) and p-tau levels in the CSF for in vivo diagnosis and to follow disease progression (27,28). A␤(1-42) is a longer form of the A␤ peptide that is more prone to aggregation, and decreased A␤ in the CSF reflects a reduction in A␤(1-42) clearance in the brain and, therefore, increased amyloid pathology (29).…”

Convergent Results from Neuropsychology and from Neuroimaging in Patients with Mild Cognitive Impairment

“…Considerable advances in linking different biomarkers with cognitive symptoms have been achieved [3,4]. Although diagnostic research criteria for Alzheimer disease (AD) now emphasize cognitive symptoms in addition to at least 1 pathological biomarker [5], the correspondence between neuropsychological tests and standard AD neuroimaging markers remains incomplete [6,7]. …”

“…With regard to clinical prediction, evidence indicates that the most sensitive neuropsychological tests have similar or better predictive utility than biomarkers with regard to conversion to dementia [28,29,38,39]. Many studies modify classical tests or they may use elaborate composite scores [6,7,40], which challenges the extrapolation of research findings to the relationship between neuropsychological data available to the clinician and standard neuroimaging markers.…”