Imaging and CSF Studies in the Preclinical Diagnosis of Alzheimer's Disease

Abstract

It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Slowing of EEG correlates with CSF biomarkers and reduced cognitive speed in elderly with normal cognition over 4 years

“…Aβ42-associated pathology is for example not as correlated to hippocampal volume loss as tau pathology in early stages and Aβ-deposition on Pittsburgh compound B-PET differentiate controls from MCI and AD better in dorso-frontal regions [3,14]. Thus regions not as associated with theta activity as discussed above.…”

“…Thus regions not as associated with theta activity as discussed above. Aβ42 pathology is also suggested not to be as directly related to neuronal loss and damage as tau pathology in cross-sectional analyses [3,14]. Instead CSF Aβ42 might reflect more of a degenerative process leading to neuronal dysfunction, hereby its better ability to predict cognitive decline in normal elderly [22,53] including the current group [55].…”

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

“…The CNS is particularly vulnerable to hypoglycemic damage, and changes in glucose metabolism have been observed in a variety of neurodegenerative conditions associated with dementia (Peppard et al ., 1990, 1992; De Leon et al ., 2007; Mosconi et al ., 2007). In particular, positron emission tomography imaging studies have shown that glucose utilization is dramatically lower in AD, compared to aged‐matched, nondemented brain (Mosconi et al ., 2009; Landau et al ., 2012).…”

New Frontiers in Alzheimer's Disease Diagnosis

“…Since the complexity of this scenario impairs the use of current diagnostic tools for a correct data interpretation, in the recent years, new strategies such as the integrated and combined use of neuropsychological profiles, imaging and biological fluids biomarkers have been developed, improving current diagnosis classification [9][10][11] and predicting the conversion from MCI to AD [12,13].…”