MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers

Abstract

Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6–12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the β-amyloid (Aβ1–42) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele ɛ4 gene in Alzheimer's disease and lower CSF Aβ1–42 in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele ɛ4 and decreased CSF Aβ1–42 supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

“…These measures showed either no change or minor changes consistent with disease progression (Tables S2–S6). For example, median change in normalized brain volume by MRI was −0.56% in the 40 mg dose group and −0.4% in the 125 mg dose group, both consistent with expectations of approximately 3% annual decline in brain volume in an early AD patient population 26, 27…”

Age and neurodegeneration imaging biomarkers in persons with Alzheimer disease dementia

“…20,[22][23][24][25] The greater age dependence of HVa compared to cortical thickness suggests that hippocampal structural integrity is influenced more strongly by AD-independent processes than is isocortical structural integrity. Thickness of isocortical regions, while less agedependent, has the additional benefit as an effective AD neurodegeneration biomarker of being strongly associated with cognition both clinically (e.g., figure 2) and neuropathologically.…”

Gas chromatography–mass spectrometry analysis of the free fatty acids in serum obtained from patients with Alzheimer’s disease1

“…Although the biochemical events resulting in AD and tau deposition are not well understood, some studies have suggested that fatty acids could be contributory factors. FFAs have been shown to be capable of stimulating the formation of amyloid and tau filaments in vitro [9], similar to the neurodegenerative changes that occur during the early stages of AD [10,11]. In addition, the oxidation products of two fatty acids, arachidonic acid and docosahexaenoic acid (DHA), are thought to play an important role in neurodegenerative processes [12].…”