Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

• Published in: Human brain mapping Vol. 39; no. 2; pp. 971 - 984
• Main Authors: Tardif, Christine L., Devenyi, Gabriel A., Amaral, Robert S. C., Pelleieux, Sandra, Poirier, Judes, Rosa‐Neto, Pedro, Breitner, John, Chakravarty, M. Mallar
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2018; John Wiley and Sons Inc
• Subjects: Aged; Aging; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - cerebrospinal fluid; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - genetics; Atrophy; Bioindicators; Biomarkers; Biomarkers - cerebrospinal fluid; Brain; Cerebrospinal fluid; Circuits; Cognitive ability; Deposition; Disease control; Female; Fornix; Genetic Predisposition to Disease; Hippocampus; Hippocampus - diagnostic imaging; Humans; In vivo methods and tests; Magnetic Resonance Imaging; Male; Microstructure; Middle Aged; Neural Pathways - diagnostic imaging; Neurodegeneration; Neurodegenerative diseases; Neuroimaging; Prodromal Symptoms; Senile plaques; Structural integrity; Subiculum; Substantia alba; Tau protein; tau Proteins - cerebrospinal fluid; White Matter - diagnostic imaging; cerebrospinal fluid biomarkers; hippocampal subfields; fimbria; preclinical; APOE ɛ4; amyloid-β; structural magnetic resonance imaging; tau; fornix; Alzheimer's disease
• ISSN: 1065-9471; 1097-0193; 1097-0193
• DOI: 10.1002/hbm.23897

Neuropathological and in vivo brain imaging studies agree that the c ornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra‐hippocampal white matter structure, in relation to the progression of well‐accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid‐β 1‐42 (Aβ) and total‐ tau (tau) . We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple‐sibling familial history of AD. Apolipoprotein ( APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau , phosphorylated‐ tau (p‐ tau ) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra‐hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.