Brain Microstructure Reveals Early Abnormalities more than Two Years prior to Clinical Progression from Mild Cognitive Impairment to Alzheimer's Disease

Abstract

Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer's disease (AD) no earlier than 2 years after baseline scanning, in order to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the most substantial differences between the two groups and was the best single predictor of future progression to AD. An optimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detect early, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression.

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease

“…In these studies, longer path lengths were found in MCI [12] and mild AD [10,13], reflecting disrupted interactions of distant brain regions. This anterior-posterior disintegration has been explained by a breakdown of anatomical connections, e.g., through the cingulum bundle or the superior longitudinal fasciculus, which are particularly vulnerable in AD [97][98][99], and by an imbalance of parietal and frontal metabolism. The PCC in particular shows greater hypometabolism than frontal regions in AD [22,100].…”

Can multi-modal neuroimaging evidence from hippocampus provide biomarkers for the progression of amnestic mild cognitive impairment?

“…In a meta-analysis that compared DTI to hippocampal measurements, Clerx and colleagues revealed that the effective size of the hippocampal MD is better than that of hippocampal volume in distinguishing aMCI from controls, and MD values are more discriminatory than FA values [83] . Douaud and colleagues examined both volumetric and microstructural abnormalities and found that progressive aMCI patients have significantly smaller GM volume in the left CA region and significantly higher MD in the left hippocampus compared to stable aMCI patients [84] . These findings highlight the benefit of using information about microstructural damage and traditional GM volume to detect early, mild abnormalities in aMCI patients prior to clinical progression to AD [84] .…”

“…Douaud and colleagues examined both volumetric and microstructural abnormalities and found that progressive aMCI patients have significantly smaller GM volume in the left CA region and significantly higher MD in the left hippocampus compared to stable aMCI patients [84] . These findings highlight the benefit of using information about microstructural damage and traditional GM volume to detect early, mild abnormalities in aMCI patients prior to clinical progression to AD [84] . Another recent study combined structural MRI and fMRI methods and demonstrated that aMCI patients show GM volume loss in the bilateral hippocampus and signifi cant decreases in the amplitude of low-frequency fluctuation (ALFF) in the left hippocampus.…”

[IC‐P‐161]: MEAN DIFFUSIVITY IN CORTICAL GRAY MATTER IN ALZHEIMER's DISEASE: THE IMPORTANCE OF PARTIAL VOLUME CORRECTION

“…Previous studies on GM MD in AD reported increases of hippocampal MD and whole brain GM MD in subjects with mild cognitive impairment (MCI) as compared to healthy controls Eustache et al, 2016;Fellgiebel et al, 2004;Müller et al, 2005;Scola et al, 2010), as well as in MCI patients that converted to AD compared to MCI subjects that remained stable over a period of several years (Douaud et al, 2013;Fellgiebel et al, 2006;Scola et al, 2010;van Uden et al, 2016). In some studies, hippocampal diffusivity even demonstrated a higher diagnostic and prognostic accuracy than hippocampal volume (Fellgiebel et al, 2006;Kantarci et al, 2005;Müller et al, 2007).…”

“…In this case, MD would represent the joint effect of microstructural changes and macrostructural brain atrophy. However, most of the studies using DTI data of healthy older and AD participants did not consider PVE at all Douaud et al, 2013;Eustache et al, 2016;Müller et al, 2007). One study stated that PVC was not necessary as the regions of interest (ROIs) were not located at the surface of the brain (Eustache et al, 2016).…”