Combining viscoelasticity, diffusivity and volume of the hippocampus for the diagnosis of Alzheimer's disease based on magnetic resonance imaging

Abstract

Dementia due to Alzheimer's Disease (AD) is a neurodegenerative disease for which treatment strategies at an early stage are of great clinical importance. So far, there is still a lack of non-invasive diagnostic tools to sensitively detect AD in early stages and to predict individual disease progression. Magnetic resonance elastography (MRE) of the brain may be a promising novel tool. In this proof-of-concept study, we investigated whether multifrequency-MRE (MMRE) can detect differences in hippocampal stiffness between patients with clinical diagnosis of dementia due to AD and healthy controls (HC). Further, we analyzed if the combination of three MRI-derived parameters, i.e., hippocampal stiffness, hippocampal volume and mean diffusivity (MD), improves diagnostic accuracy.Diagnostic criteria for probable dementia due to AD were in line with the NINCDS-ADRDA criteria and were verified through history-taking (patient and informant), neuropsychological testing, routine blood results and routine MRI to exclude other medical causes of a cognitive decline.21 AD patients and 21 HC (median age 75 years) underwent MMRE and structural MRI, from which hippocampal volume and MD were calculated. From the MMRE-images maps of the magnitude |G*| and phase angle φ of the complex shear modulus were reconstructed using multifrequency inversion. Median values of |G*| and φ were extracted within three regions of interest (hippocampus, thalamus and whole brain white matter). To test the predictive value of the main outcome parameters, we performed receiver operating characteristic (ROC) curve analyses.Hippocampal stiffness (|G*|) and viscosity (φ) were significantly lower in the patient group (both p < 0.001). ROC curve analyses showed an area under the curve (AUC) for | G*| of 0.81 [95%CI 0.68–0.94]; with sensitivity 86%, specificity 67% for cutoff at |G*| = 980 Pa) and for φ an AUC of 0.79 [95%CI 0.66–0.93]. In comparison, the AUC of MD and hippocampal volume were 0.83 [95%CI 0.71–0.95] and 0.86 [95%CI 0.74–0.97], respectively. A combined ROC curve of |G*|, MD and hippocampal volume yielded a significantly improved AUC of 0.90 [95%CI 0.81–0.99].In conclusion, we demonstrated reduced hippocampal stiffness and reduced hippocampal viscosity, as determined by MMRE, in patients with clinical diagnosis of dementia of the AD type. Diagnostic sensitivity was further improved by the combination with two other MRI-based hippocampal parameters. These findings motivate further investigation whether MMRE can detect decreased brain stiffness already in pre-dementia stages, and whether these changes predict cognitive decline.

High-resolution magnetic resonance elastography reveals differences in subcortical gray matter viscoelasticity between young and healthy older adults

“…Our results may reflect the fact that we made reasonable effort to include only cognitively healthy participants; thus our sample may be more resilient to Hp microstructural alterations. This is especially relevant, given a recent study which found that Hp stiffness, determined using multifrequency MRE (MMRE), was lower in patients with AD when compared with healthy older adult controls ( Gerischer et al., 2017 ). Taken together, we can speculate that Hp stiffness may be maintained across the life span until the point of AD neurodegeneration, suggesting that MRE may be a promising noninvasive biomarker for early diagnosis.…”

“…Alterations in the mechanical properties of the brain, therefore, provide a unique contrast mechanism that appears to reflect the integrity of the underlying microstructure and health of brain tissue ( Sack et al., 2013 ). The sensitivity of MRE measures is confirmed by the observation of tissue softening in many neurological diseases ( Gerischer et al., 2017 , Huston et al., 2015 , Lipp et al., 2013 , Lipp et al, 2018 , Murphy et al., 2011 , Murphy et al., 2016 , Romano et al., 2014 , Streitberger et al., 2012 ), for a review, see Hiscox et al. (2016) or Murphy and Huston (2017) , with animal studies linking this softening to degree of myelin content ( Schregel, 2012 , Weickenmeier et al., 2016 , Weickenmeier et al., 2017 ), inflammation ( Riek et al., 2012 ), and a reduction in neuronal density related to a decrease in neurogenesis ( Freimann et al., 2013 , Klein et al., 2014 ).…”

Hippocampal viscoelasticity and episodic memory performance in healthy older adults examined with magnetic resonance elastography

“…DTI can probe the white matter pathways in the hippocampus and has previously revealed a loss of integrity with age (Yassa et al 2011) and a relationship between hippocampal mean diffusivity (MD) and verbal memory performance (van Norden et al 2012). The combination of hippocampal MRE measures, MD from DTI, and MR volumetry has recently been shown to improve the diagnostic accuracy of Alzheimer's disease (AD) (Gerischer et al 2017). Accordingly, it is conceivable to propose that a combination of imaging modalities that may include MRE could prove useful in the identification of healthy individuals at greatest risk for cognitive decline.…”

Fifty Shades of Brain: A Review on the Mechanical Testing and Modeling of Brain Tissue

“…This points towards an exciting new application of magnetic resonance elastography as a diagnostic tool to diagnose and quantify disease progression. Interestingly, however, while the stiffness seems to be a sensitive marker for taupathology, neuronal loss, and inflammation, this is not the case for amyloid-pathology [65].…”

“…3.9.6, is that they do not necessarily reflect changes in the local stiffness of the solid phase, including cells and extracellular matrix, but rather changes in the overall integrity of brain tissue, including changes in fluid transport and wave propagation. Magnetic resonance elastography shows that brain tissue softens in multiple sclerosis [156,182], Alzheimer's disease [65,124], and demyelination in general [149]. Interestingly, these softening effects scale with disease stage [86].…”