Physicians and neuroscientists interested in quantitative imaging markers for early brain tissue changes related to Alzheimer’s disease.

Alzheimer’s disease (AD), the most common cause of dementia, is marked by progressive neurodegenerative changes of brain tissue. One of the regions to be affected early in the course of the disease is the hippocampus (1). Whole brain MR elastography has been demonstrated to detect decreased overall brain stiffness in AD compared to healthy controls (2). In this pilot study we investigate whether multifrequency MR elastography (MMRE) can detect differences in the elasticity of the hippocampus between patients with clinical diagnosis of AD and healthy controls (HC).14 patients with clinical diagnosis of AD (median age 77 years, range 53-87 years, 8 females) and 14 age- and sex-matched HC underwent MMRE. The measurements were conducted on a 3T MRI system (Siemens Trio) using a single-shot EPI-based MRE sequence (3). The MRE setting is shown in figure 1. Full 3D wave fields were acquired at 7 mechanical frequencies (30 to 60Hz, 5 Hz increments) in 16 contiguous coronal slices (figure 2) and by an image resolution of 1.9×1.9×1.9mm³ (FoV: 190x160mm, TR: 2980ms, TE: 71ms, 8 instances of the wave cycle). For parameter reconstruction, multifrequency dual elasto visco (MDEV) inversion was applied as described in (3). By this method, two independent parameter maps are obtained, which represent the magnitude and the phase angle of the complex shear modulus, |G*| and φ, respectively. We chose the Hippocampus as region of interest and the Thalamus as reference region. Both regions were segmented from the individual T1-structural images using FSL-FIRST (fsl version 4.1) and co-registered to the native space elasticity parameter maps using FSL-FLIRT. The segmented regions were used as masks for the elasticity parameter maps |G*|- and φ. To compare our data to previous works we generated a whole brain white matter mask directly from the elasticity-maps. Within all masks median values were extracted.Patients in the AD-group had a median score of 20 points on the Mini-Mental-State-Exam (MMSE). In 9/14 patients, information about CSF-analysis was available; of these 6/9 displayed a typical constellation of the CSF-biomarkers. Clinical diagnosis of AD had been established for 3.6±2.2 years. HC had a median score of 29 points on the MMSE. Years of education and body-mass-index did not show significant differences between groups. In the AD group |G*|-values in the hippocampus region were significantly lower than in healthy controls (AD: median [iqr]: 781 [641-889] Pa; HC: 1015 [945-1098] Pa; p<0.001). For the phase angle φ we observed a similar reduction in the AD group (median [iqr]: 0.38 [0.36-0.44]) compared to the controls (0.48 [0.44-0.56]; p=0.001). For the thalamus we observed a trend towards lower measures in the AD-group. These differences were non-significant (|G*| in AD: 1176 [1026-1437] Pa vs. median |G*| in HC: 1368 [1276-1450] Pa; p=0.056 and φ in AD: 0.65 [0.58-0.77] vs. φ in HC: 0.72 [0.63-0.76]; p=0.352). Within the whole brain white matter mask we observed significantly lower measures of |G*| in the AD group (AD: 1402 [1305-1479] Pa vs. HC 1489 [1441-1535] Pa; p=0.016) but not for φ (AD: 0.608 [0.580-0.641] vs. HC: 0.604 [0.554-0.659]; p=0.804). Boxplots of the |G*|-parameter in the three regions are shown in figure 3. Therefore, if we postulate |G*| of the Hippocampus as a diagnostic test to differentiate between AD and HC and plot the ROC-curve, this suggests a cutoff of |G*|=900 Pa (figure 4). This would provide a sensitivity of 78% and a specificity of 92% with an AUROC-value of 0.918.Our data confirm that whole-brain white matter masks show reduced stiffness in patients with AD (2). This has also been demonstrated for patients with frontotemporal dementia, a much less common form of dementia (4). However, we report for the first time that MMRE is capable of detecting differences in the elasticity of small brain regions such as the Hippocampus. Our data suggest that the stiffness within the Hippocampus is reduced in patients with clinical diagnosis of AD. Since the Hippocampus is involved in neurodegenerative processes early in the course of AD, the detection of decreased hippocampal stiffness could become a biomarker for early diagnosis and progression monitoring. It should be mentioned that there is currently no imaging biomarker suitable for the prognosis of AD (5). The relatively high specificity observed in our study motivates further investigation whether MMRE can detect decreased brain stiffness already in early stages of the disease such as mild cognitive impairment and whether these changes predict clinical decline.