Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers

Abstract

Objective: To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.

Methods: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.

Results: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.

Conclusion: Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

© 2019 American Academy of Neurology.

Figures

Figure 1. Voxel location and representative 1H MRS from all participants

Medial frontal lobe voxel is placed on a midsagittal 3D T1-weighted image (left). Voxel landmarks include the following: (1) the posterior edge of the frontal lobe voxel is in alignment with the posterior border of the genu of the corpus callosum; and (2) the posterior lower corner is at the superior border of the corpus callosum. Examples of proton magnetic resonance spectra (1H MRS) in (A) a noncarrier, (B) an asymptomatic microtubule-associated protein tau (MAPT) mutation carrier, and (C) a patient with behavioral variant frontotemporal dementia (bvFTD) with MAPT mutation. Spectra are scaled to the creatine (Cr) peak as indicated with the dotted red line. The N-acetylaspartate (NAA) peak is decreased in (B) the asymptomatic MAPT mutation carrier and (C) the patient with bvFTD. The myo-inositol (mI) peak is elevated only in (C) the patient with bvFTD.

Figure 2. Box plots of Frontal 1H MRS metabolite ratios in MAPT mutation carriers and noncarriers

Box plots show the median proton magnetic resonance spectroscopy (1H MRS) metabolite ratios (interquartile range adjusted for age) from the medial frontal lobe voxel in asymptomatic and symptomatic microtubule-associated protein tau (MAPT) mutation carriers and noncarriers. Red marks indicate the mean value adjusted for age for (A) N-acetylaspartate (NAA)/creatine (Cr), (B) myo-inositol (mI)/Cr, and (C) NAA/mI.

Figure 3. Plots of frontal lobe 1H MRS metabolite ratios and estimated or actual proximity to symptom onset

In the horizontal axis, 0 indicates the estimated age at symptom onset for asymptomatic microtubule-associated protein tau (MAPT) mutation carriers based on the median age at symptom onset in symptomatic MAPT mutation carriers from the same family; 0 indicates the age at actual symptom onset in symptomatic MAPT mutation carriers. (A) N-acetylaspartate (NAA)/creatine (Cr), (B) myo-inositol (mI/Cr), and (C) NAA/mI.