Seven-Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

Abstract

Background: Adults with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging.

Objective: To test the hypothesis that neurochemistry in normal-appearing brains differs in adult phenotypes of X-ALD and that neurochemical changes correlate with the severity of symptoms.

Patients and methods: Using a 7-Tesla scanner, we performed structural and proton magnetic resonance spectroscopic imaging in 13 adult patients with X-ALD: 4 patients with adult cerebral ALD, 5 patients with adrenomyeloneuropathy (AMN), and 4 female heterozygotes. Nine healthy controls were included.

Results: Among adult X-ALD phenotypes, the myo-inositol to creatine ratio was 46% higher and the choline to creatine ratio was 21% higher in normal-appearing white matter of those with adult cerebral ALD compared with those with AMN (P < .05). Both N-acetylaspartate to creatine (P = .03) and glutamate to creatine (P = .04) ratios were lower in AMN patients than in controls. There were no significant differences between patients with AMN and female heterozygotes. In the cortex, patients with adult cerebral ALD had lower N-acetylaspartate to creatine ratios compared with female heterozygotes and controls (P = .02). The global myo-inositol to creatine ratio demonstrated a significant association with Expanded Disability Status Scale score (Spearman rho = 0.66, P = .04).

Conclusions: Seven-Tesla proton magnetic resonance spectroscopic imaging reveals differences in the neurochemistry of adult cerebral ALD but cannot distinguish AMN patients from female heterozygotes. Myo-inositol to creatine ratio correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD.

Figure 1. 1.5 Tesla versus 7 Tesla in adult X-ALD

1.5 compared to 7 Tesla examination in X-ALD. Images reveal a lesion within the splenium in a 26 year old man with adult cerebral adrenoleukodystrophy (A: 1.5 Tesla, B: 7 Tesla). At 7 Tesla fiber tracts beyond the lesion are visible that are not seen at 1.5 Tesla (black arrow). Spectra from normal appearing white matter are shown from the 2D proton MRSI box (C: 1.5 Tesla, D: 7 Tesla). At 7 Tesla there is better spectral resolution and detection of more metabolites, such as glutamate (Glu) and myoinositol (MI).

Figure 2. Metabolite Ratios in White Matter

Metabolite ratios of white matter in various phenotypes of X-ALD. The mean NAA/Cr ratios were reduced in patients with adrenomyeloneuropathy (AMN) and adult cerebral adrenoleukodystrophy (ACALD) compared to controls. The Cho/Cr and MI/Cr ratios were elevated in ACALD patients compared to controls, AMN and female heterozygotes. The p values given are for the difference of mean metabolite ratios derived from a multivariate ANOVA; a significant difference on a Holm's t-test (p < 0.05) is indicated by **; a trend on the Holm's t-test (p < 0.1) is indicated by *.

Figure 3. Metabolite Ratios in Gray Matter

Metabolite ratios in gray matter in adult phenotypes of X-ALD. Male hemizygote patients had a decreased NAA/Cr ratio in the cortical gray matter compared to controls. The p values given are for the difference of mean metabolite ratios derived from a multivariate ANOVA; a significant difference on a Holm's t-test (p < 0.05) is indicated by **; a trend on the Holm's t-test (p < 0.1) is indicated by *.

Figure 4. Metabolite Ratios, EDSS and plasma VLCFA

Scatter plot matrix showing interrelationship between global estimates of N acetylaspartate (NAA)/creatine (Cr), Choline (Cho)/Cr, Myo-Inositol (MI)/Cr and Glutamate (Glu)/Cr and clinical disability measures (Expanded Disability Status Scale - EDSS). The scatter points demonstrate a significantly positive correlation between MI/Cr and EDSS (Spearman ρ = 0.66, p = 0.039). We find significantly negative correlations between MI/Cr and NAA/Cr (Spearman ρ = -0.49, p = 0.03) and Glu/Cr (Spearman ρ = 0.55, p = 0.015), respectively. In addition, we find a significantly positive correlation between NAA/Cr and Glu/Cr (Spearman ρ = 0.66, p = 0.002). In the top right corner we show the inverse relationship of plasma VLCFA (C26:0 in umol/L) and global NAA/Cr values in ALD patients (Spearman ρ = -0.67, p = 0.02).