Thalamic neurometabolite alterations in patients with knee osteoarthritis before and after total knee replacement

Abstract

The weak association between disability levels and "peripheral" (ie, knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in patients with KOA, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four presurgical patients with KOA and 13 healthy controls were scanned using a PRESS sequence (TE = 30 ms, TR = 1.7 seconds, voxel size = 15 × 15 × 15 mm). In addition, 13 patients were rescanned 4.1 ± 1.6 (mean ± SD) weeks post-TKA. When using creatine (Cr)-normalized levels, presurgical KOA patients demonstrated lower N-acetylaspartate (NAA) (P < 0.001), higher myoinositol (mIns) (P < 0.001), and lower Choline (Cho) (P < 0.05) than healthy controls. The mIns levels were positively correlated with pain severity scores (r = 0.37, P < 0.05). These effects reached statistical significance also using water-referenced concentrations, except for the Cho group differences (P ≥ 0.067). Post-TKA patients demonstrated an increase in NAA (P < 0.01), which returned to the levels of healthy controls (P > 0.05), irrespective of metric. In addition, patients demonstrated postsurgical increases in Cr-normalized (P < 0.001), but not water-referenced mIns, which were proportional to the NAA/Cr increases (r = 0.61, P < 0.05). Because mIns is commonly regarded as a glial marker, our results are suggestive of a possible dual role for neuroinflammation in KOA pain and post-TKA recovery. Moreover, the apparent postsurgical normalization of NAA, a putative marker of neuronal integrity, might implicate mitochondrial dysfunction, rather than neurodegenerative processes, as a plausible pathophysiological mechanism in KOA. More broadly, our results add to a growing body of literature suggesting that some pain-related brain alterations can be reversed after peripheral surgical treatment.

Fig 1:. Voxel placement and representative spectrum

(A) Voxel overlap density map for all participants. Individual MRS voxels are converted to MNI space and then combined to show the overlap between participants. (B) Voxel centroids of all participants showing how tightly clustered MRS voxels are around a target anatomical location. (C) Representative MRS spectrum from left thalamus.

Fig 2:. Neurometabolic levels in the left thalamus of KOA and healthy controls

(A) Mean neurometabolic ratios of all KOA (n=34) and healthy controls (n=13), corrected for age. (B) Mean water-referenced neurometabolic concentrations of all KOA (n=34) and healthy controls (n=13). Statistical significances between the two groups and mean concentrations within each group are shown. Concentration values are given as mean ± SD; ***p<0.001, ****p<0.0001. Abbreviation: NAA, N-acetylaspartate; mIns, myo-inositol; cr, creatine;

Fig 3:. Correlations of neurometabolites and WOMAC pain scores

Correlation between neurometabolite concentrations and the KOA disease severity measured with the WOMAC scale, in KOA patients (n=33). (A) Correlation of thalamic mIns/Cr and WOMAC pain scale after adjusting for age (r=0.37, p=0.038). Water-referenced concentrations of thalamic mIns with (B) pain (r=0.52, p=0.002), (C) stiffness (r=0.39, p=0.026) and (D) physical (r=0.48, p=0.005) after adjusting for age. The resulting slope in linear fit is represented by the dashed-black line. See Figure 1 caption for abbreviations.

Fig 4:. Pre vs post-surgical thalamic neurometabolic levels of KOA patients

Pre and post TKA (A) ratios of mIns/Cr (p=0.0297) and NAA/Cr (p=0.01) of KOA patients (n=13) and (B) water-referenced mIns (p=0.2046) and NAA (p=0.0018). Statistical significances between the two groups and mean concentrations within each group are shown. Concentration values are given as mean ± SD; *p< 0.05, **p<0.01. Slope in linear fit is represented by the solid black line. TKA, total knee arthroplasty; see Figure 1 caption for other abbreviations.