Background & Aims
Growing evidence highlights a key role of the kynurenine pathway (KP) in neurological conditions. The KP impacts neurotransmitter systems, inflammation, and endocrine processes1–3. These processes can disrupt the balance between the neuroprotective (i.e., kynurenic acid/ tryptophan) and neurotoxic (i.e., quinolinic acid/kynurenine) branches of the KP3. Neurotoxic KP metabolites, which act as NMDA receptor agonists are altered in preclinical pain models4. Recent findings indicate elevated neurotoxic KP metabolites in neuro-degenerative/psychiatric conditions5,6 and chronic pain patients7. These elevated levels are linked with increases in glutamate in the basal ganglia among patients with depression9, and lowered gray matter (GM) levels in the cingulate cortex in schizophrenia patients10. This study examined the KP metabolites in chronic low back pain patients (LBP) and controls, investigating their relationship with pain outcomes, and their relationship with GM levels.
Methods
LBP patients and matched controls were recruited. The initial session involved a pain-oriented clinical examination and a blood sampling. At the second (~2 weeks apart), a 3D T1-weighted MRI scan was collected using a 3 T Philips Achieva scanner. Neuro-toxic/protective branches were analyzed, using an ultra–high performance liquid chromatography system, coupled to a 5500 linear ion trap quadrupole mass spectrometer11.
MRI data were processed using the FSLVBM toolkit12. Group differences in KP metabolites and total GM levels were examined using linear mixed-effects models corrected forage and sex with Cohen’s d as an effect-size measure. A Pearson correlation was used to examine the relationship of KP metabolites with patients’ pain intensity. The relationship of KP metabolites with GM volume was examined using pooled LBP and control data(because no group differences were seen in GM volume), using the FSLVBM-GLM tool correcting for age and sex.
Results
LBP patients (n = 39; males = 17; mean age= 51.43 y SD = 16.48) and matched controls (n = 29; males = 12; mean age = 49.89 y SD=17.24) were included in this analysis. The pain intensity(median= 4, range = 0-7) and pain duration (median= 79, range = 7- 628) of LBP patients at the time of the blood sampling was recorded using the 0-10 Numeric Rating Scale (NRS-11) and months respectively.
Group Differences
The neurotoxic branch was significantly elevated in LBP compared to controls (ß?=?0.01; 95CI = 0.00 to 0.01; p value= 0.03; Cohen’s d=0.51). No significant difference was seen between groups in the total amount of GM (Cohen’s d=0.04 p=0.85, 95CI= -0.44-0.54) and neuroprotective branches (Cohen’s d= -0.39, p=0.11, CI= -0.89-0.09). The neurotoxic branch was correlated with pain intensity (r=0.31; p-value=0.04, 95CI= 0.002-0.56), but not related to voxel-wise GM volume using the VBM analysis.
Conclusions
Our study examined the role of the KP in LBP patients and matched controls, investigating its relationship with pain intensity and structural brain imaging. Particularly, neurotoxic KP metabolites exhibited elevated profiles in LBP patients compared to controls, emphasizing a potential association between neurotoxicity and chronic pain. Since these metabolites can alter neurochemical transmission, they may be an earlier marker of subtle neuronal changes compared to structural brain changes. The KP metabolites are regarded as state markers and brain imaging outcomes mirror cumulative changes. Our findings underscore the need for a comprehensive understanding of the progression of the impact of pain. The positive correlation between neurotoxic levels and pain intensity further highlights the potential clinical relevance of these markers. Future analyses will examine relationships between structural changes in pain-related brain areas and the neurotoxic levels of the KP.
References
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Presenting Author
Jessica Archibald
Poster Authors
Jessica Archibald, PhD
PhD
Weill Cornell Medicine
Lead Author
Laura Sirucek
Balgrist University Hospital, University of Zurich
Lead Author
Francesco Bavato MD
PhD
University of Zurich
Lead Author
Andrea Steuer
PhD
University of Zurich
Lead Author
Stephan Dudli
PD
University of Zurich
Lead Author
John Kramer PhD
University of British Columbia
Lead Author
Boris B Quednow
Prof. Dr. rer. nat.
University of Zurich
Lead Author
Petra Schweinhardt
University of Zurich
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)