PMC

A) Anatomic localization of regions in the brain exhibiting a significant linear correlation between ADC and neutrophil gelatinase-associated lipocalin (NGAL), diffuse throughout the brain white matter. B) Linear correlation between average ADC within this cluster and urinary NGAL concentration. C) Anatomic localization of regions in the brain exhibiting a significant linear correlation between FA and NGAL, diffusely distributed in white matter. D) Linear correlation between average FA within this cluster and urinary NGAL concentration.

A) Anatomic localization of regions in the brain exhibiting a significant linear correlation between the apparent diffusion coefficient (ADC) and urinary protein concentration of matrix metalloproteinase-2 (MMP2) within the right somatosensory cortex. B) Linear correlation between average ADC within this cluster and urinary MMP2 concentration.

A) Anatomic localization of regions in the brain exhibiting a significant linear correlation between ADC and urinary concentration of the MMP9/NGAL complex, in similar brainstem regions as MMP9. B) Linear correlation between average ADC within this cluster and urinary MMP9/NGAL concentration. C) Anatomic localization of regions in the brain exhibiting a significant linear correlation between FA and MMP9/NGAL complex, similarly observed in the brainstem. D) Linear correlation between average FA within this cluster and urinary MMP9/NGAL concentration. E) Anatomic localization of regions in the brain exhibiting a significant linear correlation between FA and MMP9/NGAL complex in the left sensorimotor region. F) Linear correlation between average FA within this cluster and urinary MMP9/NGAL concentration.

A) Anatomic localization of regions in the brain exhibiting a significant linear correlation between ADC and urinary concentration of vascular endothelial growth factor (VEGF) within the brainstem. B) No linear correlation between average ADC within this cluster and urinary VEGF concentration was observed after outlier correction. C) Anatomic localization of regions in the brain exhibiting a significant linear correlation between FA and VEGF. D) Similar to ADC, no linear correlation between average FA within this cluster and urinary VEGF concentration was observed after outlier correction. (Outliers = red circle).

A) Anatomic localization of regions in the brain exhibiting a significant linear correlation between ADC and urinary protein concentration of matrix metalloproteinase-9 (MMP9) within the midbrain portion of the brainstem, encompassing the dorsal Raphe nuclei (DRN). B) Linear correlation between average ADC within this cluster and urinary MMP9 concentration. C) Anatomic localization of regions in the brain exhibiting a significant linear correlation between fractional anisotropy (FA) and MMP9 also present in the brainstem. D) Linear correlation between average FA within this cluster and urinary MMP9 concentration. E) A second set of clusters with a significant linear correlation between FA and MMP were localized to the sensorimotor regions, bilaterally. F) Linear correlation between average FA within these two clusters and urinary MMP9 concentration.

In UCPPS patients with elevated MMP9 as a result of local or systemic inflammation, excitotoxicity and eventual death of neurons in the dorsal Raphe nuclei (DRN) may occur, as MMP9 is known to lead to excitotoxicity in glutamatergic neurons and 2/3 of neurons in the DRN are both glutamatergic and serotonergic. The DRN is known to be the primary serotonergic center for the brain and projects throughout the brain including sensorimotor (M1/S1) regions. Increased concentration of MMP9, NGAL, MMP9/NGAL complex, and altered serotonin all modulate aspects of brain plasticity through manipulation of dendritic projections, altering long-term potentiation (LTP), and other synaptic changes. Additionally, altered serotonin levels, MMP9, and NGAL have all independently been linked to other conditions including anxiety and depression, which are also commonly observed in patients with UCPPS.