Abstract
Background and Objectives Cost-effective and mechanistically-informative biomarkers are needed to advance novel therapeutics for dementia. We focus on neuroinflammation in disorders associated with frontotemporal lobar degeneration (FTLD). Commonly used assays include positron emission tomography (PET) imaging and peripheral blood markers. However, PET is limited by radioactivity, which impedes repeated measurements, while peripheral markers are indirect measures of neuropathology. This study investigates the potential of proton magnetic resonance spectroscopy (MRS) – a non-invasive technique that can be deployed alongside structural imaging sequences – to quantify myo-inositol, an inflammatory metabolite found in astroglial and microglial cells. We test the following hypotheses (1) myo-inositol is elevated in brain regions affected by FTLD disorders; (2) myo-inositol in affected brain regions correlates with peripheral immune markers; and (3) myo-inositol in affected brain regions correlates with cognitive decline.
Methods 54 people with FTLD-associated disorders (29 behavioural variant frontotemporal dementia, 25 progressive supranuclear palsy) and 73 age/sex-matched controls underwent single-voxel 7 Tesla MRS. 2cm isotropic voxels were placed over the right inferior frontal gyrus (R IFG, a disease-affected region of interest), and right occipital lobe (R OCC, a control region). Serum inflammatory markers were measured using nucleic acid-linked immuno-sandwich assays (NULISA). Cognition was assessed with the revised Addenbrooke’s Cognitive Examination (ACE-R). Mixed-effects and general linear models were used to evaluate diagnostic differences in regional myo-inositol and its association with cognition. Partial least squares regression identified two serum inflammatory components that covaried with myo-inositol; these components were subsequently tested in confounder-adjusted second-level linear models.
Results Myo-inositol was elevated in the R IFG (β = 0.20, t = 5.10, p = 8.8 × 10^-7) but not in the R OCC (β = 0.05, t = 1.36, p = 0.18), in people with FTLD versus controls. In FTLD, myo-inositol in the R IFG was positively associated with a peripheral inflammatory profile characterised by IL-6, IL-1β, GFAP, CSF2, CRP, and CCL22 (β = 0.39, t = 5.12, p = 3.60 × 10^-6). R IFG myo-inositol was negatively associated with ACE-R performance in patients (β = −44.59, t = −4.12, p = 0.00016).
Conclusion MRS-derived myo-inositol is a promising neuroimaging biomarker of inflammation in FTLD. Elevated levels in disease-affected regions were associated with peripheral markers of inflammation (reflecting astrocytosis and microgliosis) and with cognitive impairment.
Authors and Affiliations
Sean YW Tan¹˒²˒⁶, Michelle Naessens¹, P Simon Jones², Emily G Todd¹, Rebecca S Williams¹, Christopher T Rodgers², Laura E Hughes¹˒², Noah L Shapiro²˒³, Julia Goddard²˒³, Meira van Schaik²˒³, Amanda Heslegrave⁴˒⁵, Henrik Zetterberg⁴˒⁵˒⁷⁻¹¹, Alexander G Murley²˒⁶, Maura Malpetti²˒³, James B Rowe¹˒²˒⁶
¹MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
²Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
³UK Dementia Research Institute at Cambridge, Cambridge, UK
⁴UK Dementia Research Institute at University College London, London, UK
⁵Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London, UK
⁶Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
⁷Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
⁸Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
⁹Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
¹⁰Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
¹¹Centre for Brain Research, Indian Institute of Science, Bangalore, India