In vivo assessment of astrocyte reactivity in patients with progressive supranuclear palsy

Emerging evidence highlights the association of reactive astrocytes with neurodegenerative diseases. Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its role in the pathophysiology of the disease is not fully understood. In this study, we aimed to assess astrocyte reactivity in vivo in patients with PSP using magnetic resonance spectroscopy and plasma biomarkers. Furthermore, given the central role of astrocytes in brain energy metabolism and their glycolytic profile, which implies a preference for lactate production, we investigated alterations in brain energy metabolism by measuring brain lactate levels and examined their relationship with astrocyte reactivity. We included 30 patients with PSP-Richardson′s syndrome and 30 healthy controls; in patients, tau deposition was confirmed via 18F-florzolotau-PET. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex (ACC) via magnetic resonance spectroscopy. The ACC was studied because previous functional imaging studies revealed its involvement as a distinctive feature of PSP. It involves in cognitive processes, such as executive function, which often exhibit deficits in patients with PSP. We measured plasma concentrations of glial fibrillary acidic protein (GFAP) as another astrocytic marker, neurofilament light chain (NfL), and tau phosphorylated at threonine 181. Reactive astrocytes, tau deposition, and synaptic loss in the ACC were assessed in post-mortem brain samples from another three patients with PSP with comparable disease durations to those of participants. The level of myo-inositol in the ACC and the plasma GFAP were significantly higher in patients than in healthy controls; these increases were significantly associated with Frontal Assessment Battery and Mini-Mental State Examination scores, respectively. The lactate level in the ACC was high in patients and correlated significantly with high myo-inositol levels. The plasma NfL outperformed other biomarkers in discriminating patients from controls (area under the curve [AUC] = 0.95), followed by lactate and myo-inositol (AUC = 0.88 and 0.78, respectively). Histological analysis of the ACC in patients revealed evident reactive astrocytes despite mild tau deposition and no marked synaptic loss. We found high levels of astrocyte biomarkers (myo-inositol in the ACC and plasma GFAP) in patients with PSP, suggesting astrocyte reactivity, and these biomarkers correlated with cognitive decline. Elevated myo-inositol levels were associated with high lactate levels, suggesting a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the ACC precedes pronounced tau pathology and neurodegenerative processes in the region and affects brain function in PSP. ### Competing Interest Statement M.-R.Z., H.Sd., and M.H. hold patents on compounds related to the present report (JP 5422782/EP 12884742.3/CA2894994/HK1208672). ### Funding Statement This work was supported by AMED under grant no. JP22dk0207063, JP19dm0207072, JP22dk0207055, and JP21zf0127004, by JSPS KAKENHI grant no. JP19H01041 and JP21K18268, and by the Collaborative Research Project of the Brain Research Institute, Niigata University. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of National Institutes for Quantum Science and Technology gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request.