In Vivo Detection of Neurofibrillary Tangles by ¹⁸ F-MK-6240 PET/MR in Patients With Ischemic Stroke

Abstract

Background and objectives:The risk of developing Alzheimer disease is increased after stroke and this association may not solely be driven by traditional vascular risk factors. Neuronal death leads to release of tau proteins which can become dephosphorylated, rephosphorylated or hyperphosphorylated in the setting of ischemia, possibly leading to formation of neurofibrillary tangles. Therefore, a potential synergistic effect between development of tauopathy and cerebrovascular lesion burden may contribute to cognitive decline after stroke. We explored the spatial and temporal distribution of neurofibrillary tangles after ischemic stroke in vivo by using18F-MK-6240 positron emission tomography (PET).Methods:We included patients with a first ischemic stroke to undergo longitudinal18F-MK-6240 PET/MR within 2 to 4 weeks and 6 months after stroke. For cross-sectional analyses, we also included age-matched healthy controls. We delineated 5 volumes-of-interest based on T2 FLAIR and T1 MR data: the ischemic lesion, 3 consecutive peri-ischemic areas and the remaining ipsilesional hemisphere. We performed region-based voxel-wise partial volume correction on the PET data and calculated standardized uptake value ratios (SUVR) with the cerebellum as reference region.Results:We did not quantify PET scans of patients within the first month after stroke (n = 17; median age 73 years [IQR: 62-82]) since the signal intensity was influenced by blood brain barrier breakdown hampering a reliable data analysis. At 6 months after the event (n = 13; median age 71 years [IQR: 60-79]),18F-MK-6240 SUVR was increased in the ischemic lesion compared to 20 age-matched healthy controls (median age 71.5 years [IQR: 66-76]; ratiolesion/controls= 1.62±0.54; one-sample t-test: p = 0.0015) and gradually decreased in the surrounding tissue (one-way within-subject ANOVA(F(1.2, 14.8) = 18.0, p = 0.00043).Discussion:These findings suggest that neurofibrillary tangles may form after ischemic stroke and spread in the peri-ischemic brain parenchyma. Further follow up is required to gain more insight in the spatial and temporal dynamics of this tauopathy after ischemic stroke.

LRP1 and RAGE Genes Transporting Amyloid and Tau Protein in the Hippocampal CA3 Area in an Ischemic Model of Alzheimer’s Disease with 2-Year Survival

“…It is now clear that post-ischemic brain neurodegeneration is a tauopathy [9,[45][46][47][48][49][50][51]. Some data suggest that in neurons and microglia, RAGE binds to the modified tau protein and facilitates the development of neuronal tau protein-related pathologies and behavioral deficits [28].…”