Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice

Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer’s disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16–41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45–65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect

診断にMRI拡散強調画像が有用であった化膿性脳室炎の１例

症例は 73歳女性である.頭痛,嘔気,発熱,項部硬直,意識障害,排尿障害を呈し当科に入院した.髄液検査で著明な炎症細胞増多あり,髄液および血液の培養検査で B群連鎖球菌陽性であり,細菌性髄膜炎と診断された. MRI拡散強調画像では左右の側脳室後角およびくも膜下腔に高信号病変がみられた. T2強調画像, FLAIR画像,ガドリニウム造影 T1強調画像では明らかな病変は指摘されなかった.細菌性髄膜炎により脳室内およびくも膜下腔に膿が波及した結果,化膿性脳室炎を呈し,拡散強調画像で高信号病変として指摘されたものと考えられた.抗生剤およびステロイド投与により排尿障害以外の後遺症なく症状は改善し,拡散強調画像でも高信号病変は消失した.本症例により,細菌性髄膜炎や化膿性脳室炎の診断および病態の評価に拡散強調画像の撮影が有用である可能性が示された