Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.
Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Geroscience. 2017 Feb;39(1):33-42. doi: 10.1007/s11357-017-9964-z. Epub 2017 Feb 4.
Whole brain irradiation (WBI) is a mainstream therapy for patients with both identifiable brain metastases and prophylaxis for microscopic malignancies. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients surviving long term after treatment, due to γ-irradiation-induced cerebromicrovascular injury. Moment-to-moment adjustment of cerebral blood flow (CBF) via neuronal activity-dependent cerebromicrovascular dilation (functional hyperemia) has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with impaired cerebromicrovascular function, C56BL/6 mice (3 months) subjected to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), sensorimotor coordination (computerized gait analysis, CatWalk), and cerebromicrovascular function (whisker-stimulation-induced increases in CBF, measured by laser Doppler flowmetry) at 3 to 6 months post-irradiation. We found that mice with WBI exhibited impaired cerebromicrovascular function at 3 months post-irradiation, which was associated with impaired performance in the radial arm water maze. At 6 months, post-irradiation progressive impairment in gait coordination (including changes in the regularity index and phase dispersion) was also evident. Collectively, our findings provide evidence for early and persisting neurovascular impairment after a clinically relevant protocol of fractionated WBI, which predict early manifestations of cognitive impairment.
全脑照射（WBI）是治疗有明确脑转移瘤和预防微小恶性肿瘤的主流疗法。然而，它也会促进健康组织的加速衰老，并导致多达 50%的肿瘤患者在长期治疗后出现进行性认知功能障碍，这是由于γ辐射引起的脑微血管损伤。通过神经元活动依赖性脑微血管扩张（功能性充血）对脑血流（CBF）进行即时调整，对于维持健康的认知功能至关重要。为了确定 WBI 引起的认知能力下降是否与脑微血管功能障碍有关，我们比较了接受临床相关分割 WBI 方案（每周两次 5Gy，共 4 周）的 C56BL/6 小鼠（3 个月）和对照组小鼠。在辐照后 3 至 6 个月，用放射臂水迷宫测试小鼠的空间记忆表现（放射臂水迷宫）、感觉运动协调（计算机步态分析、CatWalk）和脑微血管功能（通过激光多普勒血流测量测量，由胡须刺激引起的 CBF 增加）。我们发现，接受 WBI 的小鼠在辐照后 3 个月表现出脑微血管功能障碍，这与放射臂水迷宫中的表现受损有关。在 6 个月时，辐照后步态协调逐渐受损（包括规律性指数和相位分散的变化）也很明显。总之，我们的研究结果为临床相关分割 WBI 方案后早期和持续的神经血管损伤提供了证据，这预测了认知障碍的早期表现。
