Li Lian, Ding Guangliang, Zhang Li, Davoodi-Bojd Esmaeil, Chopp Michael, Li Qingjiang, Zhang Zheng Gang, Jiang Quan
Department of Neurology, Henry Ford Health System, Detroit, MI, United States.
Department of Physics, Oakland University, Rochester, MI, United States.
Front Aging Neurosci. 2022 Mar 10;14:841798. doi: 10.3389/fnagi.2022.841798. eCollection 2022.
Impaired glymphatic waste clearance function during brain aging leads to the accumulation of metabolic waste and neurotoxic proteins (e.g., amyloid-β, tau) which contribute to neurological disorders. However, how the age-related glymphatic dysfunction exerts its effects on different cerebral regions and affects brain waste clearance remain unclear.
We investigated alterations of glymphatic transport in the aged rat brain using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and advanced kinetic modeling. Healthy young (3-4 months) and aged (18-20 months) male rats ( = 12/group) underwent the identical MRI protocol, including T2-weighted imaging and 3D T1-weighted imaging with intracisternal administration of contrast agent (Gd-DTPA). Model-derived parameters of infusion rate and clearance rate, characterizing the kinetics of cerebrospinal fluid (CSF) tracer transport via the glymphatic system, were evaluated in multiple representative brain regions. Changes in the CSF-filled cerebral ventricles were measured using contrast-induced time signal curves (TSCs) in conjunction with structural imaging.
Compared to the young brain, an overall impairment of glymphatic transport function was detected in the aged brain, evidenced by the decrease in both infusion and clearance rates throughout the brain. Enlarged ventricles in parallel with reduced efficiency in CSF transport through the ventricular regions were present in the aged brain. While the age-related glymphatic dysfunction was widespread, our kinetic quantification demonstrated that its impact differed considerably among cerebral regions with the most severe effect found in olfactory bulb, indicating the heterogeneous and regional preferential alterations of glymphatic function.
The robust suppression of glymphatic activity in the olfactory bulb, which serves as one of major efflux routes for brain waste clearance, may underlie, in part, age-related neurodegenerative diseases associated with neurotoxic substance accumulation. Our data provide new insight into the cerebral regional vulnerability to brain functional change with aging.
脑衰老过程中类淋巴系统废物清除功能受损会导致代谢废物和神经毒性蛋白（如β淀粉样蛋白、tau蛋白）的积累，进而引发神经疾病。然而，与年龄相关的类淋巴系统功能障碍如何对不同脑区产生影响并影响脑废物清除尚不清楚。
我们使用动态对比增强磁共振成像（DCE-MRI）和先进的动力学模型研究了老年大鼠脑内类淋巴转运的变化。健康的年轻（3-4个月）和老年（18-20个月）雄性大鼠（每组n = 12）接受相同的MRI方案，包括T2加权成像和经脑池内注射造影剂（钆喷酸葡胺）的三维T1加权成像。在多个代表性脑区评估了表征脑脊液（CSF）示踪剂通过类淋巴系统转运动力学的模型衍生参数，即输注速率和清除速率。结合结构成像，使用对比剂诱导的时间信号曲线（TSCs）测量充满CSF的脑室变化。
与年轻大脑相比，老年大脑中检测到类淋巴转运功能整体受损，表现为全脑输注速率和清除速率均下降。老年大脑中存在脑室扩大，同时CSF通过脑室区域的转运效率降低。虽然与年龄相关的类淋巴系统功能障碍普遍存在，但我们的动力学定量分析表明，其影响在不同脑区有很大差异，其中嗅球受影响最严重，这表明类淋巴系统功能存在异质性和区域优先性改变。
嗅球作为脑废物清除的主要流出途径之一，其类淋巴活性受到强烈抑制可能在一定程度上是与神经毒性物质积累相关的年龄相关性神经退行性疾病的基础。我们的数据为大脑区域对衰老引起的脑功能变化的易损性提供了新的见解。
