Nguchu Benedictor Alexander, Zhao Jing, Lu Yu, Han Yifei, Jin Han, Wang Xiaoxiao, Li Hongjun, Shaw Peter
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang, China.
School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Psychiatry. 2025 May 28;16:1509093. doi: 10.3389/fpsyt.2025.1509093. eCollection 2025.
Existing evidence indicates that HIV enters the nervous system in the early days of infection. However, the involvement of HIV in the pathogenesis of key biological aspects of the brain, such as glymphatic clearance and brain aging, and its role in explaining complex phenomena like motoric and executive dysfunction, remains unrecognized.
Herein, we recruited 145 subjects to study the brain aging using brain-predicted age differences (brain-PADs) and investigate how HIV affects the typical trajectory of glymphatic clearance in aging brain. The assessment of glymphatic clearance in the aging brain was performed using a technique called "diffusion tensor image analysis along the perivascular space" (DTI-ALPS). We further evaluated the association between accelerated brain aging trajectories and cognitive performance to explain impairments observed in motor and executive functions in people living with HIV.
Our results showed that subjects with HIV had increased brain-PAD in several brain structures compared to those who were HIV-negative, suggesting underlying neuropathology associated with HIV. The brain structures demonstrating accelerated aging (increased brain-PAD) include the middle frontal gyrus, pre-and post-central gyri, supramarginal gyrus, precuneus, cuneus, parietal lobule and operculum, and superior and middle occipital gyri of the left hemisphere. While normal subjects maintained typical trajectories of glymphatic clearance (as measured by the DTI-ALPS index) with age or brain-PADs for several structures, including the left central operculum, left frontal operculum, left opercular inferior frontal gyrus, and left triangular inferior frontal gyrus, none of these trajectories were maintained in subjects with HIV. Our data also show that increased brain-PAD in brain regions was associated with lower performance in motor and executive functions.
These findings suggest that HIV infection accelerates brain aging and disrupts the trajectory of glymphatic clearance in aging brain, which may explain the complex mechanisms underlying cognitive impairment in motor and executive domains often seen in HIV patients. These new insights may shift our understanding of HIV pathology and aid the development of new therapeutic targets, contrary to previous approaches.
现有证据表明，HIV在感染早期就会进入神经系统。然而，HIV在大脑关键生物学方面（如类淋巴系统清除和脑老化）的发病机制中的参与情况，以及其在解释运动和执行功能障碍等复杂现象中的作用，仍未得到认识。
在此，我们招募了145名受试者，使用脑预测年龄差异（brain-PADs）来研究脑老化，并调查HIV如何影响衰老大脑中类淋巴系统清除的典型轨迹。使用一种称为“沿血管周围间隙的扩散张量图像分析”（DTI-ALPS）的技术对衰老大脑中的类淋巴系统清除进行评估。我们进一步评估了加速脑老化轨迹与认知表现之间的关联，以解释HIV感染者在运动和执行功能方面观察到的损伤。
我们的结果表明，与HIV阴性者相比，HIV感染者在几个脑结构中的脑PAD增加，这表明存在与HIV相关的潜在神经病理学。显示加速老化（脑PAD增加）的脑结构包括左半球的额中回、中央前后回、缘上回、楔前叶、楔叶、顶叶小叶和岛盖，以及枕上回和枕中回。虽然正常受试者在包括左中央岛盖、左额岛盖、左岛盖下回和左三角下回在内的几个结构中，随着年龄或脑PADs保持类淋巴系统清除的典型轨迹，但HIV感染者中这些轨迹均未保持。我们的数据还表明，脑区脑PAD增加与运动和执行功能的较低表现相关。
这些发现表明，HIV感染会加速脑老化并破坏衰老大脑中类淋巴系统清除的轨迹，这可能解释了HIV患者中常见的运动和执行领域认知障碍的复杂机制。这些新见解可能会改变我们对HIV病理学的理解，并有助于开发新的治疗靶点，这与以前的方法不同。
