Glymphatic system impairment in Alzheimer's disease associations with perivascular space volume and cognitive function

Objectives: To investigate glymphatic function in Alzheimer's disease (AD) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations between DTI-ALPS index and perivascular space (PVS) volume, as well as between DTI-ALPS index and cognitive function.

Methods: Thirty patients with PET-CT-confirmed AD (15 AD dementia; 15 mild cognitive impairment due to AD) and 26 age- and sex-matched cognitively normal controls (NCs) were included in this study. All participants underwent neurological MRI and cognitive assessments. Bilateral DTI-ALPS indices were calculated. PVS volume fractions were quantitatively measured at three locations: basal ganglia (BG), centrum semiovale, and lateral ventricle body level. DTI-ALPS index and PVS volume fractions were compared among three groups; correlations among the DTI-ALPS index, PVS volume fraction, and cognitive scales were analyzed.

Results: Patients with AD dementia showed a significantly lower DTI-ALPS index in the whole brain (p = 0.009) and in the left hemisphere (p = 0.012) compared with NCs. The BG-PVS volume fraction in patients with AD was significantly larger than the fraction in NCs (p = 0.045); it was also negatively correlated with the DTI-ALPS index (r = - 0.433, p = 0.021). Lower DTI-ALPS index was correlated with worse performance in the Boston Naming Test (β = 0.515, p = 0.008), Trail Making Test A (β = - 0.391, p = 0.048), and Digit Span Test (β = 0.408, p = 0.038).

Conclusions: The lower DTI-ALPS index was found in patients with AD dementia, which may suggest impaired glymphatic system function. DTI-ALPS index was correlated with BG-PVS enlargement and worse cognitive performance in certain cognitive domains.

Clinical relevance statement: Diffusion tensor image analysis along the perivascular space index may be applied as a useful indicator to evaluate the glymphatic system function. The impaired glymphatic system in patients with Alzheimer's disease (AD) dementia may provide a new perspective for understanding the pathophysiology of AD.

Key points: • Patients with Alzheimer's disease dementia displayed a lower diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, possibly indicating glymphatic impairment. • A lower DTI-ALPS index was associated with the enlargement of perivascular space and cognitive impairment. • DTI-ALPS index could be a promising biomarker of the glymphatic system in Alzheimer's disease dementia.

研究目标：本研究旨在采用沿血管周围间隙的弥散张量成像分析（diffusion tensor image analysis along the perivascular space, DTI-ALPS）方法，探究阿尔茨海默病（AD）患者的胶质淋巴系统（glymphatic system）功能，并分析DTI-ALPS指数与血管周围间隙（PVS）容积、以及DTI-ALPS指数与认知功能之间的关联。

研究方法：本研究纳入30例经PET-CT确认的AD患者（其中15例为AD痴呆，15例为AD相关性轻度认知障碍），以及26例年龄、性别匹配的认知正常对照（NCs）。所有受试者均接受神经磁共振成像（MRI）检查与认知功能评估。计算双侧DTI-ALPS指数。在基底神经节（BG）、半卵圆中心及侧脑室体部层面三个部位定量测量PVS容积分数。比较三组受试者的DTI-ALPS指数与PVS容积分数，并分析DTI-ALPS指数、PVS容积分数与认知量表之间的相关性。

研究结果：与NCs相比，AD痴呆患者的全脑及左侧半球DTI-ALPS指数均显著降低（p=0.009，p=0.012）。AD患者的BG-PVS容积分数显著高于NCs（p=0.045），且该分数与DTI-ALPS指数呈负相关（r=-0.433，p=0.021）。较低的DTI-ALPS指数与波士顿命名测验（β=0.515，p=0.008）、连线测验A（β=-0.391，p=0.048）及数字广度测验（β=0.408，p=0.038）的较差表现相关。

研究结论：AD痴呆患者的DTI-ALPS指数降低，提示其胶质淋巴系统功能受损。DTI-ALPS指数与BG-PVS扩大及特定认知域的认知表现下降相关。

临床相关性说明：沿血管周围间隙的弥散张量成像分析（DTI-ALPS）指数可作为评估胶质淋巴系统功能的有效指标。AD痴呆患者的胶质淋巴系统受损，这为理解阿尔茨海默病（AD）的病理生理学机制提供了新视角。

核心要点：
• 阿尔茨海默病（AD）痴呆患者的DTI-ALPS指数降低，可能提示胶质淋巴系统受损。
• 较低的DTI-ALPS指数与血管周围间隙（PVS）扩大及认知障碍相关。
• DTI-ALPS指数有望成为AD痴呆患者胶质淋巴系统的潜在生物标志物。