CSF Biomarkers and Neuropsychological Profiles in Patients with Cerebral Small-Vessel Disease

Despite existing criteria, differential diagnosis of Vascular Dementia (VD) and Alzheimer's disease (AD) remains difficult. The aim of this study is to figure out cognitive and biomarker profiles that may help to distinguish between VD, AD and AD + Cerebral Small Vessel Disease (CSVD). We examined a cohort of patients with CSVD (n = 92). After stratification of cognitive impaired patients (n = 59) using the standard CSF beta-amyloid 42/40 ratio cut-off point of 0.975, we obtained two groups which differed with respect to several features: 32 patients with normal beta-amyloid 42/40 ratio (>0.975) showed markedly impaired blood-brain-barrier function as indicated by an elevated albumin ratio (median 8.35). They also differed in cognitive profiles when compared to 27 patients with AD typical beta-amyloid ratio and normal albumin ratio. We also enrolled an additional group of patients with AD (no significant CSVD on MRI, n = 27) which showed no impairment of the blood-brain-barrier. We showed a negative correlation between the albumin ratio and executive cognitive function (p = 0.016) and a negative correlation between memory function and typical AD markers like Tau (p = 0.004) and p181-Tau (p = 0.023) in our cohort. We suppose that the group of patients with normal beta-amyloid ratio represents VD while patients in the other groups represent AD+CSVD and pure AD. Our results support the idea that a dysfunction of the blood-brain-barrier might be contributing factor in the development of cognitive decline in CSVD as it seems to be of more importance than the severity of white matter lesions.

尽管已有现行诊断标准，血管性痴呆（Vascular Dementia, VD）与阿尔茨海默病（Alzheimer's Disease, AD）的鉴别诊断仍颇具难度。本研究旨在明确可用于区分血管性痴呆、阿尔茨海默病以及阿尔茨海默病合并脑小血管病（Cerebral Small Vessel Disease, CSVD）的认知特征与生物标志物谱。我们纳入了92例脑小血管病患者队列。以脑脊液β-淀粉样蛋白42/40比值（CSF beta-amyloid 42/40 ratio）0.975作为截断值，对59例认知受损患者进行分层后，得到两组存在多项特征差异的人群：32例β-淀粉样蛋白42/40比值正常（>0.975）的患者，其血脑屏障（blood-brain-barrier）功能显著受损，表现为白蛋白比值（albumin ratio）升高（中位数为8.35）；与27例具有典型阿尔茨海默病特征的β-淀粉样蛋白比值异常且白蛋白比值正常的患者相比，该组患者的认知特征亦存在显著差异。本研究同时纳入了27例经MRI检查无显著脑小血管病的单纯阿尔茨海默病患者队列，该队列未出现血脑屏障受损情况。在本研究队列中，我们发现白蛋白比值与执行认知功能呈负相关（p=0.016），记忆功能与Tau蛋白（Tau）、p181-Tau蛋白（p181-Tau）等典型阿尔茨海默病生物标志物亦呈负相关（分别为p=0.004与p=0.023）。我们推测，β-淀粉样蛋白42/40比值正常的患者组对应血管性痴呆，而其余两组则分别对应阿尔茨海默病合并脑小血管病与单纯阿尔茨海默病。本研究结果支持血脑屏障功能异常可能是脑小血管病患者认知衰退的潜在致病因素，且其重要性高于脑白质病变的严重程度。