血管危险因素和脑血管病与无痴呆个体阿尔茨海默病病理改变的关联。

Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

机构信息

From the Department of Radiology and Nuclear Medicine (L.L., S.I., L.E.C., M.T., A.M.W., F.B.), Amsterdam University Medical Centre, Vrije Universiteit; Amsterdam Neuroscience (L.L., S.I., L.E.C., A.M.W., H.M.), Brain Imaging, Amsterdam, The Netherlands; Department of Neurology and Laboratory of Neuroscience (A.M., F.V., N.T., V.S.), IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Radiology (S.I.), Copenhagen University Hospital Rigshospitalet; Cerebriu A/S (S.I.), Copenhagen, Denmark; Clinical Memory Research Unit (L.E.C.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Advanced Biomedical Sciences (M.T.), University "Federico II," Naples, Italy; Department of Psychiatry and Neurochemistry (K.B., C.H.S.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburgn; Clinical Neurochemistry Laboratory (K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Neuroradiology Department (C.D.P.), University Hospital of Coventry and Warwickshire (UHCW), Coventry; GE HealthCare (C.F.), Amersham; Dementia Research Centre (N.C.F.), UCL Queen Square Institute of Neurology; UK Dementia Research Institute at University College London (N.C.F.), United Kingdom; Laboratory Alzheimer's Neuroimaging and Epidemiology (G.B.F.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; University Hospitals and University of Geneva (G.B.F.); CIMC - Centre d'Imagerie Médicale de Cornavin (S.H.), Place de Cornavin 18, Genève, Switzerland; Department of Surgical Sciences (S.H.), Radiology, Uppsala University, Sweden; Department of Radiology (S.H.), Beijing Tiantan Hospital, Capital Medical University, P. R. China; Centro de Investigación y Terapias Avanzadas (P.M.-L.), Neurología, CITA-Alzheimer Foundation, San Sebastián, Spain; Centre for Clinical Brain Sciences (D.M., A.W., J.M.W.), The University of Edinburgh; Department of Psychiatry (J.O.B.), School of Clinical Medicine, CB2 0SP, University of Cambridge, United Kingdom; Department of Nuclear Medicine (P.P.), Toulouse University Hospital; ToNIC (P.P.), Toulouse NeuroImaging Center, University of Toulouse, Inserm, UPS, France; Edinburgh Dementia Prevention (C.R.), Centre for Clinical Brain Sciences, Outpatient Department 2, Western General Hospital, University of Edinburgh Brain Health Scotland (C.R.), Edinburgh, United Kingdom; Alzheimer Center Amsterdam (P.S., B.M.T., P.J.V.), Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc; Amsterdam Neuroscience (P.S., B.M.T., P.J.V.), Neurodegeneration, Amsterdam, The Netherlands; Takeda Pharmaceuticals Ltd. (A.J.S.), Cambridge, MA; Department of Medical Physics and Biomedical Engineering (C.H.S.), Centre for Medical Image Computing (CMIC), University College London (UCL); MRC Unit for Lifelong Health & Ageing at UCL (C.H.S.), University College London; School of Biomedical Engineering and Imaging Sciences (C.H.S.), King's College London, United Kingdom; Department of Pathophysiology and Transplantation (F.V., N.T., V.S.), "Dino Ferrari" Center, Università degli Studi di Milano, Milan, Italy; Alzheimer Center Limburg (P.J.V.), Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, 6229 GS, Maastricht University, The Netherlands; Division of Neurogeriatrics (P.J.V.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Medicine (A.W.), Imperial College London; IXICO (R.W.), EC1A 9PN, London, United Kingdom; Université de Normandie (G.C.), Unicaen, Inserm, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", institut Blood-and-Brain @ Caen-Normandie, Cyceron, Caen, France; German Center for Neurodegenerative Diseases (DZNE) (M.E.), Munich, Germany; Ghent Institute for Functional and Metabolic Imaging (GIfMI) (H.M.), Ghent University, Belgium; Barcelonaβeta Brain Research Center (BBRC) (J.D.G.), Pasqual Maragall Foundation; CIBER Bioingeniería (J.D.G.), Biomateriales y Nanomedicina (CIBER-BBN), Madrid; IMIM (Hospital del Mar Medical Research Institute) (J.D.G.); Universitat Pompeu Fabra (J.D.G.), Barcelona, Spain; UK Dementia Research Institute Centre at the University of Edinburgh (J.M.W.); and Institutes of Neurology and Healthcare Engineering (F.B.), University College London, United Kingdom.

出版信息

Neurology. 2024 Oct 8;103(7):e209801. doi: 10.1212/WNL.0000000000209801. Epub 2024 Sep 17.

DOI:10.1212/WNL.0000000000209801

PMID:39288341

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11450612/

Abstract

BACKGROUND AND OBJECTIVES

Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau), atrophy, and cognition.

METHODS

This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ, P-tau, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal).

RESULTS

A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all < 0.05) and a negative association between FRS and Aβ (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ (all < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ.

DISCUSSION

In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

摘要

背景与目的

血管危险因素（VRFs）和脑小血管病（cSVD）在阿尔茨海默病（AD）患者中很常见。目前尚不清楚这种共存是反映了共同的危险因素还是一种机制关系，以及血管和淀粉样蛋白病理学是否对临床前阶段 AD 病理生理学有独立或协同的影响。我们研究了 VRFs、cSVD 和淀粉样蛋白水平（Aβ）之间的联系，以及它们对下游 AD 生物标志物（即 CSF 磷酸化 tau（P-tau）、萎缩和认知）的联合影响。

方法

这项回顾性研究纳入了来自欧洲预防阿尔茨海默病（EPAD）队列的非痴呆参与者（临床痴呆评定<1），并使用视觉量表和脑白质高信号容积来评估 Framingham 风险评分（FRS）和 MRI 上的 cSVD 特征。在初步线性分析后，我们使用结构方程模型（SEM）创建了一个“cSVD 严重程度”潜在变量，并评估了 FRS 和 cSVD 严重程度对 Aβ、P-tau、灰质体积（基线和纵向）和认知表现（基线和纵向）的直接和间接影响。

结果

共有 1592 名参与者接受了评估（平均年龄=65.5±7.4 岁；56.16%为女性）。我们观察到 FRS 与所有 cSVD 特征之间存在正相关（均<0.05），而 FRS 与 CSF Aβ 之间存在负相关（β=-0.04±0.01）。所有 cSVD 特征均与 CSF Aβ 呈负相关（均<0.05）。使用 SEM，cSVD 严重程度完全介导了 FRS 与 CSF Aβ 之间的关联（间接效应：β=-0.03±0.01），即使排除了血管淀粉样蛋白相关标志物也是如此。我们观察到 cSVD 严重程度对 P-tau（间接效应：β=0.12±0.03）、基线和纵向灰质体积（间接效应：β=-0.10±0.03；β=-0.12±0.05）和基线认知表现（间接效应：β=-0.16±0.03）具有显著的间接影响，这是通过 CSF Aβ 实现的。

讨论

在一个大型的非痴呆人群中，我们的研究结果表明，cSVD 是 VRFs 与 CSF Aβ 之间关系的中介，并影响下游神经退行性变和认知障碍。我们提供了 VRFs 间接影响 AD 发病机制的证据，强调了在 AD 风险评估中考虑 cSVD 负担的重要性，以及作为干预的早期窗口。这些结果突出了 VRFs 和脑血管病理学作为准确设计抗淀粉样蛋白临床试验和为患者分层提供新视角的关键生物标志物的作用。