Neuroimaging and Vascular Correlates of Mild Cognitive Impairment Subtypes

描述(由申请人提供)： 由于老龄化人口正以前所未有的速度增长，被诊断为痴呆症的退伍军人人数估计将大幅增加。在出现明显的临床症状之前对个体进行识别，对于在治疗可能最有效的时候促进干预至关重要。识别前驱痴呆症潜在生物标志物的一种方法是评估阿尔茨海默病(AD)高危人群的大脑结构，如轻度认知障碍(MCI)患者。随着最近MCI研究的爆炸性增长，它是一种异质性疾病，并提出了不同的临床亚型(例如，遗忘性、非遗忘性)。MCI临床表现的异质性可能部分与潜在神经病理机制的异质性有关(S)。尽管存在争议，但有证据表明，遗忘型MCI患者在AD早期表现出更大的内侧颞叶损害(例如，Singh等人，2006年)。相比之下，那些患有非遗忘性MCI的患者在MRI上表现出更大的额叶受累(Nobili等人，2008)和更大的脑血管疾病(如白质异常所证明的)(Delano-Wood等人，2009)。混合性MCI以多个认知能力领域的损害为特征，可能代表具有神经退行性和脑血管特征的混合病理个体(Libon等人，2010)。综上所述，以前的研究强调了MCI、白质、AD病理和脑血管功能之间的复杂关系。这项拟议的研究将结合脑白质异常的成像标记物和血管风险标记物与AD相关的生物标记物(例如，脑脊液[CSF]对淀粉样蛋白和tau的测量、海马体体积)，并考虑MCI临床亚型，以便更全面地表征AD和脑血管风险对痴呆先兆的贡献。在这样做的时候，我们可以比较MCI和AD生物标记物的流行模型，该模型强调神经退行性变(例如，Jack等人，2013年)与一个将血管和AD病理的综合影响与发展为痴呆症的概率联系起来的模型(Chui等人，2012年)。目前的研究旨在(1)更好地描述不同MCI亚型背后的脑结构变化和血管风险概况，(2)严格检查可能区分MCI亚型并有助于认知损害的性质和严重程度的新的神经成像指标，以及(3)确定哪些白质和灰质改变的神经成像标记物和痴呆的其他危险因素(即血管风险因素，APOE？4状态)在预测认知能力下降和进展为痴呆症方面最有用。在拟议的研究中，92名老年人(23名认知正常，23名遗忘性MCI，23名非遗忘性MCI，23名混合/多领域MCI)将接受全面的神经心理评估；评估血管风险因素(例如空腹血糖)的实验室测试；脑脊液淀粉样蛋白和tau的测量；以及神经成像检查，包括高分辨率结构、灌注和白质成像。白质成像方案包括T2加权液体衰减反转恢复(FLAIR)以及两种前沿技术：扩散峰度成像(DKI)和一种新颖的髓鞘选择性技术(T1和T2的多分量驱动平衡单脉冲观察[mcDESPOT])。假设额区较大的血管风险负担和白质改变将与非遗忘性MCI和混合/多域MCI相关。相反，内侧颞叶区域的白质改变将与遗忘性MCI和混合/多域MCI相关。更好地了解与不同MCI临床亚型相关的潜在神经病理学，以及实施更好地检测异质性病理的多模式神经成像标记物，可能对诊断、预后、治疗选择、监测治疗的疾病修改效果以及临床试验的选择标准具有重要意义。

DESCRIPTION (provided by applicant): Since the aging population is growing at an unprecedented pace, the number of Veterans diagnosed with dementia is estimated to increase dramatically. Identification of individuals before the onset of significant clinical symptoms is essential for facilitating intervention when therapies may be most effective. One approach to identifying potential biomarkers of prodromal dementia involves assessing brain structure in individuals at increased risk for developing Alzheimer's disease (AD), such as those with mild cognitive impairment (MCI). With a recent explosion in MCI research, it has become clear that it is a heterogeneous disorder and distinct clinical subtypes (e.g., amnestic, nonamnestic) have been proposed. Heterogeneity in the clinical presentation of MCI may relate in part to the heterogeneity of underlying neuropathological mechanism(s). Although debated, evidence suggests that individuals with amnestic MCI demonstrate greater medial temporal lobe damage typical of early AD (e.g., Singh et al., 2006). In contrast, those with nonamnestic MCI show greater frontal lobe involvement (Nobili et al., 2008) and greater cerebrovascular disease (as evidenced by white matter abnormalities) on MRI (Delano-Wood et al., 2009). Mixed MCI characterized by impairment in multiple domains of cognitive ability may represent individuals with mixed pathology with both neurodegenerative and cerebrovascular features (Libon et al., 2010). Taken together, previous studies highlight a complex relationship between MCI, white matter, AD pathology, and cerebrovascular functioning. The proposed study will combine imaging markers of white matter abnormalities and vascular risk markers with AD-related biomarkers (e.g., cerebrospinal fluid [CSF] measures of amyloid and tau, hippocampal volume) as well as take into account MCI clinical subtypes in order to more completely characterize the contributions of AD and cerebrovascular risk to the dementia prodrome. In doing so, we can compare the prevailing model of biomarkers of MCI and AD, which emphasizes neurodegeneration (e.g., Jack et al., 2013) with a model relating the combined effects of vascular and AD pathologies to the probability of developing dementia (Chui et al., 2012). The current study aims to (1) better characterize the structural brain changes and vascular risk profiles underlying distinct MCI subtypes, (2) critically examine novel neuroimaging measures that might distinguish MCI subtypes and contribute to the nature and severity of cognitive impairment, and (3) determine which neuroimaging markers of white and gray matter alterations and additional risk factors for dementia (i.e., vascular risk factors, APOE ¿4 status) are most useful in predicting cognitive decline and progression to dementia. In the proposed study, 92 older adults (23 cognitively normal, 23 amnestic MCI, 23 nonamnestic MCI, and 23 mixed/multiple domain MCI) will undergo comprehensive neuropsychological assessment; laboratory testing to assess vascular risk factors (e.g., fasting glucose); CSF measurement of amyloid and tau; and neuroimaging exams including high resolution structural, perfusion, and white matter imaging. White matter imaging protocols include T2-weighted fluid attenuated inversion recovery (FLAIR) as well as two cutting edge techniques: diffusional kurtosis imaging (DKI) and a novel, myelin-selective technique (multi-component driven equilibrium single pulse observation of T1 and T2 [mcDESPOT]). It is hypothesized that greater vascular risk burden and white matter changes in frontal regions will be associated with nonamnestic MCI and mixed/multiple domain MCI. In contrast, white matter changes in medial temporal lobe regions will be associated with amnestic MCI and mixed/multiple domain MCI. A better understanding of the underlying neuropathology associated with distinct MCI clinical subtypes and the implementation of multimodal neuroimaging markers that better detect heterogeneous pathologies may have important implications for diagnosis, prognosis, treatment selection, and monitoring of disease-modifying effects of therapy as well as selection criteria for clinical trials.