Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease
Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease
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DOI：
10.1001/jamaneurol.2017.4907
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发表时间：
2018-05-01
期刊：
影响因子：
29
通讯作者：
Johnson, Keith A.
中科院分区：
文献类型：
--
作者：
Quiroz, Yakeel T.;Sperling, Reisa A.;Johnson, Keith A.
尽早提高我们诊断和追踪阿尔茨海默病（AD）的能力至关重要。患有常染色体显性AD的个体可以提供线索，说明在临床症状出现之前，哪些生物学变化以及何时可靠地出现。目的探讨早老素1 (PSEN1) E280A突变认知功能未受损和受损携带者大脑中淀粉样蛋白和tau沉积之间的关系。设计、环境和参与者在这项横断面成像研究中，我们利用了来自同质常染色体显性AD亲属的数据，这使我们能够检查可测量的tau沉积作为个体接近预期痴呆发病的功能。采用碳11标记的匹兹堡化合物B正电子发射断层扫描（PET）和flortaucipir F 18（以前称为AV 1451， T807） PET成像的横断测量方法对24名PSEN1 E280A亲属（年龄范围28-55岁）进行了评估，包括12名携带者，其中9名认知未受损，3名有轻度认知障碍，12名认知未受损的非携带者。我们比较了碳11标记的匹兹堡化合物B PET脑与突变携带者和非携带者的小脑分布体积比以及flortaucipir f18 PET脑与小脑标准化摄取值比。Spearman相关性表征了两组中年龄与平均皮质匹兹堡化合物B分布体积比水平或区域flortaucipir标准化摄取值比水平之间的关系。结果：24例患者的平均（SD）年龄为38.0（7.4）岁，比携带者预期的临床症状发病年龄小约6岁。与非携带者相比，认知功能未受损的突变携带者在20多岁时平均皮质匹兹堡化合物B分布体积比水平升高，30岁以上的9名携带者中有7名达到淀粉样变性的阈值（分布体积比水平> 1.2）。淀粉样蛋白阳性突变携带者在阿尔茨海默病临床发病前6年，在内侧颞叶区域发现tau沉积水平升高。新皮层中大量tau沉积仅在1名未受损的携带者和轻度认知障碍患者中观察到。在未受损的携带者中，β -淀粉样蛋白摄取水平在轻度认知障碍预期发病前约15年弥漫性升高。在携带者中，较高水平的tau沉积与小精神状态检查（内嗅皮层：r = -0.60; P = 0.04；下颞叶：r = -0.54; P = 0.06）和建立阿尔茨海默病单词列表延迟回忆登记联盟（内嗅皮层：r = -0.86; P < 0.001；下颞叶：r = -0.70; P = 0.01）的较差表现相关。目前的研究结果进一步证明，分子标记可以表征认知未受损个体中与AD相关的生物学变化。研究结果还表明，tau PET成像可能是一种有用的生物标志物，可用于区分阿尔茨海默病临床症状的高风险个体，并跟踪疾病进展。
IMPORTANCE It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms.OBJECTIVE To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation.DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers.MAIN OUTCOMES AND MEASURES We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups.RESULTS Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. beta-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01).CONCLUSIONS AND RELEVANCE The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.