扩张型携带者中的聚（GP）、神经丝和灰质缺陷。
Poly(GP), neurofilament and grey matter deficits in expansion carriers.
作者信息
Meeter Lieke H H, Gendron Tania F, Sias Ana C, Jiskoot Lize C, Russo Silvia P, Donker Kaat Laura, Papma Janne M, Panman Jessica L, van der Ende Emma L, Dopper Elise G, Franzen Sanne, Graff Caroline, Boxer Adam L, Rosen Howard J, Sanchez-Valle Raquel, Galimberti Daniela, Pijnenburg Yolande A L, Benussi Luisa, Ghidoni Roberta, Borroni Barbara, Laforce Robert, Del Campo Marta, Teunissen Charlotte E, van Minkelen Rick, Rojas Julio C, Coppola Giovanni, Geschwind Dan H, Rademakers Rosa, Karydas Anna M, Öijerstedt Linn, Scarpini Elio, Binetti Giuliano, Padovani Alessandro, Cash David M, Dick Katrina M, Bocchetta Martina, Miller Bruce L, Rohrer Jonathan D, Petrucelli Leonard, van Swieten John C, Lee Suzee E
机构信息
Alzheimer Center Rotterdam and Department of Neurology Erasmus Medical Center PO Box 2040 3000 CA Rotterdam the Netherlands.
Department of Neuroscience Mayo Clinic Jacksonville Florida.
出版信息
Ann Clin Transl Neurol. 2018 Apr 6;5(5):583-597. doi: 10.1002/acn3.559. eCollection 2018 May.
OBJECTIVE
To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic repeat expansion carriers and patients with associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.
METHODS
We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses.
RESULTS
Poly(GP) was present in expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.
INTERPRETATION
This study of expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.
目的
评估二肽重复蛋白多聚（GP）和神经丝轻链（NfL）作为症状前重复扩增携带者及相关额颞叶痴呆患者生物标志物的情况。此外，研究多聚（GP）与通过NfL和灰质体积测量的神经退行性变指标之间的关系。
方法
我们测量了25名症状前扩增携带者、64名患有痴呆的症状性扩增携带者和12名非携带者脑脊液（CSF）中的多聚（GP）和NfL水平。我们使用感兴趣区域和体素分析来探索与灰质体积的关联。
结果
多聚（GP）存在于扩增携带者中，而在非携带者中不存在（特异性100%，敏感性97%）。症状前携带者的多聚（GP）水平低于症状性携带者。症状性携带者的NfL水平高于症状前携带者和健康非携带者。NfL在合并运动神经元病的患者中最高，且与疾病严重程度和生存率相关。多聚（GP）水平与小灰质区域之间出现了关联，但在多重比较校正后未留存，而较高的NfL水平与额颞顶叶皮质和丘脑萎缩相关。
解读
这项对扩增携带者的研究表明：（1）多聚（GP）水平可将症状前和症状性扩增携带者与非携带者区分开来，但与神经退行性变指标无关；（2）NfL水平与灰质萎缩、疾病严重程度和较短生存期相关。总之，多聚（GP）和NfL有望作为相关额颞叶痴呆临床试验的互补生物标志物，多聚（GP）作为靶点参与的潜在标志物，NfL作为疾病活动和进展的标志物。
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