Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA.
Prog Neurobiol. 2011 Dec;95(4):636-48. doi: 10.1016/j.pneurobio.2011.04.012. Epub 2011 Apr 30.
Neuronal and glial changes associated with tau, TAR DNA binding protein of ∼43 kDa (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.
与 tau、TAR DNA 结合蛋白约 43kDa（TDP-43）和肉瘤融合（FUS）相关的神经元和神经胶质变化共同构成了额颞叶变性（FTLD）的病理谱。大多数 FTLD 患者表现为突出的行为或语言变化，有时伴有锥体外系症状或运动神经元病。FTLD 患者中 tau、TDP-43 和 FUS 基因突变的鉴定强烈支持它们在 FTLD 中的致病作用，阐明它们的功能障碍将为开发特定底物的治疗方法铺平道路。然而，目前仍然没有可靠的生物标志物来早期检测 FTLD 或预测潜在的 FTLD 病理变化。临床综合征通常反映了最早受影响的脑区，在结构 MRI 上可以观察到这些脑区的萎缩，但无论是临床还是基于结构的生物标志物，都不能在个体患者水平上与潜在的病理变化准确相关。脑脊液（CSF）中的生化标志物也在 FTLD 和相关疾病中进行了研究，包括肌萎缩侧索硬化症（ALS）和进行性核上性麻痹（PSP）。然而，它们的准确性和病理意义需要在未来的多中心研究中得到证实。在这里，我们回顾了 FTLD 生物标志物的研究进展，包括临床表型/特征描述、神经心理学分析、CSF 和血浆分析物，以及在脑成像上可检测到的脑萎缩和网络功能障碍模式。鉴于 FTLD 与 ALS 和 PSP 的病理重叠，与这些领域的专家合作对于将有前途的 FTLD 生物标志物转化为临床实践至关重要。
