Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
Wellcome Trust Centre for Neuroimaging, University College London Institute of Neurology, London WC1N 3BG, UK.
Alzheimers Res Ther. 2012 Sep 24;4(5):41. doi: 10.1186/alzrt144. eCollection 2012.
Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.
Following a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.
Patients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.
Disease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.
额颞叶痴呆（FTD）是一种常见的早发性痴呆症，具有重要的遗传成分，最近发现 C9ORF72 基因中的重复扩展是 FTD 和运动神经元疾病的主要原因。了解这种新型突变的神经生物学和临床表型学目前是一个主要的研究重点。然而，关于这种遗传性疾病的纵向演变，可用的数据很少。在这里，我们展示了一组 C9ORF72 病理性重复扩展患者的纵向神经心理学和神经影像学数据。
在回顾了伦敦大学学院 FTD DNA 数据库后，我们回顾性地确定了 20 例 C9ORF72 扩展病例。其中 12 例有纵向神经心理学数据，其中 6 例有纵向容积磁共振成像数据。使用 FreeSurfer 提取皮质和皮质下体积。为每个受试者计算全脑、半球、小脑和脑室变化的速率。对随访与基线扫描的非线性流体配准进行了非线性能量注册，以可视化脑萎缩和脑室扩张的纵向个体内模式。
患者在基线时有较低的平均言语和表现智商，在随访时下降到受损（<第 5 百分位）。特别是视觉记忆、命名和优势顶叶技能都出现了恶化。与健康对照组相比，C9ORF72 突变患者的全脑萎缩率（1.4%/年）和脑室扩张率（3.2ml/年）明显更高；在 C9ORF72 突变组中，大脑半球之间的萎缩是对称的。丘脑和小脑明显萎缩，而没有皮质区域受到优先影响。个别患者的纵向流体成像显示出进行性体积损失的异质模式；然而，脑室扩张和小脑体积损失是一致的发现。
C9ORF72 相关 FTD 的疾病演变在神经心理学上与顶叶和健忘功能的逐渐参与有关，在神经解剖学上与更广泛和多变的皮质和中枢萎缩有关，但更一致地涉及小脑和丘脑。这些纵向特征与在分布式皮质下网络内的疾病传播一致，并证明了用于跟踪 C9ORF72 突变表型演变的纵向生物标志物的可行性。
