Diagnostic and prognostic certainty in behavioral variant frontotemporal dementia

摘要 额颞叶痴呆（FTD）是一种常见的神经退行性疾病的早期年龄发作的痴呆。的 FTD的行为变体（bvFTD）导致人格以及社会和情感的深刻变化 功能诊断不确定性仍然是bvFTD中的常见问题，尽管改进了诊断 标准侧重于特定的行为和认知特征，并伴有特征性神经影像学 模式.第一次就诊时的准确诊断尤其具有挑战性，因为认知障碍可能是 温和的和功能性的能力得到更好的保留。其他痴呆综合征可模仿bvFTD的特征， 与精神疾病的症状有部分重叠。通过纵向提供的清晰度， 随访临床医生有时会改变bvFTD诊断。有超过15个潜在的神经病理学 bvFTD的基础诊断。即使bvFTD诊断明确，预测特定的 导致个体患者症状的分子亚型。在临床上有很大的异质性， bvFTD的病程也是如此，一些在2-3年内迅速下降，另一些存活超过1年。 十年运动功能可能存在或不存在，其在bvFTD背景下的严重程度可能影响 患者需要的护理水平。很少有可靠的指标来说明病人的病程。 拟定的研究将纵向研究60例bvFTD患者的神经系统检查， 认知测试，结构和功能神经成像，并将回顾性审查临床 284例bvFTD尸检患者的特征。这一建议的核心假设是，尽管 bvFTD患者之间的临床、神经心理学、神经影像学、血清 标记物、遗传和基因表达差异，允许在第一次访问时提高预测的确定性。在 目的1我们将使用诊断稳定性的纵向评估，以确定预测 bvFTD诊断的确定性在目标2中，我们将确定临床，基因表达和成像概况， 能够准确预测患者病理诊断的bvFTD尸检患者队列。在 目的3：我们将使用bvFTD患者的纵向数据来确定允许准确评估的因素。 临床过程的详细说明。拟议研究的结果将为临床医生提供指导 正在考虑诊断bvFTD并将改善现有诊断和预后信息的患者 患者、家属和临床医生，从第一次就诊开始就改善了临床护理。它还将 促进患者入组观察性研究和分子靶向临床试验。

ABSTRACT Frontotemporal dementia (FTD) is a common neurodegenerative cause of early age-of-onset dementia. The behavioral variant of FTD (bvFTD) results in profound changes in personality, as well as social and emotional functioning. Diagnostic uncertainty remains a common concern in bvFTD in spite of improved diagnostic criteria that focus on particular behavioral and cognitive features accompanied by characteristic neuroimaging patterns. Accurate diagnoses at the first visit are especially challenging, when cognitive impairment can be mild and functional abilities are more preserved. Other dementia syndromes can mimic features of bvFTD and there is partial overlap with the symptoms of psychiatric illnesses. With the clarity provided by longitudinal follow-up clinicians sometimes change bvFTD diagnoses. There are over 15 potential neuropathological diagnoses that underlie bvFTD. Even when a bvFTD diagnosis is clear it is challenging to predict the specific molecular subtype causing an individual patient’s symptoms. There is substantial heterogeneity in the clinical course in bvFTD as well, with some declining rapidly within 2-3 years and others surviving over more than a decade. Motor features may be present or absent, and their severity in the context of bvFTD can impact the level of care a patient requires. There are few reliable indicators to prognosticate a patient’s disease course. The proposed research will study 60 patients with bvFTD longitudinally with neurological examinations, cognitive testing, and structural and functional neuroimaging, and will retrospectively review the clinical features of 284 autopsied patients with bvFTD. The central hypothesis of this proposal is that in spite of the similarities between patients with bvFTD there will be clinical, neuropsychological, neuroimaging, serum marker, genetic, and gene expression differences that permit improved predictive certainty at the first visit. In Aim 1 we will use longitudinal assessment of diagnostic stability in order to determine factors that predict certainty in the bvFTD diagnosis. In Aim 2 we will identify clinical, gene expression, and imaging profiles in a cohort of autopsied patients with bvFTD that allow accurate prediction of a patient’s pathological diagnosis. In Aim 3 we will use longitudinal data on patients with bvFTD to determine factors that allow accurate prognostication of the clinical course. The results of the proposed research will provide guidance to clinicians who are considering a diagnosis of bvFTD and will improve the diagnostic and prognostic information available to patients, families, and clinicians, leading to improved clinical care from the time of the first visit. It will also facilitate enrollment of patients into observational research and molecularly targeted clinical trials.