Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (IBMPFD) presents with multiple symptoms and an unknown etiology. Valosin-containing protein (VCP) has been identified as the main causative gene of IBMPFD. However, no studies on neurofilament light chain (NFL) as a cerebrospinal fluid (CSF) marker of axonal neurodegeneration or on YKL-40 as a CSF marker of glial neuroinflammation have been conducted in IBMPFD patients with VCP mutations. A 65-year-old man presented with progressive muscle atrophy and weakness of all limbs, non-fluent aphasia, and changes in personality and behavior. Cerebral MRI revealed bilateral frontal and temporal atrophy. 99mTc-HMDP bone scintigraphy and pelvic CT revealed remodeling changes and active osteoblastic accumulations in the right medial iliac bone. Muscle biopsy demonstrated multiple rimmed vacuoles in muscle cells with myogenic and neurogenic pathological alterations. After the patient was clinically diagnosed with IBMPFD, DNA analysis of the VCP gene revealed a cytosine (C) to thymine (T) (C→ T) mutation, resulting in an amino acid exchange of arginine to cysteine (p.R155C mutation). The CSF levels of NFL at two time points (12 years apart) were higher than those in non-dementia controls (CTR) and Alzheimer's disease (AD); lower than those in frontotemporal dementia with motor neuron disease (FTD-MND); and comparable to those in patients with behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The CSF levels of YKL-40 were comparable at both time points and higher than those in CTR; lower than those in FTD-MND; and comparable to those in bvFTD, PSP, CBS, and AD. The CSF levels of phosphorylated tau 181 (P-Tau) and total tau (T-Tau) were not significantly different from those in CTR and other neurodegenerative diseases, except those in AD, which were significantly elevated. This is the first report that demonstrates increased NFL and YKL-40 CSF levels in an IBMPFD patient with a VCP mutation (p.R155C); NFL and YKL-40 levels were comparable to those in bvFTD, PSP, CBS, and AD and higher than those in CTR. Our results suggest that IBMPFD neuropathology may involve both axonal neurodegeneration and glial neuroinflammation.

中文翻译：

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一名VCP R155C突变的日本IBMPFD患者中神经丝轻链和YKL-40 CSF水平升高：CSF生物标志物分析的临床病例报告。

包涵体肌病（IBM）与佩吉特氏骨病（PDB）和额颞叶痴呆（IBMPFD）表现出多种症状和病因不明。含缬氨酸的蛋白（VCP）已被确定为IBMPFD的主要致病基因。但是，尚未对具有VCP突变的IBMPFD患者进行神经丝轻链（NFL）作为轴突神经变性的脑脊髓液（CSF）标记或对YKL-40作为神经胶质神经炎症的CSF标记的研究。一名65岁的男子表现出进行性肌肉萎缩和四肢无力，非流利性失语症以及性格和行为改变。脑MRI显示双侧额叶和颞叶萎缩。99mTc-HMDP骨闪烁显像和骨盆CT显示右侧media骨的重塑变化和活跃的成骨细胞堆积。肌肉活检显示肌肉细胞中有多个缘空泡，并伴有肌源性和神经源性病理改变。患者临床诊断为IBMPFD后，对VCP基因的DNA分析显示胞嘧啶（C）变为胸腺嘧啶（T）（C→T）突变，导致精氨酸经氨基酸交换为半胱氨酸（p.R155C突变）。在两个时间点（相隔12年），NFL的CSF水平高于非痴呆对照组（CTR）和阿尔茨海默氏病（AD）；低于额颞叶痴呆伴运动神经元疾病（FTD-MND）的患者；并与行为变异性额颞叶痴呆（bvFTD），进行性核上性麻痹（PSP）和肾上腺皮质综合征（CBS）的患者相媲美。在两个时间点，YKL-40的脑脊液水平均相当，并且高于点击率；低于FTD-MND的水平；并可以与bvFTD，PSP，CBS和AD中的数据相媲美。磷酸化的tau 181（P-Tau）和总tau（T-Tau）的CSF水平与CTR和其他神经退行性疾病的CSF水平没有显着差异，除了AD中的CSF水平显着升高。这是第一份证明具有VCP突变的IBMPFD患者NFL和YKL-40 CSF水平升高的报告（p.R155C）；NFL和YKL-40的水平与bvFTD，PSP，CBS和AD中的水平相当，并且高于CTR中的水平。我们的结果表明，IBMPFD神经病理学可能涉及轴突神经变性和神经胶质神经炎症。明显升高。这是第一份证明具有VCP突变的IBMPFD患者NFL和YKL-40 CSF水平升高的报告（p.R155C）；NFL和YKL-40的水平与bvFTD，PSP，CBS和AD中的水平相当，并且高于CTR中的水平。我们的结果表明，IBMPFD神经病理学可能涉及轴突神经变性和神经胶质神经炎症。明显升高。这是第一份证明具有VCP突变的IBMPFD患者NFL和YKL-40 CSF水平升高的报告（p.R155C）；NFL和YKL-40的水平与bvFTD，PSP，CBS和AD中的水平相当，并且高于CTR中的水平。我们的结果表明，IBMPFD神经病理学可能涉及轴突神经变性和神经胶质神经炎症。