Abstract
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.
Highlights
Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and frontotemporal dementia (IBMPFD) is a multi-organ disease with still unknown etiology [1, 2]
The CSF samples were analyzed in this patient, patients with neurodegenerative diseases, and non-dementia control subjects (CTR: n = 18)
IBMPFD is clinically characterized by adult-onset muscle weakness and atrophy, early-onset PDB, and frontotemporal dementia (FTD) [1, 2, 15]
Summary
Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and frontotemporal dementia (IBMPFD) is a multi-organ disease with still unknown etiology [1, 2]. During the first hospitalization at the age of 52 years, the patient showed atrophy and weakness of the muscles of all limbs but most prominently of the bilateral quadriceps. 99mTc-HMDP bone scintigraphy showed active osteoblastic accumulation in the right medial iliac bone (Figure 1H), whereas pelvic CT revealed remodeling changes in the corresponding area indicated by arrows (Figure 1I). Gomori trichrome staining showed rimmed vacuoles in muscle cells and small angulated fibers (Figure 1L), which were compatible with the pathological findings of IBMPFD during the first hospitalization. The neurological finding of this case revealed general muscle weakness and atrophy, especially, proximal muscles of lower extremities, progressive cognitive decline, speech disturbance, and character change. In muscle biopsy, rimmed vacuoles were pathologically confirmed and neurogenic muscle changes were observed. 99mTc-HMDP bone scintigraphy of the patient was compatible with Paget’s disease of bone (PDB)
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