Abstract Details

Title CSF Calretinin, a Novel Specific Biomarker of Multiple System Atrophy

Topic Movement Disorders

Presentation(s) S43 - Movement Disorders: Biomarkers, Mechanisms, and Pathophysiology (2:24 PM-2:36 PM)

Poster/Presentation
Number 008

Objective To identify multiple system atrophy (MSA)-specific biomarker (BM).

Background The clinical diagnostic criteria for MSA (Gilman, MDS criteria) require the involvement of multiple systems for diagnosis. In the early stages of MSA, the disease presents as a single-system disorder, making it difficult to distinguish from Parkinson’s disease (PD) and spinocerebellar degeneration (SCD).

Design/Methods Cerebrospinal fluid (CSF) samples were obtained from 56 MSA patients, 33 SCD, 71 PD, and 68 healthy controls. Comprehensive proteomic analysis was carried out employing SomaScan^? Assay for more than 7,000 proteins. BM candidates were obtained by volcano plots, and their diagnostic performance was assessed using the area under the curve (AUC) of receiver operating characteristics curve. We performed immunostaining for calretinin (CR), a top priority BM, using autopsy brains from controls and patients with MSA and those with other neurodegenerative diseases, including SCD.

Results Volcano plot comparing MSA-cerebellar type (MSA-C) and SCD revealed the highest fold change (log₂FC 1.060) and lowest p-value (p = .001) in CR. CR level enabled accurate discrimination between MSA-C and SCD (AUC 0.970), and MSA-parkinsonian type (MSA-P) and PD (AUC 0.860). The AUC values of patients within 3 years of onset were further improved (MSA-C and SCD, 0.993; MSA-P and PD, 0.921). CR levels showed significant negative correlations with the severity (r = -0.425, p = 0.049) and duration (r = -0.578, p < 0.001) in MSA-C. Immunostaining showed a specific reduction of CR immunoreactivity in the pontine nuclei, pontine transverse fibers, and cerebellar white matter of MSA patients.

Conclusions We identified a novel MSA-specific BM, CSF CR, useful for early diagnosis. The enhanced values in the early stage with subsequent decrease might be explained by the extent of initial cellular damage followed by gradual neuronal loss. These results provide a novel clue to elucidate the pathogenesis of MSA.

Authors/Disclosures
Fumiko K. Nakamoto, MD, PhD PRESENTER	Dr. Nakamoto has nothing to disclose.
TERUNORI SANO, MD, PhD	Dr. SANO has nothing to disclose.
Kaoru Yagita, MD, PhD	The institution of Dr. Yagita has received research support from Takeda Science Foundation.
Kotaro Hattori, MD, PhD	An immediate family member of Dr. Hattori has received personal compensation for serving as an employee of ALG&Associates LPC. Dr. Hattori has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AMED Data Access Review Committee. Dr. Hattori has stock in Dowakai healthcare corporation. The institution of Dr. Hattori has received research support from AMED. The institution of Dr. Hattori has received research support from Japan Pharmaceutical Manufacturers Association. The institution of Dr. Hattori has received research support from Takeda Pharmaceutical Co., Ltd.. The institution of Dr. Hattori has received research support from ONO PHARMACEUTICAL CO., LTD.. Dr. Hattori has received publishing royalties from a publication relating to health care. Dr. Hattori has received personal compensation in the range of $500-$4,999 for serving as a committee member with CIBER.
Masaki Takao, MD, PhD	Prof. Takao has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Igaku Shoin. Prof. Takao has received publishing royalties from a publication relating to health care. Prof. Takao has received publishing royalties from a publication relating to health care.
Yuichi Goto, MD, PhD	The institution of Dr. Goto has received research support from Asahi Kasei Corporation. The institution of Dr. Goto has received research support from Astellas Pharma Inc.. The institution of Dr. Goto has received research support from Eisai, Co., Ltd. The institution of Dr. Goto has received research support from Ono Pharmaceutical Co., Ltd. The institution of Dr. Goto has received research support from Daiichi-Sankyo, Co., Ltd. The institution of Dr. Goto has received research support from Mitsubishi Tanabe Pharma, Co., Ltd. The institution of Dr. Goto has received research support from Nipon Shinyaku Co., Ltd.
Yuji Takahashi, MD, PhD (National Center of Neurology and Psychiatry)	The institution of Dr. Takahashi has received research support from Nihon Medi-Physics Co. Limit.. The institution of Dr. Takahashi has received research support from Takeda Pharmaceutical Company Limited.

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