Investigation of the mechanism for and psychiatric symptoms due to elevation of inflammatory cytokines in mood disorders.

• Project/Area Number: 26860946
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Jikei University School of Medicine
• Principal Investigator: KOBAYASHI Nobuyuki 東京慈恵会医科大学, 医学部, 講師 (20385321)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: うつ病 / 気分障害 / サイトカイン / 酸化ストレス / 動物モデル / 炎症性サイトカイン / HHV-6 / 疲労 / モデルマウス / SITH-1 / 双極性障害

Outline of Final Research Achievements

The study aimed to clarify the mechanism for the elevation of inflammatory cytokines, and the psychiatric symptoms produced by it, in major depressive disorder (MDD) through clinical investigation and the use of an animal model.
However, in this study there were no significant differences in inflammatory cytokines between MDD patients and normal controls (NC). On the other hand, the oxidative stress marker was more elevated in MDD patients than NC.
Transgenic (Tg) mice with regulated expression of SITH-1 (the latent protein of human herpesvirus 6) were prepared. Although the Tg mice showed depressive-like behavior compared to wild-type mice, there was no significant association between SITH-1 and the inflammatory cytokine.

Research Products

• [Journal Article] Increased interleukin-1β and basic fibroblast growth factor levels in the cerebrospinal fluid during human herpesvirus-6B (HHV-6B) encephalitis (2017)
  • Author(s): Tamai Masato、Kobayashi Nobuyuki、Shimada Kazuya、Oka Naomi、Takahashi Mayumi、Tanuma Akiko、Tanemoto Tomohiro、Namba Hiroyuki、Saito Yoshihiro、Wada Yasuyuki、Okamoto Aikou、Ida Hiroyuki、Kondo Kazuhiro
  • Journal Title: Biochemical and biophysical research communications Volume: 486 Issue: 3 Pages: 706-711
  • DOI: 10.1016/j.bbrc.2017.03.102
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of DNA Methylation Levels in COASY and SPINT1 Gene Promoter Regions as Biomarkers inDiagnosis of Alzheimer's Disease and Amnestic Mild Cognitive Impairment. (2016)
  • Author(s): Kobayashi N, Shinagawa S, Nagata T, Shimada K, Shibata N, Ohnuma T, Kasanuki K, Arai H, Yamada H, Nakayama K, Kondo K.
  • Journal Title: PloS one Volume: 11 Issue: 12 Pages: e0168816-e0168816
  • DOI: 10.1371/journal.pone.0168816
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic association between RAGE polymorphisms and Alzheimer's disease and Lewy body dementias in a Japanese cohort: a case-control study. (2016)
  • Author(s): Takeshita Y, Shibata N, Kasanuki K, Nagata T, Shinagawa S, Kobayashi N, Ohnuma T, Suzuki A, Kawai E, Takayama T, Nishioka K, Motoi Y, Hattori N, Nakayama K, Yamada H, Arai H.
  • Journal Title: International Journal of Geriatric Psychiatry Volume: 4 Issue: 12 Pages: 1241-1246
  • DOI: 10.1002/gps.4600
  • Peer Reviewed
• [Journal Article] Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue. (2016)
  • Author(s): Aoki, R., Kobayashi, N., Suzuki, G., Kuratsune, H., Shimada, K., Oka, N., Takahashi, M., Yamadera, W., Iwashita, M., Tokuno, S., Nibuya, M., Tanichi, M., Mukai, Y., Mitani, K., Kondo, K., Ito, H., Nakayama, K.
  • Journal Title: Biochem. Biophy. Res. Commun. Volume: 478 Issue: 1 Pages: 424-430
  • DOI: 10.1016/j.bbrc.2016.07.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DNA methylation in the NCAPH2/LMF2 promoter region is associated with hippocampal atrophy in Alzheimer's disease and amnesic mild cognitive impairment patients. (2016)
  • Author(s): Shinagawa S, Kobayashi N, Nagata T, Kusaka A, Yamada H, Kondo K, Nakayama K.
  • Journal Title: Neurosci Lett Volume: 629 Pages: 33-37
  • DOI: 10.1016/j.neulet.2016.06.055
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Caregiver burden and fatigue in caregivers of people with dementia: Measuring human herpesvirus (HHV)-6 and & -7 DNA levels in saliva, (2016)
  • Author(s): Tohmi Osaki, Takako Morikawa, Hiroyuki Kajita, Nobuyuki Kobayashi, Kazuhiro Kondo, Kiyoshi Maeda.
  • Journal Title: Archives of Gerontology and Geriatrics Volume: 66 Pages: 42-48
  • DOI: 10.1016/j.archger.2016.04.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Biomarkers Based on DNA Methylation in the NCAPH2/LMF2 Promoter Region for Diagnosis of Alzheimer’s Disease and Amnesic Mild Cognitive Impairment． (2016)
  • Author(s): Nobuyuki Kobayashi, Shunichiro Shinagawa, Tomoyuki Nagata, Kazuya Shimada, Nobuto Shibata, Tohru Ohnuma, Koji Kasanuki, Heii Arai, Hisashi Yamada, Kazuhiko Nakayama, Kazuhiro Kondo.
  • Journal Title: PLoS ONE Volume: 11(1) Issue: 1 Pages: e0146449-e0146449
  • DOI: 10.1371/journal.pone.0146449
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population. (2016)
  • Author(s): Suzuki A, Shibata N, Kasanuki K, et al.
  • Journal Title: Dement Geriatr Cogn Dis Extra. Volume: 16 Issue: 1 Pages: 90-97
  • DOI: 10.1159/000444080
  • Peer Reviewed
• [Journal Article] 疲労の尺度と疾病 (2015)
  • Author(s): 小林伸行、近藤一博
  • Journal Title: 臨牀透析 Volume: 31 Pages: 1447-1452
• [Journal Article] Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer's Disease (2015)
  • Author(s): Nagata T, Kobayashi N, Ishii J, Shinagawa S, Nakayama R, Shibata N, Kuerban B, Ohnuma T, Kondo K, Arai H, Yamada H, Nakayama K
  • Journal Title: Dement Geriatr Cogn Dis Extra Volume: 5 Issue: 1 Pages: 64-73
  • DOI: 10.1159/000375367
  • Peer Reviewed / Open Access
• [Presentation] 分子機構から明らかにする疲労とストレスとの相違に関する検討 (2017)
  • Author(s): 小林伸行、岡直美、髙橋麻弓、玉井将人、嶋田和也、近藤一博
  • Organizer: 第13回日本疲労学会
• [Presentation] 疲労を引き起こす分子メカニズムの解明 (2017)
  • Author(s): 小林伸行、岡直美、髙橋麻弓、嶋田和也、近藤一博
  • Organizer: 第134回成医会
• [Presentation] さまざまな変性性認知症疾患におけるDNAメチル化変化とその臨床的意義の検討 (2017)
  • Author(s): 小林伸行、品川俊一郎、永田智行、嶋田和也、柴田展人、大沼徹、笠貫浩史、新井平伊、繁田雅弘、近藤一博
  • Organizer: 第36回日本認知症学会
• [Presentation] Human herpesvirus 6 (HHV-) and HHV-7 reactivation in fatigue, which distinguishes between physiological fatigue and pathological fatigue. (2016)
  • Author(s): Nobuyuki Kobayashi, Ryo Aoki, Hirohiko Kuratsune, Naomi Oka, Mayumi Takahashi, Kazuya Shimada, Wataru Yamadera, Masayuki Iwashita, Hiroshi Ito, Kazuhiko Nakayama, Kazuhiro Kondo.
  • Organizer: 第64回日本ウイルス学会 (The 64th Annual Meeting of the Japanese Society for Virology)
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-24
• [Presentation] 血液中DNAメチル化変化を利用したアルツハイマー病と軽度認知機能障害の新規診断法に関する検討. (2016)
  • Author(s): 小林伸行, 品川俊一郎, 永田智行, 嶋田和也, 柴田展人, 大沼徹, 笠貫浩史, 新井平伊, 山田尚, 中山和彦, 近藤一博.
  • Organizer: 第31回日本老年精神医学会
  • Place of Presentation: 金沢
  • Year and Date: 2016-06-23
• [Presentation] 唾液中ヒトヘルペスウイルス(HHV-)6及びHHV-7量による病的疲労と生理的疲労との鑑別に関する検討. (2016)
  • Author(s): 小林伸行, 青木亮, 岡直美, 髙橋麻弓, 嶋田和也, 玉井将人, 山寺亘, 岩下正幸, 倉恒弘彦, 伊藤洋, 中山和彦, 近藤一博.
  • Organizer: 第12回日本疲労学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-05-20
• [Presentation] 睡眠時無呼吸症候群を対象とした、HHV-6、HHV-7の再活性化メカニズムの検討 (2015)
  • Author(s): 小林伸行、青木亮、嶋田和也、玉井将人、山寺亘、岩下正幸、伊藤洋、中山和彦、近藤一博
  • Organizer: 第63回日本ウイルス学会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-23
• [Presentation] 疲労・ストレスによるヒトヘルペスウイルス6の再活性化機構の検討 (2014)
  • Author(s): 小林伸行、嶋田和也、岡直美、玉井将人、近藤一博.
  • Organizer: 第62回日本ウイルス学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10
• [Presentation] Novel human herpesvirus 6 stress-related latent protein induces depression and suicide. (2014)
  • Author(s): Nobuyuki Kobayashi, Naomi Oka, Kazuya Shimada, Kazuhiro Kondo.
  • Organizer: The 39th Annual International Herpesvirus Workshop 2014
  • Place of Presentation: Kobe
  • Year and Date: 2014-07-20
• [Presentation] Molecular mechanism of depressive disorder caused by HHV-6 latent infection. (2014)
  • Author(s): Naomi Oka, Nobuyuki Kobayashi, Kazuya Shimada, Kazuhiro Kondo.
  • Organizer: The 39th Annual International Herpesvirus Workshop 2014
  • Place of Presentation: Kobe
  • Year and Date: 2014-07-19 – 2014-07-20
• [Presentation] 唾液中ヒトヘルペスウイルス量変化を利用した客観的疲労評価法による、生理的疲労と慢性疲労症候群との鑑別 (2014)
  • Author(s): 小林伸行、岡直美、嶋田和也、鈴木豪、徳野慎一、丹生谷正史、三谷圭司、小原健幸、山本哲生、向井保雄、清水邦夫、丸山徹、立花正一、妻鳥元太郎、倉恒弘彦、杉野友啓、梶本修身、渡辺恭良、近藤一博.
  • Organizer: 第10回日本疲労学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-31