Different AT(N) profiles and clinical progression classified by two different N markers using total tau and neurofilament light chain in cerebrospinal fluid

Kensaku Kasuga; Masataka Kikuchi; Tamao Tsukie; Kazushi Suzuki; Ryoko Ihara; Atsushi Iwata; Norikazu Hara; Akinori Miyashita; Ryozo Kuwano; Takeshi Iwatsubo; Takeshi Ikeuchi; Japanese Alzheimer’s Disease Neuroimaging Initiative

doi:10.1136/bmjno-2022-000321

Different AT(N) profiles and clinical progression classified by two different N markers using total tau and neurofilament light chain in cerebrospinal fluid

BMJ Neurol Open. 2022 Aug 10;4(2):e000321. doi: 10.1136/bmjno-2022-000321. eCollection 2022.

Collaborators

Japanese Alzheimer’s Disease Neuroimaging Initiative:
Takeshi Iwatsubo, Takeshi Ikeuchi, Ryozo Kuwano, Takashi Asada, Hiroyuki Arai, Morihiro Sugishita, Hiroshi Matsuda, Kengo Ito, Michio Senda, Kenji Ishii, Noriko Sato, Hajime Sato, Shun Shimohama, Masaki Saitoh, Rika Yamauchi, Takashi Hayashi, Seiju Kobayashi, Norihito Nakano, Junichiro Kanazawa, Takeshi Ando, Chiyoko Takanami, Masato Hareyama, Masamitsu Hatakenaka, Eriko Tsukamoto, Shinji Ochi, Mikio Shoji, Etsuro Matsubara, Takeshi Kawarabayashi, Yasuhito Wakasaya, Takashi Nakata, Naoko Nakahata, Shuichi Ono, Yoshihiro Takai, Satoshi Takahashi, Hisashi Yonezawa, Junko Takahashi, Masako Kudoh, Makoto Sasaki, Yutaka Matsumura, Yohsuke Hirata, Tsuyoshi Metoki, Susumu Hayakawa, Yuichi Sato, Masayuki Takeda, Toshiaki Sasaki, Koichiro Sera, Kazunori Terasaki, Yoshihiro Saitoh, Shoko Goto, Kuniko Ueno, Hiromi Sakashita, Kuniko Watanabe, Ken Nagata, Yuichi Sato, Tetsuya Maeda, Yasushi Kondoh, Takashi Yamazaki, Daiki Takano, Mio Miyata, Hiromi Komatsu, Mayumi Watanabe, Tomomi Sinoda, Rena Muraoka, Kayoko Kikuchi, Hitomi Ito, Aki Sato, Toshibumi Kinoshita, Hideyo Toyoshima, Kaoru Sato, Shigeki Sugawara, Isao Ito, Fumiko Kumagai, Katsutoshi Furukawa, Masaaki Waragai, Naoki Tomita, Nobuyuki Okamura, Mari Ootsuki, Katsumi Sugawara, Satomi Sugawara, Shunji Mugikura, Atsushi Umetsu, Takanori Murata, Tatsuo Nagasaka, Yukitsuka Kudo, Manabu Tashiro, Shoichi Watanuki, Masatoyo Nishizawa, Takayoshi Tokutake, Saeri Ishikawa, Emiko Kishida, Nozomi Sato, Mieko Hagiwara, Kumi Yamanaka, Takeyuki Watanabe, Taeko Takasugi, Shoichi Inagawa, Kenichi Naito, Masanori Awaji, Tsutomu Kanazawa, Kouiti Okamoto, Masaki Ikeda, Tsuneo Yamazaki, Yuiti Tasiro, Syunn Nagamine, Shiori Katsuyama, Sathiko Kurose, Sayuri Fukushima, Etsuko Koya, Makoto Amanuma, Noboru Oriuti, Kouiti Ujita, Kazuhiro Kishi, Kazuhisa Tuda, Katsuyoshi Mizukami, Tetsuaki Arai, Etsuko Nakajima, Katsumi Miyamoto, Kousaku Saotome, Tomoya Kobayashi, Saori Itoya, Jun Ookubo, Toshiya Akatsu, Yoshiko Anzai, Junya Ikegaki, Yuuichi Katou, Kaori Kimura, Ryou Kuchii, Hajime Saitou, Kazuya Shinoda, Satoka Someya, Hiroko Taguchi, Kazuya Tashiro, Masaya Tanaka, Tatsuya Nemoto, Ryou Wakabayashi, Daisuke Watanabe, Harumasa Takano, Tetsuya Suhara, Hitoshi Shinoto, Hitoshi Shimada, Makoto Higuchi, Takaaki Mori, Hiroshi Ito, Takayuki Obata, Yoshiko Fukushima, Kazuko Suzuki, Izumi Izumida, Katsuyuki Tanimoto, Takahiro Shiraishi, Hitoshi Shinotoh, Hitoshi Shimada, Junko Shiba, Hiroaki Yano, Miki Satake, Aimi Nakui, Yae Ebihara, Tomomi Hasegawa, Yasumasa Yoshiyama, Mami Kato, Yuki Ogata, Hiroyuki Fujikawa, Nobuo Araki, Yoshihiko Nakazato, Takahiro Sasaki, Tomokazu Shimadu, Kimiko Yoshimaru, Hiroshi Matsuda, Etsuko Imabayashi, Asako Yasuda, Etuko Yamamoto, Natsumi Nakamata, Noriko Miyauchi, Keiko Ozawa, Rieko Hashimoto, Taishi Unezawa, Takafumi Ichikawa, Hiroki Hayashi, Masakazu Yamagishi, Tunemichi Mihara, Masaya Hirano, Shinichi Watanabe, Junichiro Fukuhara, Hajime Matsudo, Nobuyuki Saito, Atsushi Iwata, Hisatomo Kowa, Toshihiro Hayashi, Ryoko Ihara, Toji Miyagawa, Mizuho Yoshida, Yuri Koide, Eriko Samura, Kurumi Fujii, Kaori Watanabe, Nagae Orihara, Toshimitsu Momose, Akira Kunimatsu, Harushi Mori, Miwako Takahashi, Takuya Arai, Yoshiki Kojima, Masami Goto, Takeo Sarashina, Syuichi Uzuki, Seiji Katou, Yoshiharu Sekine, Yukihiro Takauchi, Chiine Kagami, Kazutomi Kanemaru, Shigeo Murayama, Yasushi Nishina, Maria Sakaibara, Yumiko Okazaki, Rieko Okada, Maki Obata, Yuko Iwata, Mizuho Minami, Yasuko Hanabusa, Hanae Shingyouji, Kyoko Tottori, Aya Tokumaru, Makoto Ichinose, Kazuya Kume, Syunsuke Kahashi, Kunimasa Arima, Tadashi Tukamoto, Shin Tanaka, Yuko Nagahusa, Masuhiro Sakata, Mitsutoshi Okazaki, Yuko Saito, Maki Yamada, Tiine Kodama, Maki Obata, Tomoko Takeuchi, Keiichiro Ozawa, Yuko Iwata, Hanae Shingyouji, Yasuko Hanabusa, Yoshiko Kawaji, Kyouko Tottori, Noriko Sato, Yasuhiro Nakata, Satoshi Sawada, Makoto Mimatsu, Daisuke Nakkamura, Takeshi Tamaru, Shunichirou Horiuchi, Heii Arai, Tsuneyoshi Ota, Aiko Kodaka, Yuko Tagata, Tomoko Nakada, Eizo Iseki, Kiyoshi Sato, Hiroshige Fujishiro, Norio Murayama, Masaru Suzuki, Satoshi Kimura, Masanobu Takahashi, Haruo Hanyu, Hirofumi Sakurai, Takahiko Umahara, Hidekazu Kanetaka, Kaori Arashino, Mikako Murakami, Ai Kito, Seiko Miyagi, Kaori Doi, Kazuyoshi Sasaki, Mineo Yamazaki, Akiko Ishiwata, Yasushi Arai, Akane Nogami, Sumiko Fukuda, Kyouko Tottori, Mizuho Minami, Yuko Iwata, Koichi Kozaki, Yukiko Yamada, Sayaka Kimura, Ayako Machida, Kuninori Kobayashi, Hidehiro Mizusawa, Nobuo Sanjo, Mutsufusa Watanabe, Takuya Ohkubo, Hiromi Utashiro, Yukiko Matsumoto, Kumiko Hagiya, Yoshiko Miyama, Takako Shinozaki, Haruko Hiraki, Hitoshi Shibuya, Isamu Ohashi, Akira Toriihara, Shinichi Ohtani, Toshifumi Matsui, Yu Hayasaka, Tomomi Toyama, Hideki Sakurai, Kumiko Sugiura, Hirofumi Taguchi, Shizuo Hatashita, Akari Imuta, Akiko Matsudo, Daichi Wakebe, Hideki Hayakawa, Mitsuhiro Ono, Takayoshi Ohara, Yukihiko Washimi, Yutaka Arahata, Akinori Takeda, Yoko Konagaya, Akiko Yamaoka, Masashi Tsujimoto, Hideyuki Hattori, Takashi Sakurai, Miura Hisayuki, Hidetoshi Endou, Syousuke Satake, Young Jae Hong, Katsunari Iwai, Kenji Yoshiyama, Masaki Suenaga, Sumiko Morita, Teruhiko Kachi, Kenji Toba, Rina Miura, Takiko Kawai, Ai Honda, Kengo Itou, Takashi Kato, Ken Fujiwara, Rikio Katou, Mariko Koyama, Naohiko Fukaya, Akira Tsuji, Hitomi Shimizu, Hiroyuki Fujisawa, Tomoko Nakazawa, Satoshi Koyama, Takanori Sakata, Masahito Yamada, Mitsuhiro Yoshita, Miharu Samuraki, Kenjiro Ono, Moeko Shinohara, Yuki Soshi, Kozue Niwa, Chiaki Doumoto, Mariko Hata, Miyuki Matsushita, Mai Tsukiyama, Nozomi Takeda, Sachiko Yonezawa, Ichiro Matsunari, Osamu Matsui, Fumiaki Ueda, Yasuji Ryu, Masanobu Sakamoto, Yasuomi Ouchi, Madoka Chita, Yumiko Fujita, Rika Majima, Hiromi Tsubota, Umeo Shirasawa, Masashi Sugimori, Wataru Ariya, Yuuzou Hagiwara, Yasuo Tanizaki, Hidenao Fukuyama, Ryosuke Takahashi, Hajime Takechi, Chihiro Namiki, Kengo Uemura, Takeshi Kihara, Hiroshi Yamauchi, Shizuko Tanaka-Urayama, Emiko Maeda, Natsu Saito, Shiho Satomi, Konomi Kabata, Shin-Ichi Urayama, Tomohisa Okada, Koichi Ishizu, Shigeto Kawase, Satoshi Fukumoto, Masanori Nakagawa, Takahiko Tokuda, Masaki Kondo, Fumitoshi Niwa, Toshiki Mizuno, Yoko Oishi, Mariko Yamazaki, Daisuke Yamaguchi, Kyoko Ito, Yoku Asano, Chizuru Hamaguchi, Kei Yamada, Chio Okuyama, Kentaro Akazawa, Shigenori Matsushima, Takamasa Matsuo, Toshiaki Nakagawa, Takeshi Nii, Takuji Nishida, Kuniaki Kiuchi, Masami Fukusumi, Hideyuki Watanabe, Toshiaki Taoka, Akihiro Nogi, Masatoshi Takeda, Toshihisa Tanaka, Naoyuki Sato, Hiroaki Kazui, Kenji Yoshiyama, Takashi Kudo, Masayasu Okochi, Takashi Morihara, Shinji Tagami, Noriyuki Hayashi, Masahiko Takaya, Tamiki Wada, Mikiko Yokokoji, Hiromichi Sugiyama, Daisuke Yamamoto, Shuko Takeda, Keiko Nomura, Mutsumi Tomioka, Eiichi Uchida, Yoshiyuki Ikeda, Mineto Murakami, Takami Miki, Hiroyuki Shimada, Suzuka Ataka, Motokatsu Kanemoto, Jun Takeuchi, Akitoshi Takeda, Rie Azuma, Yuki Iwamoto, Naomi Tagawa, Junko Masao, Yuka Matsumoto, Yuko Kikukawa, Hisako Fujii, Junko Matsumura, Susumu Shiomi, Joji Kawabe, Yoshihiro Shimonishi, Yukio Miki, Mitsuji Higashida, Tomohiro Sahara, Takashi Yamanaga, Shinichi Sakamoto, Hiroyuki Tsushima, Kiyoshi Maeda, Yasuji Yamamoto, Toshio Kawamata, Kazuo Sakai, Haruhiko Oda, Takashi Sakurai, Taichi Akisaki, Mizuho Adachi, Masako Kuranaga, Sachi Takegawa, Yoshihiko Tahara, Seishi Terada, Takeshi Ishihara, Hajime Honda, Osamu Yokota, Yuki Kishimoto, Naoya Takeda, Nao Imai, Mayumi Yabe, Kentaro Ida, Daigo Anami, Seiji Inoue, Toshi Matsushita, Reiko Wada, Shinsuke Hiramatsu, Hiromi Tonbara, Reiko Yamamoto, Kenji Nakashima, Kenji Wada-Isoe, Saori Yamasaki, Eijiro Yamashita, Yu Nakamura, Ichiro Ishikawa, Sonoko Danjo, Tomomi Shinohara, Miyuki Ueno, Yuka Kashimoto, Yoshihiro Nishiyama, Yuka Yamamoto, Narihide Kimura, Kazuo Ogawa, Yasuhiro Sasakawa, Takashi Ishimori, Yukito Maeda, Tatsuo Yamada, Shinji Ouma, Aika Fukuhara-Kaneumi, Nami Sakamoto, Rie Nagao, Kengo Yoshimitsu, Yasuo Kuwabara, Ryuji Nakamuta, Minoru Tanaka, Manabu Ikeda, Mamoru Hashimoto, Keiichirou Kaneda, Yuusuke Yatabe, Kazuki Honda, Naoko Ichimi, Fumi Akatuka, Mariko Morinaga, Miyako Noda, Mika Kitajima, Toshinori Hirai, Shinya Shiraishi, Naoji Amano, Shinsuke Washizuka, Toru Takahashi, Shin Inuzuka, Tetsuya Hagiwara, Nobuhiro Sugiyama, Yatsuka Okada, Tomomi Ogihara, Takehiko Yasaki, Minori Kitayama, Tomonori Owa, Akiko Ryokawa, Rie Takeuchi, Satoe Goto, Keiko Yamauchi, Mie Ito, Tomoki Kaneko, Hitoshi Ueda, Shuichi Ikeda, Masaki Takao, Ban Mihara, Hirofumi Kubo, Akiko Takano, Gou Yasui, Masami Akuzawa, Kaori Yamaguchi, Toshinari Odawara, Megumi Shimamura, Mikiko Sugiyama, Atsushi Watanabe, Naomi Oota, Shigeo Takebayashi, Yoshigazu Hayakawa, Mitsuhiro Idegawa, Noriko Toya, Kazunari Ishii

Affiliations

¹ Molecular Genetics, Niigata University Brain Research Institute, Niigata, Japan.
² Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
³ Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
⁴ Neurology, National Defense Medical College, Tokorozawa, Japan.
⁵ Neurology, Tokyo Metropolitan Geriatric Medical Center Hospital, Tokyo, Japan.
⁶ Asahigawaso Research Institute, Okayama, Japan.
⁷ Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

^# Contributed equally.

Abstract

Background: The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population.

Methods: We stratified 177 individuals who participated in the Japanese Alzheimer's Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)_tau and AT(N)_NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles.

Results: We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer's disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)_tau and AT(N)_NfL classifications. When we used t-tau as the N marker (AT(N)_tau), those who had T- were more frequently assigned to (N)-, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)_NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)_tau and AT(N)_NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)_tau classification, but not in the AT(N)_NfL classification.

Conclusions: AT(N)_tau and AT(N)_NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

Keywords: ALZHEIMER'S DISEASE; AMYLOID; BIOCHEMISTRY; CSF.