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Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3

Garcia-Moreno, Hector ; Prudencio, Mercedes ; Thomas-Black, Gilbert ; Solanky, Nita ; Jansen-West, Karen R ; Hanna Al-Shaikh, Rana ; Heslegrave, Amanda ; Zetterberg, Henrik LU ; Santana, Magda M and Pereira de Almeida, Luis , et al. (2022) In European Journal of Neurology 29(8). p.2439-2452
Abstract

BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.

METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.

RESULTS: Plasma t-tau levels... (More)

BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.

METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.

RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).

CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Biomarkers/blood, Cerebellum/chemistry, Heterozygote, Humans, Machado-Joseph Disease/blood, Mice, Mice, Transgenic, Neurofilament Proteins/blood, tau Proteins/blood
in
European Journal of Neurology
volume
29
issue
8
pages
2439 - 2452
publisher
Wiley-Blackwell
external identifiers
  • pmid:35478426
  • scopus:85130605712
ISSN
1351-5101
DOI
10.1111/ene.15373
language
English
LU publication?
yes
additional info
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
id
0d803d65-f2a3-4bc6-b38a-4ca82ae24b95
date added to LUP
2022-08-16 15:21:19
date last changed
2024-06-09 22:40:37
@article{0d803d65-f2a3-4bc6-b38a-4ca82ae24b95,
  abstract     = {{<p>BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.</p><p>METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.</p><p>RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p &lt; 0.001).</p><p>CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.</p>}},
  author       = {{Garcia-Moreno, Hector and Prudencio, Mercedes and Thomas-Black, Gilbert and Solanky, Nita and Jansen-West, Karen R and Hanna Al-Shaikh, Rana and Heslegrave, Amanda and Zetterberg, Henrik and Santana, Magda M and Pereira de Almeida, Luis and Vasconcelos-Ferreira, Ana and Januário, Cristina and Infante, Jon and Faber, Jennifer and Klockgether, Thomas and Reetz, Kathrin and Raposo, Mafalda and Ferreira, Ana F and Lima, Manuela and Schöls, Ludger and Synofzik, Matthis and Hübener-Schmid, Jeannette and Puschmann, Andreas and Gorcenco, Sorina and Wszolek, Zbigniew K and Petrucelli, Leonard and Giunti, Paola}},
  issn         = {{1351-5101}},
  keywords     = {{Animals; Biomarkers/blood; Cerebellum/chemistry; Heterozygote; Humans; Machado-Joseph Disease/blood; Mice; Mice, Transgenic; Neurofilament Proteins/blood; tau Proteins/blood}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2439--2452}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{European Journal of Neurology}},
  title        = {{Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3}},
  url          = {{http://dx.doi.org/10.1111/ene.15373}},
  doi          = {{10.1111/ene.15373}},
  volume       = {{29}},
  year         = {{2022}},
}