The Generative Brain

CSF 14-3-3 and total tau

CSF 14-3-3 and total tau are older surrogate markers of rapid neuronal damage that support a CJD diagnosis: about 85 to 86 percent sensitive in sporadic CJD, above 93 percent in combination, but raised in other conditions and still counted in the CDC criteria only for illness shorter than two years. Where RT-QuIC is unavailable (India) they are the available CSF test.

Key facts

  • At the US centre, a negative RT-QuIC with total tau under 499 gives under 0.2 percent likelihood of prion disease; tau 500 to 2499 gives under 1 percent.
  • The Australian registry runs 14-3-3 and RT-QuIC weekly on Mondays.
  • Limits: Indirect markers; raised in many non-prion conditions. India relies on 14-3-3 where RT-QuIC is unavailable.
  • What it asks of the person: Lumbar puncture.
  • In 1,859 CJD patients and 1,117 controls, 14-3-3 and tau had 85 and 86 percent sensitivity in sporadic CJD and combining them with S100b or NSE raised it above 93 percent.
  • Sensitivity was highest with the shortest disease duration, onset after age 40 and codon 129 homozygosity; a second lumbar puncture helped when the first test was negative.
  • The 2018 CDC criteria count a positive 14-3-3 only when disease duration is under 2 years, and make positive CSF RT-QuIC sufficient on its own for probable CJD.
  • 14-3-3 proteins are found in CSF in various neurological disorders but are more elevated in CJD, which limits specificity.
  • NIMHANS built an in-house dot blot for CSF 14-3-3 with about ten-fold higher levels in CJD (N=50) than disease controls (N=70).
  • In a 2003 to 2016 consecutive Bologna cohort, CSF RT-QuIC had 82.1 percent sensitivity and 99.4 percent specificity and was compared with 14-3-3, tau and other surrogate markers by subtype.

Timeline

  1. 2016NIMHANS dot blot assay published.
  2. 2017Bologna cohort analysis published (2003 to 2016 samples).
  3. 2018CDC criteria make RT-QuIC sufficient for probable CJD.
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