Three challenges in interpreting neurogenesis data from banked human brains

One field where the methods of studying postmortem human brain tissue have been relevant recently is adult neurogenesis.

In 2018, Sorrells et al made a splash when they used brain samples from 37 donated brain samples and 22 neurosurgical specimens from people with epilepsy to suggest that neurogenesis only occurs at negligible levels during adulthood. This data seemed to contradict results from rodents.

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DCX staining in rats; Oomen et al 2009 10.1371/journal.pone.0003675

I recently came across Lucassen et al 2018, which critiques Sorrells et al 2018 on a few methodological grounds:

  1. Postmortem interval: Very little clinical data was made available for each brain donor in Sorrells et al, and the postmortem interval (PMI) was one of the omitted variables. The neurogenesis marker DCX appears to be broken down or otherwise be negative on staining shortly after death, so these extended PMIs could cause false negative for DCX staining. Lucassen et al also noted that there might be differential effects of PMI in old and young human brains, for example as a result of differences in myelination.
  2. Cause of death: Lucassen et al noted that certain causes of death, such as sepsis, might be more likely to cause a breakdown of protein post-translational modifications. In the case of the other neurogenesis marker studied, PSA-NCAM, its poly-sialic group might have been lost in hypoxic brains that have substantial perimortem lactic acid production and resulting acidity.
  3. Need for 3d data: Lucassen et al note that the individual EM images presented by Sorrells et al are difficult to interpret because brain cells have complicated, branching morphologies. Instead, they suggest that 3d reconstructions of serial EM images would be more dispositive. Creating 3d reconstructions is often more difficult to accomplish in postmortem human brain tissue compared to rodent brain tissue if the cell processes span a volume that is too large to be effectively preserved by immersion fixation and perfusion fixation is not possible.

I don’t know enough about human neurogenesis, DCX, PSA-NCAM, or the other areas discussed to know if Lucassen’s critiques mean that Sorrells et al’s data truly won’t replicate. But I found the methodological critiques to be valid and important.