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J Neuropathol Exp Neurol. 2018 Feb 1;77(2):149-161. doi: 10.1093/jnen/nlx113.

Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study.

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Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California.
Brazilian Aging Brain Study Group, LIM-22, Department of Pathology.
Division of Geriatrics, Department of Clinical Medicine, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Department of Pathology, University of California, San Francisco, San Francisco, California.
Department of Psychiatry, University of California, San Francisco and San Francisco VA Medical Center, San Francisco, California.
LIM-44, University of Sao Paulo Medical School, Sao Paulo, Brazil and Clinic of Psychiatry, University of W├╝rzburg, Wurzburg, Germany.


The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment.


Alzheimer disease; Corticobasal degeneration; Human brainstem; Progressive supranuclear palsy; Reticular formation; Selective vulnerability; Tauopathies


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