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Mixed TDP-43 proteinopathy and tauopathy in frontotemporal lobar degeneration: nine case series

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Abstract

Objectives

To determine the clinical, anatomical, genetic and pathological features of dual frontotemporal lobar degeneration (FTLD) pathology: FTLD-tau and FTLD-TDP-43 in a large clinicopathological cohort.

Methods

We selected subjects with mixed FTLD-TDP and FTLD-tau from 247 FTLD cases from the University of California, San Francisco, Neurodegenerative Disease Brain Bank collected between 2000 and 2016 and compared their clinical, anatomical, genetic, imaging and pathological signatures with those of subjects with pure FTLD.

Results

We found nine cases (3.6%) with prominent FTLD-TDP and FTLD-tau. Six cases were sporadic, whereas one case had a C9ORF72 expansion, another had a TARDBP A90V variant, and the other had an MAPT p.A152T variant. The subtypes of FTLD-TDP and FTLD-tau varied. Mixed FTLD cases were older and tended to show a higher burden of Alzheimer disease pathology (3/9, 33%). The neuroimaging signature of mixed cases, in general, included more widespread atrophy than that of pure groups. Specifically, cases of mixed corticobasal degeneration (CBD) with FTLD-TDP showed more prominent asymmetric left-sided atrophy than did those of pure CBD. However, the clinical phenotype of mixed cases was similar to that seen in pure FTLD.

Conclusions

Although patients with mixed FTLD-TDP and FTLD-tau are rare, in-depth clinical, pathological and genetic investigations may shed light on the genetic and biochemical pathways that cause the accumulation of multiple proteinaceous inclusions and inform therapeutic targets that may be beneficial to each one of these abnormal protein misfoldings.

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Acknowledgments

This study was supported by the Financial Supporting Project of Long-term Overseas Dispatch of PNU's Tenure-track Faculty, 2015 to Eun-Joo Kim.

Funding

Funding was provided by the NIH Grant #K24AG053435, P50AG023501 and P01AG019724, Rainwater Foundation to Lea T. Grinberg.

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Authors and Affiliations

  1. Department of Neurology, Memory and Aging Center, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA

    Eun-Joo Kim, Jesse A. Brown, Jersey Deng, Ji-Hye L. Hwang, Salvatore Spina, Zachary A. Miller, Mary G. DeMay, Victor Valcour, Anna Karydas, Bruce L. Miller, Howard J. Rosen, William W. Seeley & Lea T. Grinberg

  2. Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea

    Eun-Joo Kim

  3. Department of Neurology, University of California, Los Angeles, USA

    Eliana Marisa Ramos & Giovanni Coppola

  4. Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA

    Eliana Marisa Ramos & Giovanni Coppola

  5. Department of Pathology, University of California, San Francisco, USA

    William W. Seeley & Lea T. Grinberg

Authors
  1. Eun-Joo Kim
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  2. Jesse A. Brown
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Correspondence to Lea T. Grinberg.

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Kim, EJ., Brown, J.A., Deng, J. et al. Mixed TDP-43 proteinopathy and tauopathy in frontotemporal lobar degeneration: nine case series. J Neurol 265, 2960–2971 (2018). https://doi.org/10.1007/s00415-018-9086-2

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  • DOI: https://doi.org/10.1007/s00415-018-9086-2

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