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J Neurol. 2018 Oct 15. doi: 10.1007/s00415-018-9086-2. [Epub ahead of print]

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

Author information

1
Department of Neurology, Memory and Aging Center, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
2
Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea.
3
Department of Neurology, University of California, Los Angeles, USA.
4
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA.
5
Department of Pathology, University of California, San Francisco, USA.
6
Department of Neurology, Memory and Aging Center, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA. lea.grinberg@ucsf.edu.
7
Department of Pathology, University of California, San Francisco, USA. lea.grinberg@ucsf.edu.

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.

KEYWORDS:

Frontotemporal lobar degeneration; TAR-DNA binding protein-43; Tau

PMID:
30324308
DOI:
10.1007/s00415-018-9086-2

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