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Abstract
Objective: To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia.
Methods: DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9ORF72 expansions. α-Synuclein and p62 immunohistochemistry of the substantia nigra (SN) was undertaken in brains of 17 ALS cases with (C9ORF72+) and 51 without (C9ORF72−) the C9ORF72 expansion.
Results: Only 1 of 338 cases with pathologically confirmed idiopathic Parkinson disease had a C9ORF72 expansion. Similarly, only 1 of 17 C9ORF72+ brains displayed features suggestive of α-synucleinopathy. In contrast, p62-positive, TDP-43–negative neuronal cytoplasmic inclusions within the SN were considerably more frequent in C9ORF72+ brain tissue than in the C9ORF72− brains (p = 0.005). Furthermore, there was a more marked loss of dopaminergic neurons in the SN of C9ORF72+ ALS brains than C9ORF72− ALS brains (p = 0.029).
Conclusions: SN involvement is common in C9ORF72+ ALS but can be clearly distinguished from Parkinson disease–related mechanisms by the presence of p62-positive inclusions and the absence of α-synuclein–positive Lewy bodies or Lewy neurites.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- C9ORF72=
- chromosome 9 open reading frame 72;
- FTD=
- frontotemporal dementia;
- FTLD=
- frontotemporal lobar degeneration;
- iPD=
- idiopathic Parkinson disease;
- PD=
- Parkinson disease;
- SN=
- substantia nigra;
- TDP-43=
- TAR DNA-binding protein 43
Footnotes
↵* These authors contributed equally to this work.
↵‡ These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at www.neurology.org
- Received February 15, 2013.
- Accepted in final form May 24, 2013.
- © 2013 American Academy of Neurology
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