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J Neuropathol Exp Neurol. 2018 Aug 1;77(8):703-709. doi: 10.1093/jnen/nly047.

Systematic Screening of Ubiquitin/p62 Aggregates in Cerebellar Cortex Expands the Neuropathological Phenotype of the C9orf72 Expansion Mutation.

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Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain.
Alzheimer disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain.
Department of Anatomical Pathology, FISEVI-Hospital Universitario Virgen del Rocío, Sevilla, Spain.
Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Center for Networked Biomedical Research Into Neurodegenerative Diseases (CIBERNED).
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Center for Networked Biomedical Research Into Rare Diseases (CIBERER), Spain.
Fundación ACE, Barcelona, Spain.
Movement Disorders and Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, and Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain.
Department of Neurology, Sant Boi de Llobregat, Hospital Germanes Hospitalàries Benito Menni, Barcelona, Spain.
Department of Neurology, Parc de Salut Marx, Barcelona, Spain.
Department of Geriatry, Hospital Universitari de la Santa Creu de Vic, Barcelona, Spain.
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Institute of Neurology, Medical University of Vienna, Austria.


The neuropathological hallmark of the C9orf72 intronic hexanucleotide expansion in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the presence of small ubiquitin/p62-positive and transactive response DNA binding protein 43 kDa (TDP-43)-negative cytoplasmic inclusions in several brain areas. The identification of this histopathological signature is highly predictive of an underlying mutation. In this study, we screened 1800 cases of the Barcelona IDIBAPS Brain Bank, independently of the clinical and final neuropathological diagnosis of the brain donor, for the presence of ubiquitin/p62-positive inclusions in the cerebellum (UPPI). Positive cases were also stained for dipeptide repeats. We identified a total of 21 donors with UPPI and in all of them the C9orf72 hexanucleotide expansion was genetically confirmed. Most donors had an FTLD or to a lesser extent ALS clinico-pathological phenotype. However, 3 cases had been previously classified as having clinically and neuropathologically Lewy body disease. Other co-existing pathologies, especially of the PART-type, were also frequently encountered. This study highlights the importance of the evaluation of ubiquitin/p62-positive cytoplasmic inclusions in all neurodegenerative diseases as a good screening method for the detection of C9orf72 expansion mutation, since this mutation is not rare and can overlap with other neurodegenerative entities.


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