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. 2016 Oct;42(6):547-60.
doi: 10.1111/nan.12284.

Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review

L J Schipper  1 , J Raaphorst  2   3 , E Aronica  4 , F Baas  5 , R de Haan  6 , M de Visser  1 , D Troost  4
Affiliations

Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review

L J Schipper et al. Neuropathol Appl Neurobiol. 2016 Oct.

Abstract

Aim: The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists.

Methods: We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD.

Results: In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%).

Discussion: The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.

Keywords: C9ORF72; TDP-43; amyotrophic lateral sclerosis; dipeptide repeat proteins; frontotemporal dementia; p62.

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