L J Schipper1, J Raaphorst2,3, E Aronica4, F Baas5, R de Haan6, M de Visser1, D Troost4. 1. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. joost.raaphorst@radboudumc.nl. 3. Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands. joost.raaphorst@radboudumc.nl. 4. Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5. Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Clinical Research Unit, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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.
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.
Authors: Vincent Picher-Martel; Paul N Valdmanis; Peter V Gould; Jean-Pierre Julien; Nicolas Dupré Journal: Acta Neuropathol Commun Date: 2016-07-11 Impact factor: 7.801
Authors: C Maurel; A Dangoumau; S Marouillat; C Brulard; A Chami; R Hergesheimer; P Corcia; H Blasco; C R Andres; P Vourc'h Journal: Mol Neurobiol Date: 2018-01-10 Impact factor: 5.590
Authors: Ahmed Yousef; John L Robinson; David J Irwin; Matthew D Byrne; Linda K Kwong; Edward B Lee; Yan Xu; Sharon X Xie; Lior Rennert; EunRan Suh; Vivianna M Van Deerlin; Murray Grossman; Virginia M-Y Lee; John Q Trojanowski Journal: Acta Neuropathol Commun Date: 2017-09-06 Impact factor: 7.801