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Comparative Study
. 2011 Dec;122(6):673-90.
doi: 10.1007/s00401-011-0907-y. Epub 2011 Nov 15.

Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72

Melissa E Murray  1 , Mariely DeJesus-Hernandez, Nicola J Rutherford, Matt Baker, Ranjan Duara, Neill R Graff-Radford, Zbigniew K Wszolek, Tanis J Ferman, Keith A Josephs, Kevin B Boylan, Rosa Rademakers, Dennis W Dickson
Affiliations
Comparative Study

Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72

Melissa E Murray et al. Acta Neuropathol. 2011 Dec.

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.

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Figures

Figure 1
Figure 1
Macroscopic findings in c9FTD/ALS (Case 1: a, b & c; Case 9: d, e & f; Case 14: g, h & i)). ALS case with mild peri-Rolandic cortical atrophy (a, arrow), but no ventricular enlargement on a coronal section at level of the subthalamic nucleus (b) and no gross hippocampal atrophy (c). FTLD-MND case (Mackenzie Type 3) with moderate peri-Rolandic cortical atrophy (arrow) and moderate frontal-predominant atrophy (d). Enlargement of the frontal, but not temporal horn of the lateral ventricle can be seen on a coronal section at level of the subthalamic nucleus (e) and mild hippocampal atrophy of the subiculum (f). FTLD-TDP case (Mackenzie Type 1) with no peri-Rolandic atrophy (arrow), but moderate frontal and temporal atrophy (g), as well as enlargement of both frontal and temporal horns of the lateral ventricle on a coronal section at level of the subthalamic nucleus (h). Hippocampal sclerosis was severe and correlates with atrophy in CA1 and the subiculum (arrow) (i).
Figure 2
Figure 2
Ubiquitin immunohistochemistry of cerebellum of c9FTD/ALS shows many NCI in internal granular cell layer in FTLD-TDP (a) and fewer in ALS (b). Insets show higher magnification of NCI. (bar = 30 μm for a & b and 90 μm for insets)
Figure 3
Figure 3
Phospho-TDP-43 immunohistochemistry of c9FTD/ALS cases with range of TDP-43 pathology. (a) ALS cortex has many GCI in lower cortical layers. (b) Type 1 cases have many NCI and DN in the superficial cortical layers, with lentiform NII (upper left inset) and dense, globular PV astrocytic inclusions (lower right inset). (c) Type 2 cases have large thick dystrophic neurites in lower (in this figure) and upper cortical layers, with dense round Pick body like NCI in the hippocampal dentate fascia (upper left inset) (d) Type 3 cases have many granular or pre-inclusion type NCI with sparse or absent DN in cortex and hippocampal dentate fascia (upper left inset). (bar = 30 μm for a, b, c & d and 90 μm for insets)
Figure 4
Figure 4
Phospho-TDP-43 immunohistochemistry of c9FTD/ALS shows unusual neuritic and synaptic pathology. Fine neurites in CA1 of hippocampus (a); Synaptic-like TDP-43 grains in CA3 of hippocampus (b), superficial cortical layer (c) and globus pallidus (d). (bar = 30 μm for a, b, c & d)
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References

    1. Amador-Ortiz C, Lin WL, Ahmed Z, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol. 2007;61:435–445. - PMC - PubMed
    1. Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351:602–611. - PubMed
    1. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916–919. - PubMed
    1. Boxer AL, Mackenzie IR, Boeve BF, et al. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. 2011;82:196–203. - PMC - PubMed
    1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. - PubMed

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