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A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia.

Lashley T, Rohrer JD, Mahoney C, Gordon E, Beck J, Mead S, Warren J, Rossor M, Revesz T - Neuropathol. Appl. Neurobiol. (2014)

Bottom Line: Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes.Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive 'star-like' inclusions found in the hippocampal formation and cerebellum.However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism.

View Article: PubMed Central - PubMed

Affiliation: Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.

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Related in: MedlinePlus

TDP-43, p62 and Ubiquilin2 immunohistochemistry in case 2.1. Numerous p62 positive neuronal cytoplasmic inclusions (NCIs) were evident in the granule cell layer (GCL) of the hippocampus (A) compared to sparse numbers of TDP-43 positive NCIs in the GCL (B, arrows). Ubiquilin2 positive NCIs were also found in the GCL showing similar numbers to those observed with p62 (C). The cerebellum granule cells (D) and the neurones found in other subregions of the hippocampus (CA4) were also found to contain p62-positive ‘star-like’ inclusions (E). TDP-43 pathology was evident in the frontal cortex (F) and found in the frontal cortex white matter (G). Double fluorescent immunohistochemistry revealed that the number of p62 (I) positive inclusions were greater than those immunostained with Ubiquilin2 (H). TDP-43 and p62 immunohistochemistry was combined in the GCL and cerebellum, where a TDP-43 NCI (L, arrow) was outnumbered by the smaller ‘star-like’ p62 positive inclusions (K). This was also seen in the cerebellum where normal nuclear staining of TDP-43 was observed (O) and no colocalization was seen with the p62 positive inclusions (N). Bar on A represents 50 microns on A, B and C; 20 microns on D, F and G; 10 microns on E. The original magnification on panels H-P ×40.
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fig04: TDP-43, p62 and Ubiquilin2 immunohistochemistry in case 2.1. Numerous p62 positive neuronal cytoplasmic inclusions (NCIs) were evident in the granule cell layer (GCL) of the hippocampus (A) compared to sparse numbers of TDP-43 positive NCIs in the GCL (B, arrows). Ubiquilin2 positive NCIs were also found in the GCL showing similar numbers to those observed with p62 (C). The cerebellum granule cells (D) and the neurones found in other subregions of the hippocampus (CA4) were also found to contain p62-positive ‘star-like’ inclusions (E). TDP-43 pathology was evident in the frontal cortex (F) and found in the frontal cortex white matter (G). Double fluorescent immunohistochemistry revealed that the number of p62 (I) positive inclusions were greater than those immunostained with Ubiquilin2 (H). TDP-43 and p62 immunohistochemistry was combined in the GCL and cerebellum, where a TDP-43 NCI (L, arrow) was outnumbered by the smaller ‘star-like’ p62 positive inclusions (K). This was also seen in the cerebellum where normal nuclear staining of TDP-43 was observed (O) and no colocalization was seen with the p62 positive inclusions (N). Bar on A represents 50 microns on A, B and C; 20 microns on D, F and G; 10 microns on E. The original magnification on panels H-P ×40.

Mentions: In case 2.1 neurofibrillary tangles (NFTs) and neuropil threads (NTs) were found in the hippocampus, entorhinal and transentorhinal cortices. TDP-43 positive NCIs were observed in the granule cells of the dentate fascia but these were outnumbered by numerous p62-positive ‘star-like’ inclusions (Figure 4). The majority of the p62-positive inclusions were also immunostained with ubiquilin2 (Figure 4), although there were still inclusions that were only positively stained with p62. The p62-positive ‘star-like’ inclusions were also found in the CA4 subregion, which was negative for TDP-43. Case 2.2 showed a similar distribution of TDP-43 and p62 inclusions as that observed in cases 2.1; however no additional pathology was evident.


A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia.

Lashley T, Rohrer JD, Mahoney C, Gordon E, Beck J, Mead S, Warren J, Rossor M, Revesz T - Neuropathol. Appl. Neurobiol. (2014)

TDP-43, p62 and Ubiquilin2 immunohistochemistry in case 2.1. Numerous p62 positive neuronal cytoplasmic inclusions (NCIs) were evident in the granule cell layer (GCL) of the hippocampus (A) compared to sparse numbers of TDP-43 positive NCIs in the GCL (B, arrows). Ubiquilin2 positive NCIs were also found in the GCL showing similar numbers to those observed with p62 (C). The cerebellum granule cells (D) and the neurones found in other subregions of the hippocampus (CA4) were also found to contain p62-positive ‘star-like’ inclusions (E). TDP-43 pathology was evident in the frontal cortex (F) and found in the frontal cortex white matter (G). Double fluorescent immunohistochemistry revealed that the number of p62 (I) positive inclusions were greater than those immunostained with Ubiquilin2 (H). TDP-43 and p62 immunohistochemistry was combined in the GCL and cerebellum, where a TDP-43 NCI (L, arrow) was outnumbered by the smaller ‘star-like’ p62 positive inclusions (K). This was also seen in the cerebellum where normal nuclear staining of TDP-43 was observed (O) and no colocalization was seen with the p62 positive inclusions (N). Bar on A represents 50 microns on A, B and C; 20 microns on D, F and G; 10 microns on E. The original magnification on panels H-P ×40.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260146&req=5

fig04: TDP-43, p62 and Ubiquilin2 immunohistochemistry in case 2.1. Numerous p62 positive neuronal cytoplasmic inclusions (NCIs) were evident in the granule cell layer (GCL) of the hippocampus (A) compared to sparse numbers of TDP-43 positive NCIs in the GCL (B, arrows). Ubiquilin2 positive NCIs were also found in the GCL showing similar numbers to those observed with p62 (C). The cerebellum granule cells (D) and the neurones found in other subregions of the hippocampus (CA4) were also found to contain p62-positive ‘star-like’ inclusions (E). TDP-43 pathology was evident in the frontal cortex (F) and found in the frontal cortex white matter (G). Double fluorescent immunohistochemistry revealed that the number of p62 (I) positive inclusions were greater than those immunostained with Ubiquilin2 (H). TDP-43 and p62 immunohistochemistry was combined in the GCL and cerebellum, where a TDP-43 NCI (L, arrow) was outnumbered by the smaller ‘star-like’ p62 positive inclusions (K). This was also seen in the cerebellum where normal nuclear staining of TDP-43 was observed (O) and no colocalization was seen with the p62 positive inclusions (N). Bar on A represents 50 microns on A, B and C; 20 microns on D, F and G; 10 microns on E. The original magnification on panels H-P ×40.
Mentions: In case 2.1 neurofibrillary tangles (NFTs) and neuropil threads (NTs) were found in the hippocampus, entorhinal and transentorhinal cortices. TDP-43 positive NCIs were observed in the granule cells of the dentate fascia but these were outnumbered by numerous p62-positive ‘star-like’ inclusions (Figure 4). The majority of the p62-positive inclusions were also immunostained with ubiquilin2 (Figure 4), although there were still inclusions that were only positively stained with p62. The p62-positive ‘star-like’ inclusions were also found in the CA4 subregion, which was negative for TDP-43. Case 2.2 showed a similar distribution of TDP-43 and p62 inclusions as that observed in cases 2.1; however no additional pathology was evident.

Bottom Line: Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes.Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive 'star-like' inclusions found in the hippocampal formation and cerebellum.However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism.

View Article: PubMed Central - PubMed

Affiliation: Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.

Show MeSH
Related in: MedlinePlus