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Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities.

Sosunov AA, McGovern RA, Mikell CB, Wu X, Coughlin DG, Crino PB, Weiner HL, Ghatan S, Goldman JE, McKhann GM - Acta Neuropathol Commun (2015)

Bottom Line: Perituberal giant cells and astrocytes together formed characteristic "microtubers".A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers.

Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.

Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

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Astrocytes in microtubers reveal activation (phosphorylation) of ribosomal protein S6 (S6) and p44/42 MAPK (p44). (a) p-S6+ astrocytes (arrowheads, marked only some) in microtubers in cortical layer V. A giant p-S6+ cell is marked with an arrow. Note that several microtubers are located near each other. (b,c) p44+ astrocytes (arrowheads) in microtubers detected with polyclonal (b, red) and monoclonal (c, green) primary antibodies. Giant cell p–S6+ and p44+ is marked with an arrow. (d) Many SPARC+ fibrous astrocytes express p-S6 (arrowheads). Giant p-S6+ /SPARC+ cell is marked with an arrow. Confocal microscopy, double immunostaining, counterstaining with Nissl (a-c), triple immunostaining (d). a1, b1, c1, and d1–enlarged boxed area in a, b, c, and d, respectively. a1’, b1’, c1’,d1’ and d1”represent split a1, b1, c1, and d1 images, respectively. scale bars: 150 μm.
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Fig4: Astrocytes in microtubers reveal activation (phosphorylation) of ribosomal protein S6 (S6) and p44/42 MAPK (p44). (a) p-S6+ astrocytes (arrowheads, marked only some) in microtubers in cortical layer V. A giant p-S6+ cell is marked with an arrow. Note that several microtubers are located near each other. (b,c) p44+ astrocytes (arrowheads) in microtubers detected with polyclonal (b, red) and monoclonal (c, green) primary antibodies. Giant cell p–S6+ and p44+ is marked with an arrow. (d) Many SPARC+ fibrous astrocytes express p-S6 (arrowheads). Giant p-S6+ /SPARC+ cell is marked with an arrow. Confocal microscopy, double immunostaining, counterstaining with Nissl (a-c), triple immunostaining (d). a1, b1, c1, and d1–enlarged boxed area in a, b, c, and d, respectively. a1’, b1’, c1’,d1’ and d1”represent split a1, b1, c1, and d1 images, respectively. scale bars: 150 μm.

Mentions: We suggest that the astrocytes with long, non-branched processes in type I microtubers are similar in many ways to the CD44+ long-process/interlaminar astrocytes in gray matter and/or to fibrous astrocytes in white matter, whereas astrocytes with processes of protoplasmic astrocytes size and shape, but CD44+, in type II microtubers are reactive protoplasmic astrocytes. To test this hypothesis we used immunostaining for SPARC/osteonectin, a glycoprotein we have found to be a characteristic marker of CD44+ interlaminar and fibrous astrocytes in human brain [17]. Indeed, type I microtubers contained many SPARC+ astrocytes whereas only a few SPARC+ cells were observed in type II microtubers (11.8 ± 0.824 per microtuber in type I vs 0.824 ± 0.3 in type II, p < 0.001) (Figure 3a,b). In addition, all SPARC+ astrocytes were CD44+ and had clearly outlined, long main branches without lamellipodial-like processes (Figure 3c). It should be noted that many giant cells also showed immunolabelling for SPARC (Figures 3b,d; 4c,d).Figure 3


Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities.

Sosunov AA, McGovern RA, Mikell CB, Wu X, Coughlin DG, Crino PB, Weiner HL, Ghatan S, Goldman JE, McKhann GM - Acta Neuropathol Commun (2015)

Astrocytes in microtubers reveal activation (phosphorylation) of ribosomal protein S6 (S6) and p44/42 MAPK (p44). (a) p-S6+ astrocytes (arrowheads, marked only some) in microtubers in cortical layer V. A giant p-S6+ cell is marked with an arrow. Note that several microtubers are located near each other. (b,c) p44+ astrocytes (arrowheads) in microtubers detected with polyclonal (b, red) and monoclonal (c, green) primary antibodies. Giant cell p–S6+ and p44+ is marked with an arrow. (d) Many SPARC+ fibrous astrocytes express p-S6 (arrowheads). Giant p-S6+ /SPARC+ cell is marked with an arrow. Confocal microscopy, double immunostaining, counterstaining with Nissl (a-c), triple immunostaining (d). a1, b1, c1, and d1–enlarged boxed area in a, b, c, and d, respectively. a1’, b1’, c1’,d1’ and d1”represent split a1, b1, c1, and d1 images, respectively. scale bars: 150 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4383198&req=5

Fig4: Astrocytes in microtubers reveal activation (phosphorylation) of ribosomal protein S6 (S6) and p44/42 MAPK (p44). (a) p-S6+ astrocytes (arrowheads, marked only some) in microtubers in cortical layer V. A giant p-S6+ cell is marked with an arrow. Note that several microtubers are located near each other. (b,c) p44+ astrocytes (arrowheads) in microtubers detected with polyclonal (b, red) and monoclonal (c, green) primary antibodies. Giant cell p–S6+ and p44+ is marked with an arrow. (d) Many SPARC+ fibrous astrocytes express p-S6 (arrowheads). Giant p-S6+ /SPARC+ cell is marked with an arrow. Confocal microscopy, double immunostaining, counterstaining with Nissl (a-c), triple immunostaining (d). a1, b1, c1, and d1–enlarged boxed area in a, b, c, and d, respectively. a1’, b1’, c1’,d1’ and d1”represent split a1, b1, c1, and d1 images, respectively. scale bars: 150 μm.
Mentions: We suggest that the astrocytes with long, non-branched processes in type I microtubers are similar in many ways to the CD44+ long-process/interlaminar astrocytes in gray matter and/or to fibrous astrocytes in white matter, whereas astrocytes with processes of protoplasmic astrocytes size and shape, but CD44+, in type II microtubers are reactive protoplasmic astrocytes. To test this hypothesis we used immunostaining for SPARC/osteonectin, a glycoprotein we have found to be a characteristic marker of CD44+ interlaminar and fibrous astrocytes in human brain [17]. Indeed, type I microtubers contained many SPARC+ astrocytes whereas only a few SPARC+ cells were observed in type II microtubers (11.8 ± 0.824 per microtuber in type I vs 0.824 ± 0.3 in type II, p < 0.001) (Figure 3a,b). In addition, all SPARC+ astrocytes were CD44+ and had clearly outlined, long main branches without lamellipodial-like processes (Figure 3c). It should be noted that many giant cells also showed immunolabelling for SPARC (Figures 3b,d; 4c,d).Figure 3

Bottom Line: Perituberal giant cells and astrocytes together formed characteristic "microtubers".A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers.

Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.

Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

Show MeSH
Related in: MedlinePlus