Limits...
Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome.

Greco CM, Navarro CS, Hunsaker MR, Maezawa I, Shuler JF, Tassone F, Delany M, Au JW, Berman RF, Jin LW, Schumann C, Hagerman PJ, Hagerman RJ - Mol Autism (2011)

Bottom Line: All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation.Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

View Article: PubMed Central - HTML - PubMed

Affiliation: MIND Institute, University of California-Davis Medical Center, Sacramento, CA, USA. randi.hagerman@ucdmc.ucdavis.edu.

ABSTRACT

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available.

Methods: Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis.

Results: Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.

Conclusions: Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

No MeSH data available.


Related in: MedlinePlus

Calbindin immunofluorescent staining in the cerebellar cortex. Calbindin immunofluorescent staining of the cerebellar cortex indicates decreased numbers of PCs and diminished complexity of the PC dendritic arborization compared with age-matched controls. Similar changes were observed in all vermal lobules and in lateral posterior lobe cortex. (A) Vermal inferior lobule and (B) lateral posterior lobe cerebellar cortex. Original magnification ×10; scale bar = 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3045897&req=5

Figure 3: Calbindin immunofluorescent staining in the cerebellar cortex. Calbindin immunofluorescent staining of the cerebellar cortex indicates decreased numbers of PCs and diminished complexity of the PC dendritic arborization compared with age-matched controls. Similar changes were observed in all vermal lobules and in lateral posterior lobe cortex. (A) Vermal inferior lobule and (B) lateral posterior lobe cerebellar cortex. Original magnification ×10; scale bar = 250 μm.

Mentions: Based on the improved characteristics of calbindin antibody staining over standard Nissl stains as a marker for PCs in postmortem human brains [25], we used calbindin immunofluorescence (IF) to evaluate the morphology of PCs and to confirm any reductions in cell number identified in H&E-stained cerebella. In age-matched controls (Figure 3), calbindin-immunoreactive PCs were spaced regularly, although somewhat variably, depending on the plane of the section, and the dendrites of control PCs had fine processes from their dendritic trees. By contrast, the three patients had a substantial reduction in calbindin-immunoreactive PCs, with attenuation of dendritic arborization. Similar features were seen throughout the vermis and lateral cortex.


Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome.

Greco CM, Navarro CS, Hunsaker MR, Maezawa I, Shuler JF, Tassone F, Delany M, Au JW, Berman RF, Jin LW, Schumann C, Hagerman PJ, Hagerman RJ - Mol Autism (2011)

Calbindin immunofluorescent staining in the cerebellar cortex. Calbindin immunofluorescent staining of the cerebellar cortex indicates decreased numbers of PCs and diminished complexity of the PC dendritic arborization compared with age-matched controls. Similar changes were observed in all vermal lobules and in lateral posterior lobe cortex. (A) Vermal inferior lobule and (B) lateral posterior lobe cerebellar cortex. Original magnification ×10; scale bar = 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045897&req=5

Figure 3: Calbindin immunofluorescent staining in the cerebellar cortex. Calbindin immunofluorescent staining of the cerebellar cortex indicates decreased numbers of PCs and diminished complexity of the PC dendritic arborization compared with age-matched controls. Similar changes were observed in all vermal lobules and in lateral posterior lobe cortex. (A) Vermal inferior lobule and (B) lateral posterior lobe cerebellar cortex. Original magnification ×10; scale bar = 250 μm.
Mentions: Based on the improved characteristics of calbindin antibody staining over standard Nissl stains as a marker for PCs in postmortem human brains [25], we used calbindin immunofluorescence (IF) to evaluate the morphology of PCs and to confirm any reductions in cell number identified in H&E-stained cerebella. In age-matched controls (Figure 3), calbindin-immunoreactive PCs were spaced regularly, although somewhat variably, depending on the plane of the section, and the dendrites of control PCs had fine processes from their dendritic trees. By contrast, the three patients had a substantial reduction in calbindin-immunoreactive PCs, with attenuation of dendritic arborization. Similar features were seen throughout the vermis and lateral cortex.

Bottom Line: All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation.Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

View Article: PubMed Central - HTML - PubMed

Affiliation: MIND Institute, University of California-Davis Medical Center, Sacramento, CA, USA. randi.hagerman@ucdmc.ucdavis.edu.

ABSTRACT

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available.

Methods: Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis.

Results: Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.

Conclusions: Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

No MeSH data available.


Related in: MedlinePlus