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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

Purkinje cell counts in the cerebellum. Purkinje cell (PC) counts in: (A) superior lobule; (B) posterior lobule; (C) inferior lobule; and (D) lateral cortex, in the three fragile X cases and age-matched controls.
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Figure 4: Purkinje cell counts in the cerebellum. Purkinje cell (PC) counts in: (A) superior lobule; (B) posterior lobule; (C) inferior lobule; and (D) lateral cortex, in the three fragile X cases and age-matched controls.

Mentions: Based on the cell-density measurements performed in the present study, there was a 52% reduction in PCs per mm in the superior lobule, a 54% reduction in the posterior lobule, a 49% reduction in the inferior lobule and a 58% reduction in the lateral cortex sample, compared with control cerebellar sections. There was no numerical overlap between counts of PCs between the cases and controls; all patients with FXS had clear reductions in PC density in all cerebellar regions evaluated (Figure 4A-D). These results suggest a global reduction in PC number in the patients with FXS relative to the age-matched non-FXS controls. This reduction in PC number was supported by the calbindin IF results.


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)

Purkinje cell counts in the cerebellum. Purkinje cell (PC) counts in: (A) superior lobule; (B) posterior lobule; (C) inferior lobule; and (D) lateral cortex, in the three fragile X cases and age-matched controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Purkinje cell counts in the cerebellum. Purkinje cell (PC) counts in: (A) superior lobule; (B) posterior lobule; (C) inferior lobule; and (D) lateral cortex, in the three fragile X cases and age-matched controls.
Mentions: Based on the cell-density measurements performed in the present study, there was a 52% reduction in PCs per mm in the superior lobule, a 54% reduction in the posterior lobule, a 49% reduction in the inferior lobule and a 58% reduction in the lateral cortex sample, compared with control cerebellar sections. There was no numerical overlap between counts of PCs between the cases and controls; all patients with FXS had clear reductions in PC density in all cerebellar regions evaluated (Figure 4A-D). These results suggest a global reduction in PC number in the patients with FXS relative to the age-matched non-FXS controls. This reduction in PC number was supported by the calbindin IF results.

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