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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

Hippocampal formation. Images of the hippocampal formation at the level of the lateral geniculate body from (A) patient 1 and (C) patient 3 show abnormal expansion of CA1 by increased numbers of pyramidal neurons. These are compared with the more usual hippocampal microarchitecture that shows a thinner linear band of neurons in CA1, as seen in (B) a 62-year-old male control. Haematoxylin and eosin, original magnification ×10; scale bar = 1 mm. Arrow indicates bulge/expansion composed of increased numbers of pyramidal cells in (A) patient 1 and (C) patient 3.
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Figure 1: Hippocampal formation. Images of the hippocampal formation at the level of the lateral geniculate body from (A) patient 1 and (C) patient 3 show abnormal expansion of CA1 by increased numbers of pyramidal neurons. These are compared with the more usual hippocampal microarchitecture that shows a thinner linear band of neurons in CA1, as seen in (B) a 62-year-old male control. Haematoxylin and eosin, original magnification ×10; scale bar = 1 mm. Arrow indicates bulge/expansion composed of increased numbers of pyramidal cells in (A) patient 1 and (C) patient 3.

Mentions: Because the structural features of the CA1/Sommer sector of the hippocampus were overshadowed by ischemic changes in patient 2, we limited our analysis of hippocampal microscopic structure to patients 1 and 3. In both cases, in several sections throughout the hippocampus evaluated, CA1 had similar abnormalities in the microanatomic organization of the pyramidal cell layer. There was a bulge or expansion composed of increased numbers of pyramidal cells (Figure 1) arranged in an undulating pattern. In neighboring regions, there appeared to be a reduction in pyramidal cell number. In all three cases, the penetrating cortical arterioles of the temporal cortex showed vascular hyalinosis. These vessel walls were negative for amyloid birefringence with Congo red stain, and showed faint staining with ß-amyloid antibody (not shown). Immunostaining was negative in brain parenchyma for β-amyloid, α-synuclein, ubiquitin and tau, stains that are routinely used for the neuropathologic diagnosis of the most commonly occurring neurodegenerative disorders, such as Alzheimer's disease, Lewy Body disease and frontotemporal dementia.


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)

Hippocampal formation. Images of the hippocampal formation at the level of the lateral geniculate body from (A) patient 1 and (C) patient 3 show abnormal expansion of CA1 by increased numbers of pyramidal neurons. These are compared with the more usual hippocampal microarchitecture that shows a thinner linear band of neurons in CA1, as seen in (B) a 62-year-old male control. Haematoxylin and eosin, original magnification ×10; scale bar = 1 mm. Arrow indicates bulge/expansion composed of increased numbers of pyramidal cells in (A) patient 1 and (C) patient 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Hippocampal formation. Images of the hippocampal formation at the level of the lateral geniculate body from (A) patient 1 and (C) patient 3 show abnormal expansion of CA1 by increased numbers of pyramidal neurons. These are compared with the more usual hippocampal microarchitecture that shows a thinner linear band of neurons in CA1, as seen in (B) a 62-year-old male control. Haematoxylin and eosin, original magnification ×10; scale bar = 1 mm. Arrow indicates bulge/expansion composed of increased numbers of pyramidal cells in (A) patient 1 and (C) patient 3.
Mentions: Because the structural features of the CA1/Sommer sector of the hippocampus were overshadowed by ischemic changes in patient 2, we limited our analysis of hippocampal microscopic structure to patients 1 and 3. In both cases, in several sections throughout the hippocampus evaluated, CA1 had similar abnormalities in the microanatomic organization of the pyramidal cell layer. There was a bulge or expansion composed of increased numbers of pyramidal cells (Figure 1) arranged in an undulating pattern. In neighboring regions, there appeared to be a reduction in pyramidal cell number. In all three cases, the penetrating cortical arterioles of the temporal cortex showed vascular hyalinosis. These vessel walls were negative for amyloid birefringence with Congo red stain, and showed faint staining with ß-amyloid antibody (not shown). Immunostaining was negative in brain parenchyma for β-amyloid, α-synuclein, ubiquitin and tau, stains that are routinely used for the neuropathologic diagnosis of the most commonly occurring neurodegenerative disorders, such as Alzheimer's disease, Lewy Body disease and frontotemporal dementia.

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