Ronald C. Kim

Gene expression changes in the course of normal brain aging are sexually dimorphic.

Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20–99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea.

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

Do radial glia give rise to both astroglial and oligodendroglial cells

Abstract The development and differentiation of glial cells in the human fetal spinal cord was studied by correlative electron microscopic and immunohistochemical analysis in 20 embryos and fetuses between 6 and 17 weeks of ovulation age. Gliogenesis is characterized initially by the formation of radial glia and astroglia and subsequently, when myelination is about to begin, by the formation of oligodendroglia. The radial glial origin of astroglial cells has previously been demonstrated. The finding of ‘transitional’ cells with cytological, ultrastructural and immunohistochemical features intermediate between those of astroglial and oligodendroglial cells and the close relationship that develops between astroglial cells and axons just prior to the onset of myelination suggest that oligodendroglia may also be derived from radial glial cells, either directly or through intermediate astroglial forms.

SPECT in dementia : clinical and pathological correlation

BACKGROUND: The clinical diagnosis of dementia continues to be flawed. Although the diagnosis of Alzheimers disease (AD) is better than 90% at research centers in highly selected patients, the diagnosis of patients with non‐AD dementias and atypical AD patients is poor. Single photon emission computed tomography (SPECT) is a functional imaging technique touted as a diagnostic technique for the degenerative disorders. However there have been few clinicopathological studies using SPECT.

Altered white matter integrity in temporal lobe epilepsy: association with cognitive and clinical profiles

Purpose:  Diffusion tensor imaging (DTI) studies have reported substantial white matter abnormalities in patients with temporal lobe epilepsy (TLE). However, limited data exist regarding the extent of white matter tract abnormalities, cognitive effects of these abnormalities, and relationship to clinical factors. The current study examined these issues in subjects with chronic TLE.

DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).

Cerebral Microbleeds in the Elderly: A Pathological Analysis

Background and Purpose— Cerebral microbleeds in the elderly are routinely identified by brain MRI. The purpose of this study was to better characterize the pathological basis of microbleeds. Methods— We studied postmortem brain specimens of 33 individuals with no clinical history of stroke and with an age range of 71 to 105 years. Cerebral microbleeds were identified by presence of hemosiderin (iron), identified by routine histochemistry and Prussian blue stain. Cellular localization of iron (in macrophages and pericytes) was studied by immunohistochemistry for smooth muscle actin, CD68, and, in selected cases, electron microscopy. Presence of &bgr;-amyloid was analyzed using immunohistochemistry for epitope 6E10. Results— Cerebral microbleeds were present in 22 cases and occurred at capillary, small artery, and arteriolar levels. Presence of microbleeds occurred independent of amyloid deposition at site of microbleeds. Although most subjects had hypertension, microbleeds were present with and without hypertension. Putamen was the site of microbleeds in all but 1 case; 1 microbleed was in subcortical white matter of occipital lobe. Most capillary microbleeds involved macrophages, but the 2 microbleeds studied by electron microscopy demonstrated pericyte involvement. Conclusions— These findings indicate that cerebral microbleeds are common in elderly brain and can occur at the capillary level.

Altered distribution of excitatory amino acid receptors in temporal lobe epilepsy

In temporal lobe epilepsy, excitatory amino acid receptors in the hippocampus and temporal lobe may contribute to both increased excitability and vulnerability to excitotoxic damage. We used receptor autoradiography to examine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors in the hippocampus and parahippocampal gyrus obtained from five patients who had undergone anterior temporal lobectomy for the treatment of intractable seizures and from six control individuals, in which the hippocampus was obtained postmortem. Within the hippocampal formation, loss of [3H]KA and NMDA-sensitive L-[3H]glutamate binding was apparent in the sclerotic regions CA3, hilus, and CA1. In the subiculum and molecular layer of the denate gyrus, binding densities were maintained or even increased in some of the epileptic patients. A two-fold increase in L-[3H]glutamate binding, along with an increase in [3H]KA binding, was observed in the parahippocampal gyrus obtained from the epileptic patients. The results suggest that the vulnerability of the hippocampus in temporal lobe epilepsy may result, at least in part, from the presence of aberrant excitatory circuits in the parahippocampal gyrus.

Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study.

Objective: The purpose of this study was to examine the role of multiple pathologies in the expression of dementia in the oldest-old. Methods: A total of 183 participants of The 90+ Study with longitudinal follow-up and autopsy were included in this clinical-pathologic investigation. Eight pathologic diagnoses (Alzheimer disease [AD], microinfarcts, hippocampal sclerosis, macroinfarcts, Lewy body disease, cerebral amyloid angiopathy, white matter disease, and others) were dichotomized. We estimated the odds of dementia in relation to each individual pathologic diagnosis and to the total number of diagnoses. We also examined dementia severity in relation to number of pathologic diagnoses. Results: The presence of multiple pathologic diagnoses was common and occurred more frequently in those with dementia compared with those without dementia (45% vs 14%). Higher numbers of pathologic diagnoses were also associated with greater dementia severity. Participants with intermediate/high AD pathology alone were 3 times more likely to have dementia (odds ratio = 3.5), but those with single non-AD pathologies were 12 times more likely to have dementia (odds ratio = 12.4). When a second pathology was present, the likelihood of dementia increased 4-fold in those with intermediate/high AD pathology but did not change in those with non-AD pathologies, suggesting that pathologies may interrelate in different ways. Conclusions: In the oldest-old, the presence of multiple pathologies is associated with increased likelihood and severity of dementia. The effect of the individual pathologies may be additive or perhaps synergistic and requires further research. Multiple pathologies will need to be targeted to reduce the burden of dementia in the population.

Increased expression of the embryonic form of a developmentally regulated mRNA in Alzheimer's disease

There is increasing evidence that an aberrant sprouting response may contribute to some of the neuronal alterations observed in Alzheimers disease (AD). In this study, we demonstrate that in the rat CNS, sprouting results in the reinduction of the embryonic form of the mRNA for alpha-tubulin. The fetal form of alpha-tubulin mRNA was also elevated in the hippocampus obtained from five AD patients, as compared to five elderly controls. These results suggest that the reexpression of embryonic forms of cytoskeletal proteins, in association with an aberrant sprouting response, may contribute to the neuropathological alterations in AD.