PubMed Health⌕ Search

Biomedical subjects

W E Kaufmann

Publications and source records attributed to W E Kaufmann.

At least 19 recordsLinked to original sources
PubMed2002

Disproportionate increases of white matter in right frontal lobe in Tourette syndrome.

OBJECTIVE: Based on previous findings implicating abnormalities of cortico-striatal-thalamo-cortical circuitry in Tourette syndrome (TS), the authors performed a volumetric analysis of frontal and nonfrontal tissue (gray + white matter) in boys with TS, with and without attention deficit hyperactivity disorder (ADHD). METHODS: Frontal and nonfrontal gray and white matter compartment volumes, obtained by a MRI protocol, were analyzed with a 2 x 2 factorial multivariate analysis of variance approach for associations with a TS or ADHD factor in 11 boys with TS only, 14 with TS + ADHD, 12 with ADHD only, and 26 healthy boys. RESULTS: In subjects with TS, the right frontal lobe showed a larger proportion of white matter. In addition, results were consistent with previous reports of reduced frontal lobe volumes associated with ADHD. Our analyses suggested these reductions to be mainly the consequence of smaller gray matter volumes, particularly on the left. CONCLUSIONS: These findings, suggesting the volumetric composition of frontal lobe tissue to be different in TS, support the hypothesis proposing frontostriatal pathway involvement in the pathophysiology of the disorder. Differences in composition of right frontal lobe attributable to white matter do not definitively implicate the hypothesized fiber pathways; however, considered in the context of the unilateral directionality of frontal-striatal circuitry, these results suggest the white matter connections as one explanation for basal ganglia anomalies (loss of normal left > right asymmetry) in TS.

Adolescent↗
PubMed2001

Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice.

The cyclooxygenases catalyze the rate-limiting step in the formation of prostaglandins from arachidonic acid and are the pharmacological targets of (NSAIDs). In brain, cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is selectively expressed in neurons of the cerebral cortex, hippocampus, and amygdala. As an immediate-early gene, COX-2 is dramatically and transiently induced in these neurons in response to NMDA receptor activation. In models of acute excitotoxic neuronal injury, elevated and sustained levels of COX-2 have been shown to promote neuronal apoptosis, indicating that upregulated COX-2 activity is injurious to neurons. COX-2 may also contribute to the development of Alzheimer's disease, for which early administration of NSAIDs is protective against development of the disease. To test the effect of constitutively elevated neuronal COX-2, transgenic mice were generated that overexpressed COX-2 in neurons and produced elevated levels of prostaglandins in brain. In cross-sectional behavioral studies, COX-2 transgenic mice developed an age-dependent deficit in spatial memory at 12 and 20 months but not at 7 months and a deficit in aversive behavior at 20 months of age. These behavioral changes were associated with a parallel age-dependent increase in neuronal apoptosis occurring at 14 and 22 months but not at 8 months of age and astrocytic activation at 24 months of age. These findings suggest that neuronal COX-2 may contribute to the pathophysiology of age-related diseases such as Alzheimer's disease by promoting memory dysfunction, neuronal apoptosis, and astrocytic activation in an age-dependent manner.

Aging↗
PubMed2001

Annexin-1 is abnormally expressed in fragile X syndrome: two-dimensional electrophoresis study in lymphocytes.

The search for targets of FMRP (the product of FMR1, the mutated gene in Fragile X syndrome) has predominantly focused on identifying transcripts that are regulated by this RNA-binding protein. This study introduces the use of two-dimensional gel electrophoresis (2D PAGE) as a novel approach for demonstrating changes in protein synthesis secondary to FMRP deficit. By a standardized 2D PAGE protocol, we studied leukocyte homogenates from 30 males with different patterns of FMR1 mutation and different levels of FMRP. Samples from these subjects were compared to those of 12 normal control males and eight subjects with other mental retardation-associated conditions (i.e., Rett and Down syndromes). We found an abnormal pattern of a major leukocytic protein, identified by 2D PAGE datasets and immunoblotting as annexin-1 (Anx-1). Anx-1 appeared in subjects with Fragile X as multiple rather than 1-2 spots, at approximately 37 kd, in the pI 5-7 range. The presence and intensity of this Anx-1 pattern was relatively independent of Anx-1 levels and inversely related to total and high MW FMRP immunoreactivities. Based on the 2D PAGE pattern, without obvious MW change, and on dephosphorylation assays, we concluded that Anx-1's abnormality represents an aberrant posttranslational modification other than phosphorylation. Comparisons of our data with published cytoskeletal protein 2D profiles suggest that Anx-1 may be abnormally acetylated and, consequently, incapable of establishing appropriate N-terminal protein-protein interactions. In addition to its peripheral anti-inflammatory function, Anx-1 mediates glucocorticoid inhibition of the hypothalamo-pituitary-adrenal axis. As the latter seems to be disrupted in Fragile X syndrome, the reported Anx-1 abnormality could be responsible for some aspects of the Fragile X neurobehavioral phenotype. Our data also emphasize the feasibility of using 2D PAGE for disclosing molecular abnormalities in Fragile X and other genetic disorders.

Adolescent↗
PubMed2001

Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis.

BACKGROUND: Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. METHODS: Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. RESULTS: Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. CONCLUSIONS: The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome.

Adolescent↗
PubMed2001

Diffusion tensor imaging of the developing mouse brain.

It is shown that diffusion tensor MR imaging (DTI) can discretely delineate the microstructure of white matter and gray matter in embryonic and early postnatal mouse brains based on the existence and orientation of ordered structures. This order was found not only in white matter but also in the cortical plate and the periventricular zone, which are precursors of the cerebral cortex. This DTI-based information could be used to accomplish the automated spatial definition of the cortical plate and various axonal tracts. The DTI studies also revealed a characteristic evolution of diffusion anisotropy in the cortex of the developing brain. This ability to detect changes in the organization of the brain during development will greatly enhance morphological studies of transgenic and knockout models of cortical dysfunction. Magn Reson Med 46:18-23, 2001.

Animals↗
PubMed2001

Gene expression profiling in postmortem Rett Syndrome brain: differential gene expression and patient classification.

The identification of mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MECP2) gene in Rett Syndrome (RTT) suggests that an inappropriate release of transcriptional silencing may give rise to RTT neuropathology. Despite this progress, the molecular basis of RTT neuropathogenesis remains unclear. Using multiple cDNA microarray technologies, subtractive hybridization, and conventional biochemistry, we generated comprehensive gene expression profiles of postmortem brain tissue from RTT patients and matched controls. Many glial transcripts involved in known neuropathological mechanisms were found to have increased expression in RTT brain, while decreases were observed in the expression of multiple neuron-specific mRNAs. Dramatic and consistent decreases in transcripts encoding presynaptic markers indicated a specific deficit in presynaptic development. Employing multiple clustering algorithms, it was possible to accurately segregate RTT from control brain tissue samples based solely on gene expression profile. Although previously achieved in cancers, our results constitute the first report of human disease classification using gene expression profiling in a complex tissue source such as brain.

Adolescent↗
PubMed2001

Diffusion tensor imaging and axonal tracking in the human brainstem.

Diffusion tensor MRI was used to demonstrate in vivo anatomical mapping of brainstem axonal connections. It was possible to identify the corticospinal tract (CST), medial lemniscus, and the superior, medial, and inferior cerebellar peduncles. In addition, the cerebral peduncle could be subparcellated into component tracts, namely, the frontopontine tract, the CST, and the temporo-/parieto-/occipitopontine tract. Anatomical landmarks and tracking thresholds were established for each fiber and, using these standards, reproducibility of automated tracking as assessed by intra- and interrater reliability was found to be high (kappa > 0.82). Reconstructed fibers corresponded well to existing anatomical knowledge, validating the tracking. Information on the location of individual tracts was coregistered with quantitative MRI maps to automatically measure MRI parameters on a tract-by-tract basis. The results reveal that each tract has a unique spatial signature in terms of water relaxation and diffusion anisotropy.

Adult↗
PubMed2001

Neuroimaging studies in Rett syndrome.

Neuroimaging is a key instrument for determining structural and in vivo functional status of the brain, non-invasively. Multiple approaches can now determine aspects of anatomic and neurochemical changes in brain, and have been utilized effectively in Rett Syndrome patients to understand the biological basis of this neurodevelopmental disorder. Studies performed at our institute include volumetric analyses of MRI, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), cerebral blood flow measurements with MRI, and positron emission tomography scans (PET). These studies have provided considerable insight into mechanisms underlying the clinical features of this disease. Volumetric analyses suggest that decreased brain volume in RS results from global reductions in both gray and white matter of the brain. A selective vulnerability of the frontal lobes is evidenced by the preferential reduction of blood flow, increased choline and reduced n-acetyl aspartate (NAA) by MRS, and increased glucose uptake in these same regions as shown by ((18)F)-fluorodeoxyglucose (FDG) PET scans. We hypothesize that the increased glucose uptake relates to increased glutamate cycling in synapses. The resulting neuroexcitotoxic injury to the developing brain contributes to the seizures, behavioral disturbance and respiratory irregularities commonly seen in phases 1 and 2 of this disorder.

Adolescent↗
PubMed2000

Quantitative 1H MR spectroscopic imaging in early Rett syndrome.

OBJECTIVE: To determine cerebral regional concentrations of N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cr) in Rett syndrome (RS) using 1H magnetic resonance spectroscopic imaging (MRSI). BACKGROUND: The biochemical defect underlying RS is unknown. Because in vivo MRSI can detect important cerebral metabolites, MRSI has a potential to reveal impairment of regional cerebral metabolism in RS noninvasively. METHODS: High-resolution, multislice 1H MRSI was carried out in 17 girls with RS. The control group consisted of nine healthy children. RESULTS: In patients with RS, average Cho concentration was 12% higher (p < 0.005) and average NAA concentration 11% lower (p < 0.0001) compared with the control group. Regional metabolic differences included significantly lower NAA concentration in the frontal gray and white matter, insula, and hippocampus in RS; no difference in regional Cho and Cr concentrations were found. A 20 to 38% higher Cho:NAA ratio in frontal and parietal gray and white matter, insular gray matter, and hippocampus (p < 0.05) and a 14 to 47% lower NAA:Cr ratio in frontal cortical gray matter, parietal and temporal white matter, insula, and putamen (p < 0.05) were found in subjects with RS compared with controls. Patients with seizures had higher average concentrations of Cho, Cr, and NAA compared with those without seizures (8-19%, p < 0.05). CONCLUSION: Metabolic impairment in RS involves both gray and white matter and particularly involves frontal and parietal lobes and the insular cortex. Loss of NAA most likely reflects reduced neuronal and dendritic tree size; increased Cho concentration may result from gliosis.

Analysis of Variance↗
PubMed2000

Dendritic anomalies in disorders associated with mental retardation.

Dendritic abnormalities are the most consistent anatomical correlates of mental retardation (MR). Earliest descriptions included dendritic spine dysgenesis, which was first associated with unclassified MR, but can also be found in genetic syndromes associated with MR. Genetic disorders with well-defined dendritic anomalies involving branches and/or spines include Down, Rett and fragile-X syndromes. Cytoarchitectonic analyses also suggest dendritic pathology in Williams and Rubinstein-Taybi syndromes. Dendritic abnormalities appear to have syndrome-specific pathogenesis and evolution, which correlate to some extent with their cognitive profile. The significance of dendritic pathology in synaptic circuitry and the role of animal models in the study of MR-associated dendritic abnormalities are also discussed. Finally, a model of genotype to neurologic phenotype pathway in MR, centered in dendritic abnormalities, is postulated.

Animals↗
PubMed2000

Dendritic cytoskeletal protein expression in mental retardation: an immunohistochemical study of the neocortex in Rett syndrome.

Many syndromes associated with mental retardation (MR) are characterized by cortical dendritic anomalies. Despite their morphological similarity, these changes appear to involve different stages of dendritic development. The neuronal cytoskeleton, which includes microfilaments, neurofilaments and microtubules, is essential for these developmental processes. Levels and phosphorylation of microtubule-associated proteins (MAPs), which stabilize microtubules, seem to determine different stages of dendritic formation with certain MAPs (e.g. MAP-2) appearing to mediate the effects of external modulators upon these processes. Early studies on neuronal cytoskeleton in MR, which have shown a selective reduction in MAP-2 expression, have focused on Rett syndrome (RS). Here, by a semiquantitative immunohistochemical analysis of the pericentral cortex, we examine the contribution of specific neuronal populations to these changes in cytoskeletal proteins. Decreased MAP-2 staining in RS was more marked in layers V-VI, while increased nonphosphorylated neurofilament immunoreactivity was found in layers II-III in RS. Age-related increases in dendritic MAP-2 immunoreactivity in layers V-VI were also absent in RS. The specificity of these cytoskeletal protein changes, their significance for RS pathogenesis and plasticity, as well as their implications for other MR-associated disorders, are also discussed.

Adolescent↗
PubMed2000

Relationship of cognitive functioning, whole brain volumes, and T2-weighted hyperintensities in neurofibromatosis-1.

Using quantitative magnetic resonance imaging morphometry, we report that the whole brain volumes of patients with neurofibromatosis-1 are significantly larger than normal, confirm the prevalence of macrocephaly as about 50%, and report that macrocephaly in patients with neurofibromatosis-1 does not appear to be related to the familial or sporadic origin of the neurofibromatosis-1 or to the presence or absence of T2-weighted hyperintensities. No strong relationship emerged between the extent of neurofibromatosis-1-associated impairment of cognitive functions and degree of macrocephaly; however, the macrocephalic neurofibromatosis-1 group did have a significant verbal impairment relative to the nonmacrocephalic neurofibromatosis-1 group in vocabulary (P < .009).

Adolescent↗
PubMed2000

Thalamic involvement in neurofibromatosis type 1: evaluation with proton magnetic resonance spectroscopic imaging.

Neurofibromatosis type 1 is a common autosomal dominant disorder associated with learning disabilities. In addition to gliomas and other tumors, T2 hyperintense lesions (unidentified bright objects or UBOs) are frequently found in the globus pallidus, cerebellum, and white matter regions. To better characterize supratentorial UBO functional significance, we studied by quantitative magnetic resonance spectroscopic imaging (MRSI) 9 male subjects with neurofibromatosis type 1 (age, 6-19 years) and 9 age-matched and sex-matched controls. Maps of the anatomical distribution of the metabolites choline (Cho), N-acetylaspartate (NAA), and creatine were calculated in four axial 15-mm slices. Absolute metabolite concentrations within UBOs, unaffected globus pallidus, and thalami demonstrated an age-related pattern, characterized by elevated Cho and relatively preserved NAA in younger subjects (<10 years) and reduced NAA and normal Cho in older subjects. These changes were found in both UBOs and thalami but were only significant for NAA, NAA/creatine, and NAA/Cho in the latter region. Decreases in NAA ratios were most severe in the thalami of subjects with UBOs in the globus pallidus, whereas UBOs showed similar but milder abnormalities than those in the thalamus. We speculate that the MRSI metabolic abnormality may represent a more generalized phenomenon, without a T2 signal counterpart in the affected brain regions. Based on the neuropathological study by DiPaolo and colleagues (1995), we postulate that Cho elevations reflect increased myelin turnover in areas of intramyelinic edema, which is followed by neuropil injury (reduced NAA). Temporal progression and behavioral correlates of these MRSI changes deserve further exploration.

Adolescent↗
PubMed1999

Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children.

This study applied a Talairach-based automated parcellation method, originally proposed for adults, to the measurement of lobar brain regions in pediatric study groups. Manual measures of lobar brain regions in a sample of 15 healthy boys, girls and adults were used initially to revise the original Talairach-based grid to increase its applicability to pediatric brains. The applicability of the revised Talairach grid was then tested on an independent sample of five girls with Rett syndrome. As Tables 3 and 4 in the text demonstrate, sensitivity, specificity and positive predictive values either remained unchanged or increased as a result of revising the sectors to fit the brains of children. High levels of sensitivity and specificity were achieved for all revised Talairach-based calculations in relation to the manual measures. Both positive predictive values and intraclass correlations between volumetric measures produced by the revised automated and manual methods varied with the relative size of the brain region. Values were relatively low for smaller structures such as the brainstem and subcortical region, and high for lobar regions. These results suggest that the automated Talairach atlas-based parcellation method can produce sensitive and specific volumetric measures of lobar brain regions in both normal children and children with brain disorders. Accordingly, the method holds much promise for facilitating quantitative pediatric neuroimaging research.

Adult↗
PubMed1999

Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome.

The study of the neurobehavioral consequences of mutations of FMR1, the gene responsible for fragile X syndrome (FraX), has been based largely on correlations between mutation patterns and cognitive profile. Following the characterization of FMRP, the FMR1 gene product, preliminary correlations between FMRP levels, and neurologic phenotype have been established. However, most of these investigations have focused on individuals at both ends of the genetic and cognitive spectra of FraX, subjects with normal or premutation (PM) alleles or males with the FMR1 full mutation (FM). The present study is designed to characterize FMRP expression and to correlate it with IQ, in a sample representing a wide spectrum of FMR1 mutations. For this purpose we developed a highly sensitive immunoblotting assay using peripheral leukocytes. Three distinct patterns of FMRP immunoreactivity (-ir) emerged. Individuals with normal (n = 28) and PM (n = 8) alleles as well as most females with the FM (n = 14) showed the highest levels with multiple approximately 70-80 kDa FMRP-ir bands. Males with the FM (n = 10) demonstrated only a 70 kDa FMRP-ir band, and had significantly lower levels when compared with any previous groups. Males with mosaicism and three of 14 females with FM displayed a doublet with equal amounts of the highest and lowest molecular weight FMRP-ir bands. Multiple regression models that adjust for the effect of parental IQ indicated that both activation ratio and FMRP-ir are significantly correlated to subject IQ. We conclude that FMRP-ir offers promise as an indicator of the impact of FMR1 mutations upon neurologic function. Furthermore, our unexpected finding of FMRP-ir in all males with FM suggests that most of them are not transcriptionally silent.

Adolescent↗
PubMed1999

FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome.

The fragile X mental retardation 1 gene (FMR1) mutation is strongly correlated with specific and marked neurobehavioral and neuroanatomical abnormalities. The protein product, FMRP, is highly expressed in neurons of the normal mammalian brain, and absent or in low levels in leukocytes from individuals with fragile X (FraX)-associated mental impairment. Inferences which arise from these findings are that FMRP has a critical role in the development and functioning of the brain, and that leukocyte-derived molecular assessments provide a good indicator of FMR1 expression in that organ. This latter conclusion appears true in most cases even though the typical FMR1 mutation is an unstable triplet repeat expansion which demonstrates somatic heterogeneity within and across tissues. Blood to brain correspondence in FraX patients has only rarely been confirmed by the direct study of human brain specimens and, to our knowledge, it has never been studied in living individuals with the FMR1 mutation. In this report, we describe the FMR1 patterns in olfactory neuroblasts (ON) from two living brothers with expansion mutations in their leukocytes who are mentally retarded and autistic. ON were chosen for study because they are accessible neurons closely linked to the brain. In both subjects, the ON genotype was highly, but not perfectly, consistent with that observed in leukocytes. Protein phenotypes across tissues were completely consistent showing the absence of FMRP-immunoreactivity (-ir). These results augment the limited amount of direct evidence which indicates that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain. This report further demonstrates the feasibility of using ON samples to evaluate the FMR1 mutation in humans in vivo.

Adult↗