Posterior cortical atrophy: neuropathological correlations.
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Alzheimer Disease↗
Biomedical subjects
H B Clark
Publications and source records attributed to H B Clark.
Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.
Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
Age of Onset↗
The impact of intensive case-managed intervention on substance-using pregnant and postpartum women.
This study examines the impact of the Women's Intervention Services and Education (WISE) Project in serving substance-using pregnant and postpartum women through an array of case-managed services and supports. A descriptive analysis of multiple outcome indicators was performed on 152 women who had a minimum 6 months of exposure to WISE services at the time of the analysis. The variables used in the analysis to assess client and program outcomes included substance use, employment, arrests, incarceration, birthweight, and social support. This group of women showed statistically significant improvements across each of these multiple outcome indicators from pre-WISE to WISE discharge. Although the findings of this study are not conclusive because no control group was employed, the results are encouraging and supportive of a growing body of literature that suggests that pregnant and postpartum polydrug-using women can be responsive to case-managed, intensive intervention, with aftercare support.
Adult↗
Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia.
BACKGROUND AND PURPOSE: We investigated whether inducible nitric oxide synthase (iNOS) is expressed after transient cerebral ischemia and, if so, we sought to define the temporal profile and cellular localization of the expression and the role of iNOS in the mechanism of ischemic brain injury. METHODS: The middle cerebral artery in rats was occluded for 2 hours by an intraluminal filament. The occurrence of transient ischemia and reperfusion was confirmed by laser-Doppler flowmetry (n = 5). iNOS message in the ischemic neocortex was determined by reverse-transcription polymerase chain reaction. iNOS enzymatic activity was assessed by citrulline assay. The cellular localization of iNOS expression was determined by immunohistochemistry. RESULTS: iNOS mRNA was maximally expressed in postischemic brain at 12 hours and was not present at 4 days (n = 3 per time point). iNOS mRNA was not observed in the contralateral cerebral cortex. iNOS enzymatic activity developed in the postischemic brain between 12 and 24 hours (P < .05) and subsided at 4 days (n = 4 to 8 per time point). iNOS immunoreactivity in the ischemic region was restricted to the wall of capillaries and of larger blood vessels at 12 to 24 hours. In regions of early necrosis, inflammatory cells were iNOS positive. Treatment with the iNOS inhibitor aminoguanidine (n = 5; 100 mg/kg IP, BID for 4 days), starting 6 hours after ischemia, reduced infarct size in neocortex by 36 +/- 7% in comparison with vehicle-treated controls (n = 5) (P < .05). CONCLUSIONS: Transient focal ischemia leads to iNOS expression in postischemic brain. However, the spatial and temporal patterns of expression differ from those occurring in permanent ischemia: iNOS is induced earlier and predominantly in vascular cells rather than in neutrophils. Thus, the temporal profile and localization of postischemic iNOS expression depend on the nature of the ischemic insult. The finding that aminoguanidine reduces infarct size adds further support to the hypothesis that postischemic iNOS expression contributes to ischemic brain damage.
Animals↗
SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration. These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions.
Animals↗
Multifocal enhancing magnetic resonance imaging lesions following cranial irradiation.
Radiation necrosis is a delayed complication of cranial irradiation, typically presenting as a single intracerebral mass that is radiographically indistinguishable from recurrent tumor. We describe 6 patients with a distinct radiographic syndrome of multifocal enhancing lesions on magnetic resonance images, and their variable clinical courses: some fluctuating, some spontaneously resolving, and some demonstrating fulminant progression to frank necrosis.
Adult↗
In vivo viability of postmitotic Purkinje neurons requires pRb family member function.
The product of the retinoblastoma susceptibility gene, pRb, is known to be an important regulator of cell division. Disrupted central nervous system development in RB null mice suggests a critical function for pRb in the proliferative arrest and initiation of terminal differentiation of certain neurons. Previously, we have shown that SV40 T-ag expression targeted to Purkinje neurons in transgenic mice causes cell-specific death. Here we describe that T-ag expression induces DNA synthesis and results in DNA fragmentation in Purkinje neurons. Characterization of transgenic mouse lines expressing mutant T-ags demonstrate that the pRb binding domain of T-ag is required for induction of Purkinje cell loss. These findings indicate that a pRb function is required well beyond the completion of Purkinje neuron differentiation and provide a link between cell cycle regulation and neurodegeneration in vivo.
Animals↗
Sacrococcygeal chordoma metastatic to the brain with review of the literature.
A 29-year-old man presented with headache, confusion, word-finding difficulty, and a visual field deficit 16 months after complete removal of a sacrococcygeal chordoma. Magnetic resonance imaging of the head demonstrated two discrete enhancing left occipital lesions with associated cerebral edema. Both masses were surgically excised and their histological appearance was consistent with chordoma. Chordoma from the sacral region is known to metastasize to the lungs and the vertebral bodies but has rarely been shown to spread to the brain. Dissemination to the brain in this case may be related to the extent of the metastatic pulmonary disease and the anaplastic appearance of the primary tumor.
Adult↗
Sneddon's syndrome with granulomatous leptomeningeal infiltration.
BACKGROUND: There is limited neuropathologic information available from cases of Sneddon's syndrome in which strokes are associated with livedo reticularis. Pathogenesis of the syndrome is controversial, although current opinion favors a coagulopathy, often with antiphospholipid antibodies. We describe a case lacking antiphospholipid antibodies but having a granulomatous infiltration of the leptomeninges. CASE DESCRIPTION: The patient presented at age 29 with stroke, livedo reticularis, essential hypertension, and Raynaud's phenomenon. Assessment uncovered no underlying disease, including absent antiphospholipid antibodies. A leptomeningeal biopsy showed granulomatous infiltration. CONCLUSIONS: The findings suggest that an inflammatory process plays a role in at least some cases of Sneddon's syndrome.
Adult↗
Stereotactic radiosurgery for recurrent malignant gliomas.
PURPOSE: To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS: We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS: The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION: Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.
Actuarial Analysis↗
Middle cerebral artery dissection: a clinicopathologic study.
We present a case report of a 17-year-old young man who developed fatal dissection of the middle cerebral artery after what appeared to be trivial trauma. The dissection was not evident on cerebral arteriogram but was identified at autopsy. Arterial dissection should be considered in the differential diagnosis of supraclinoid occlusion of the internal carotid artery seen by cerebral angiography.
Adolescent↗
Genetic approaches to pathogenesis of neurodegenerative diseases.
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Animals↗
Case management of pregnant and parenting female crack and polydrug abusers.
The increasing use of crack-cocaine among addicted women and subsequent births of polydrug-exposed infants prompted the State of Florida to undertake initiatives to seek solutions to these problems. This study, focused on one of these initiatives, explored the relationship between service components of a comprehensive treatment program and substance-free time among 120 African American and Caucasian crack-cocaine addicted women. Findings from a multiple regression analysis indicated that aftercare management (p < .0001), vocational services (p < .02), and residential treatment (p < .03) were statistically significant services associated with substance-free time. Although these findings are not conclusive, they are supportive of a growing body of literature that suggests that crack-using and polydrug-using women can be responsive to treatment when it is tailored to their individual needs and includes long-term community support.
Adolescent↗
Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice.
SV40 T antigen (Tag) expression directed to cerebellar Purkinje cells resulted in the generation of three transgenic mouse lines that displayed ataxia, a neurological phenotype characteristic of cerebellar dysfunction. Onset of symptoms and cerebellar pathology, characterized by specific Purkinje cell degeneration, appeared to be directly dependent upon transgene copy number. The SV5 line (containing > 30 transgene copies), exhibited embryonic transgene expression that caused selective death of immature Purkinje cells and a subsequent block in cerebellar development and ataxia at 2 weeks. The developmental effect of the disruption of Purkinje cells in SV5 mice suggests that a normal complement of these cells is required for early development of the cerebellar cortex, especially granule cell proliferation and migration from external to internal layers. Transgene expression in a second line, SV4 (10 copies), was detectable during the second postnatal week. Death of mature Purkinje cells in the SV4 line resulted in onset of ataxia at 9 weeks. Ataxia in a third line, SV6 (2 copies), was detected after 15 weeks. The distinct cerebellar phenotypes of the SV4-6 lines correlate with specific Tag-induced Purkinje cell ablation as opposed to tumorigenesis.
Animals↗
Peer support group for adolescents with chronic illness.
This study assessed the effects of a monthly peer support group for adolescents with cancer and other hematological diseases. These adolescents shared activities and experiences with nondisabled high school students. At the group's conclusion, the adolescents reported that the group helped them cope with their illness and improved the quality of their daily lives. Nondisabled students reported that the group favorably affected their attitudes about, and intended behavior toward, peers with chronic illnesses. These results suggest that such groups can provide important benefits for individuals with chronic illnesses as well as for their nondisabled peers.
Adaptation, Psychological↗
Metastatic carcinoid tumor to the orbit and brain.
Carcinoid tumors constitute an uncommon source of metastatic lesions to the brain. We report the case of a 63-year-old man who initially sought treatment for proptosis 15 years before coming to our attention with a metastatic intracerebral left parietal carcinoid. The pathological features of the exenterated orbital mass were interpreted as undifferentiated carcinoma, and a lesion of the left lower lobe of the lung that had been removed 6 years earlier had been reported as metastatic malignant melanoma. The long duration between the initial diagnosis and the onset of neurological symptoms brought into question the original diagnosis, which, in retrospect, was most consistent with metastatic carcinoid. Staining for cytokeratin, neuron-specific enolase, and synaptophysin in the absence of staining for S-100 and HMB-45 supported the revised pathological diagnosis. Metastatic intracerebral carcinoid from an unrecognized bronchogenic source is a rare event, particularly after an orbital metastasis, but should be suspected when the clinical course is inconsistent with the more common causes of metastatic disease.
Biomarkers, Tumor↗
Preventing relapse in obesity through posttreatment maintenance systems: comparing the relative efficacy of two levels of therapist support.
The present study compared the relative effectiveness of a therapist-supported maintenance condition with a minimal contact maintenance condition in preventing relapse following an obesity treatment program. Thirty-two subjects who completed an initial 12-week cognitive/behavioral plus aerobic exercise treatment program were matched on absolute weight loss and randomly assigned to one of two maintenance conditions. Subjects were assessed at pretreatment, posttreatment, and 3, 6, and 12 months following posttreatment using measures of weight, blood pressure, and depression. Three- and six-month follow-up results indicated that subjects who participated in the therapist-supported maintenance group continued to lose weight and/or maintained therapy-induced weight loss to a greater degree than control subjects. At the 12-month follow-up assessment therapist-supported subjects maintained therapy-induced weight loss better than the control subjects. These findings suggest that maintenance programs which provide continued contact emphasizing relapse prevention training may be an important adjunct in the maintenance of therapy-induced weight loss.
Adult↗
Nerve growth factor receptor in neural lobe of rat pituitary gland: immunohistochemical localization, biochemical characterization and regulation.
Nerve growth factor-receptor immunoreactivity was detected in the neural lobe of the pituitary gland in developing and adult rats of both sexes. The presence of nerve growth factor receptor in the neural lobe was further verified by a quantitative 125I-nerve growth factor/crosslink/immunoprecipitation assay and subsequent visualization by SDS-PAGE autoradiography. Nerve growth factor-receptor immunoreactivity was detected in the neural lobe of postnatal 5-day-old rats, had increased by 2 months and was much higher in 1-year-old rats. In 2-month-old rats, no immunoreactivity was observed in anterior or intermediate lobes. Pituitary stalk transection in young adult rats greatly increased the expression of nerve growth factor-receptor immunoreactivity in the neural lobe, although the staining pattern remained the same. This increase began 3 days after surgery, and reached peak levels at approximately 15 days. Other physiological or non-physiological changes did not alter the nerve growth factor-receptor immunoreactivity in the neural lobe; these changes included dehydration, pregnancy and lactation, castration of male rats, bilateral superior cervical ganglionectomy and intraventricular injection of colchicine. Intravenously injected 125I-nerve growth factor was specifically accumulated in both normal and denervated neural lobe. Nerve growth factor-receptor immunohistochemical electron microscopy showed that the receptor-positive cells are fusiform and found both inside and outside the basal lamina that delimits the neural lobe parenchyma. Based upon the anatomical localization, morphology and response to axotomy, we identify, at least the perivascular component, as microglia. These data suggest a role for nerve growth factor and/or nerve growth factor receptor in microglial function.
Animals↗