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J C Morris

Publications and source records attributed to J C Morris.

287 records · Page 16Linked to original sources
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The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease.

Neurofibrillary tangles and senile plaques, together with cells immunoreactive for the Alz-50 antibody (A50-ir cells) or for an antibody against paired helical filaments (PHF-ir cells), and amyloid deposits stained with antibodies against beta-(or A4)-amyloid, have been mapped throughout the ventral forebrains of 25 old people. The cognitive status of each individual was assessed and a "Clinical Dementia Rating" (CDR) assigned, either before death in the Memory and Aging Project of Washington University, or by a postmortem interview, with an appropriate collateral source. The cases studied included 13 nondemented cases (CDR = 0), six very mildly to mildly demented cases (CDR = 0/0.5 to 1) and six more severely demented cases (CDR = 2 to 3). Because even the very mildly demented brains showed substantial pathological change, emphasis was placed on examining the nondemented cases for the earliest changes that could be associated with Alzheimer's disease. Different distributions were found for tangles and plaques. Tangles (and A50-ir and PHF-ir cells) were present in all of the brains examined. In the younger nondemented cases (aged 54 to 63) there were a few affected cells in the anterior olfactory nucleus and the parahippocampal gyrus. In older nondemented cases (aged 73-89) more tangles were found in the same areas, and also in hippocampal field CA1. The very mildly demented cases had many more tangles, but their distribution was similar. Only in the severely demented cases were large numbers of tangles present in the neocortex. In contrast, no plaques (or beta-amyloid immunoreactivity) were found in any of the younger nondemented cases or in four of the eight older nondemented cases. In three older nondemented cases there were a few primitive plaques, which were restricted to localized regions of the neocortex (e.g., a portion of the inferior temporal cortex). In one nondemented case and all of the very mildly to mildly demented cases there were very large numbers of mostly primitive plaques, particularly in the neocortex. With greater severity of dementia there is a shift from primitive to mature plaques. These results were interpreted to imply that the first development of tangles and plaques occurs in different parts of the brain. Tangles appear during aging in the anterior olfactory nucleus, the parahippocampal gyrus and the hippocampus, but are rare in the neocortex except in demented brains. Conversely plaques may develop first in the neocortex. Unlike tangles, plaques are not a consistent feature of aging, at least up to age 80.

Aged↗
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Sodium iodide symporter (NIS) gene expression in human placenta.

The placenta must allow the passage of iodide from the maternal to the fetal circulation for synthesis of thyroxine by the fetal thyroid. The thyroid sodium iodide symporter (NIS) was cloned in 1996 and, although widely distributed among epithelial tissues, early studies failed to detect it in placenta. We demonstrated NIS mRNA in human placenta and in the human choriocarcinoma cell line, JAr. NIS protein was localized to trophoblasts, with a tendency to apical distribution, in sections of human placenta immunostained with a monoclonal antibody against hNIS. We conclude that NIS is expressed in placenta and may mediate placental iodide transport.

Antibodies, Monoclonal↗
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Clinical trials in Alzheimer disease: debate on the use of placebo controls.

During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new therapeutic options are being developed as rapidly as possible. The arguments on each side of the debate are provocative and important but do not provide unequivocal justification for either the abandonment or the maintenance of placebo-controlled trials in all AD research. Clinical trials differ with respect to scientific and practical goals, and these factors inherently affect the ethical priorities of each study. We present these contrasting points of view to delineate some of the issues rather than to make specific recommendations other than to urge that all clinical trials in AD should be designed with careful consideration of the ethical issues surrounding the use of placebo controls. As new and more effective treatments emerge, the ethical framework for placebo use in AD studies will require frequent re-examination. To make wise choices, patients, caregivers, physicians, and ethicists (among others) must have a voice in this continuing discussion.

Alzheimer Disease↗
PubMedDate not supplied

Evidence that age-associated memory impairment is not a normal variant of aging.

The concept of age-associated memory impairment (AAMI) suggests that clinically recognized memory dysfunction can be a feature of normal aging. To determine whether AAMI represents a variant of normal aging, we longitudinally studied individuals meeting AAMI criteria for development of dementia. Two hundred two community-living individuals (mean age, 77 years) with or without mild memory impairment were assessed annually for an average of 3 years at the Washington University Alzheimer's Disease Research Center. At baseline, no individual was unequivocally demented, as defined by a Clinical Dementia Rating (CDR) score of 1 or greater. Modified National Institute of Mental Health criteria were used to identify individuals with AAMI who otherwise met a criterion for cognitive normality. The Short Blessed Test (SBT) was used as a measure of general cognitive function; conservative (SBT = 5) and permissive (SBT = 10) cutoff scores were used as indicators of cognitive normality. With the more permissive measure of cognitive normality, 59 (29%) of the 202 individuals met AAMI criteria. Progression to dementia by 3 years occurred in 42% of AAMI individuals versus 16% of the individuals who did not meet AAMI criteria. With the more restrictive SBT cutoff of 5, 22% of individuals met AAMI criteria; progression to dementia occurred in 31% of these individuals versus 9% of the individuals without AAMI. Survival times to dementia differed significantly between AAMI and non-AAMI groups defined by either cutoff score. Our findings indicate that individuals with AAMI have a three-fold greater risk for development of dementia than individuals who do not meet AAMI criteria. Hence, AAMI may represent a dementia prodrome rather than a benign variant of aging.

Aged↗
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Interobserver disagreements on clinical dementia rating assessment: interpretation and implications for training.

The Clinical Dementia Rating (CDR) is a widely used semiobjective instrument for staging dementia severity. A global CDR score is reported that is derived from individual scores in six domains. In this study, we examined both agreement and disagreement, among raters and with a gold standard, to identify domain-specific and global dementia severity level ratings that would most benefit from further training or greater emphasis in future training. We found that raters-in-training experienced the most difficulty with rating normal and questionable dementia. They also had the most trouble scoring the memory domain. When they disagreed with the gold standard, they nearly always gave higher ratings. A third, extremely experienced group of raters were uniform in their high levels of agreement on each domain and the global CDR and tended to give lower ratings if they disagreed with the gold standard. Analysis of the agreement and disagreement patterns suggested that greater emphasis on the memory, home and hobbies, and orientation domains during CDR training, and increasing the information provided for the judgment and problem solving domain on the standardized CDR worksheets, could improve the consistency of raters and increase the efficiency with which they are trained to use the CDR.

Adult↗
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Complement activation in very early Alzheimer disease.

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.

Aged↗
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An unusual case of inappropriate secretion of thyrotropin: neoplastic or nonneoplastic?

OBJECTIVE: To report an unusual case that illustrates the difficulties in distinguishing neoplastic (nIST) from nonneoplastic inappropriate secretion of thyrotropin (nnIST). METHODS: We describe clinical, biochemical, genetic analysis, and magnetic resonance imaging (MRI) results in a patient with hyperthyroidism due to IST, and we review the related literature. RESULTS: The patient demonstrated overt clinical and biochemical hyperthyroidism with inappropriately increased thyrotropin levels, which failed to respond to thyrotropin-releasing hormone (TRH) stimulation. Sex hormone-binding globulin (SHBG) levels were in the hyperthyroid range. Alpha subunit levels were normal, as was the alpha subunit/thyrotropin molar ratio. MRI of the pituitary was negative for tumor during a 2-year period, and octreotide scan was also negative for sellar uptake. Basal oxygen consumption was abnormally increased. Genetic analysis failed to reveal mutations of the thyroid receptor b gene. The patient responded well to radioiodine ablation of his thyroid. CONCLUSION: This patient had clinical symptoms of hyperthyroidism associated with some features characteristic of nIST (increased level of SHBG, lack of thyrotropin response to TRH stimulation, absence of thyroid receptor b mutations) and others typical of nnIST (normal alpha subunit and its molar ratio to thyrotropin, absence of tumor on sellar imaging). Close follow-up with periodic MRI of the sella is important because of the possible existence of a small pituitary tumor, which may become apparent at a later date. Therapy to control symptoms is important. Hormone replacement, if needed, should be adjusted to maintain clinical euthyroidism, guided by free thyroxine levels.

Adenoma↗
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The use of a football helmet to secure a nasogastric tube.

We describe the case of a 83-yr-old diabetic woman who, during convalescence for treatment of hyperosmolar nonketotic diabetic coma, required nasogastric intubation for enteral feeding. Her course was complicated by delirium during which time she repeatedly removed the nasogastric tube. A football helmet was used to secure the feeding tube and prevent its premature removal. Thereafter nasogastric feeding was uncomplicated. We recommend the use of a football helmet in patients with delirium who repeatedly remove their nasogastric tubes.

Aged↗
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Receptor-specific activity of heteromeric thyrotropin (TSH) analogs: development of synthetic TSH antagonists.

In an attempt to create potent and specific inhibitors of the interaction of thyrotropin (thyroid-stimulating hormone [TSH]) with its receptor, we designed a series of 18 synthetic peptides containing sequences of both alpha and beta subunits that were shown previously to interact with the TSH receptor. These "heteromeric" peptide analogs included amino acid residues from alpha 26-46, beta 31-52, beta 88-95 and beta 101-112 that were arranged variously and were separated from each other by artificial amino acid spacers. Each peptide was tested for its ability to interact with the TSH receptor in a radio-receptor assay (TSH-RRA) using porcine thyroid membranes and a bio-assay for TSH using FRTL-5 cells. Twelve of the 18 peptides showed binding activity in the TSH-RRA. None of the analogs demonstrated thyroid stimulatory activity, but five inhibited TSH bioactivity and were, thus, pure antagonists, the most potent possessing EC50 values in the 3-5 microM range. Specificity of the antagonists was tested by measuring their ability to inhibit hCG binding to ovarian membranes, hCG-stimulated progesterone production in MA-10 rat Leydig tumor cells and FSH binding to testicular membranes. Only those peptides that included the alpha-subunit sequence CFSR or CCFSR exhibited binding activity for the heterologous receptors, and that activity was 10-fold lower than in the TSH assays. None of the heteromeric peptides showed activity in the hCG bioassays, further demonstrating their specificity as TSH antagonists. These studies illustrate the utility of a synthetic peptide approach in the development of analogs of peptide hormones. Future alterations that significantly enhance the potency of these antagonists may result in substances with clinical efficacy in diseases such as Graves' disease and differentiated thyroid cancer that involve the thyrotropin receptor.

Amino Acid Sequence↗
PubMedDate not supplied

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Alzheimer Disease↗