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L E Harrell

Publications and source records attributed to L E Harrell.

At least 55 records · Page 3Linked to original sources
PubMed1994

Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative.

OBJECTIVE: To assess interrater reliability and validity of NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer's disease (AD). DESIGN: A multisite reliability and validity study in which clinicians from each site diagnosed 60 case summaries yielding a preconsensus estimate of reliability and validity. A consensus conference was conducted for each disagreement, leading to a postconsensus estimate of validity. The criterion standard was a diagnosis of AD by autopsy. SETTING: Three academic medical centers. SUBJECTS: A convenience sample of 60 detailed case summaries, 40 with AD and 20 with other dementing disorders. MAIN OUTCOME MEASURES: The kappa coefficient, sensitivity, and specificity. RESULTS: The kappa coefficient for preconsensus agreement on a diagnosis of probable or possible AD vs non-AD was 0.51; the sensitivity of a diagnosis of probable or possible AD for a pathological diagnosis of AD was 0.81, and the specificity was 0.73. The postconsensus sensitivity was 0.83, and the specificity was 0.84. CONCLUSIONS: The results support the reliability and validity of NINCDS-ADRDA criteria and show that the consensus process may improve diagnostic accuracy. The cases are reviewed with a focus on the sources of diagnostic disagreements and errors and possible changes that might improve the accuracy of the criteria.

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PubMed1994

Hippocampal sympathetic ingrowth and cholinergic denervation alter hippocampal muscarinic cholinergic receptors.

Cholinergic denervation of the hippocampus by medial septal (MS) lesions results in the ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglia, into the hippocampus. To determine the effect of hippocampal sympathetic ingrowth (HSI) [3H]-QNB (L-quinuclidinyl [benzilic-4,4(n)] binding was assessed in the dorsal and ventral hippocampus four weeks after MS lesions. In dorsal hippocampus, HSI was found to significantly increase the number (Bmax) of [3H]-QNB binding sites and to normalize the decrease in affinity found in animals with MS lesions plus ganglionectomy (i.e., no ingrowth). In ventral hippocampus, HSI was found to normalize the increased number of binding sites and decreased affinity found in animals with MS lesions without ingrowth. No effect on either Kd or Bmax was found in animals that had undergone ganglionectomy with sham MS lesions. These results suggest that HSI can induce changes in hippocampal muscarinic cholinergic receptors.

Animals↗
PubMed1994

Determining the competency of Alzheimer patients to consent to treatment and research.

Loss of competency is an inevitable consequence of Alzheimer disease (AD) and other progressive dementias. Of particular importance to clinicians and researchers studying dementia is determining whether a patient has the capacity to provide informed consent to treatment and medical research. No widely accepted standardized instruments exist for competency assessment, nor has competency assessment training been available to physicians. As a result, physician competency assessment has been a subjective and even idiosyncratic process. Recent studies have suggested that physicians have difficulty assessing capacity to consent in older adults and frequently disagree in their competency judgments. Accordingly, one important goal for advancing ethical and legal research in AD will involve the development of standardized approaches to determining patient capacity to give consent. This article reports the findings of recent empirical studies of competency determination in AD, focusing on work in the areas of physician competency assessment, development of standardized assessment instruments, and neuropsychological modeling of competency loss. Future directions for research in these three areas are identified.

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PubMed1993

Female circulating sex hormones and hippocampal sympathetic ingrowth.

Following cholinergic denervation of the hippocampal formation, via medial septal (MS) lesions, sympathetic fibers, originating from the superior cervical ganglia, growth into the hippocampus. Previous studies have demonstrated a sexually dimorphic effect of this neuronal rearrangement on recovery of a spatial-learning task, with this rearrangement being detrimental in male but protective in female rats. Circulating male sex hormones were found to interact with this effect in male animals. In this study we assessed the role of circulating female sex hormones on the behavioral and biochemical effects of hippocampal sympathetic ingrowth (HSI). For the behavioral studies female rats underwent either sham ovariectomy (sham OVARX) or OVARX and were taught a standard radial-8-arm maze task. Following attainment of criterion, animals underwent one of three surgical procedures: sham surgery; MS lesions+sham ganglionectomy (MS); HSI group; MS lesions+ganglionectomy (MSGx). As in our previous study, animals with HSI (i.e. MS group) were found to recover learning faster (in fact, these animals did not differ from controls) than animals with MS lesions without HSI. Gonadal status did not affect this behavioral recovery. For the biochemical studies hippocampal norepinephrine (NE) and choline acetyltransferase (ChAT) were measured in animals sham OVARX and OVARX, 8-12 weeks after the neurosurgical procedure. MS lesions (i.e. MSGx; MS) were found to reduce ChAT activity, regardless of circulating sex hormones. In controls NE levels were similar between OVARX and sham OVARX. NE levels were markedly elevated in the OVARX MS group compared to all other groups including sham OVARX. In the MSGx groups, NE levels were reduced compared to controls, while comparisons between these groups revealed a significant reduction in NE levels in the OVARX MSGx group compared to sham OVARX MSGx group. These studies suggest that female circulating sex hormones interact with brain injury in a very complex manner. However, this interaction does not appear to mediate the changes in behavior observed after HSI.

Adrenergic Fibers↗
PubMed1993

Recruitment of black elderly for clinical research studies of dementia: the CERAD experience.

Nine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) sites were surveyed to identify barriers to recruiting black subjects. Major cited obstacles were expenses, transportation difficulties, and especially lack of rapport with clinic staff. Major factors in overcoming these barriers are a good referral network involving the black community, community education about Alzheimer's disease (AD), and professional staff who are particularly sensitive to the needs of the black population. CERAD efforts to increase community awareness of Alzheimer's disease and staff sensitivity to minority needs have nearly doubled the proportion of black subjects enrolled.

Black or African American↗
PubMed1993

Autopsy in dementing illness: who participates?

The frequency of occurrence of various types of dementing disorders has been ascertained primarily from autopsied series. Since autopsy is voluntary, it is unknown if these series are representative of the entire demented population. To assess this issue, all deaths occurring over a 5-year period in our Memory Disorders Clinic were reviewed, and clinical variables and diagnoses were compared between patients who were autopsied and those who were not. Sixty-nine patients died; 43% (n = 30) underwent autopsy, and 57% (n = 39) did not. Race (no black patients were autopsied), age of disease onset, age of presentation to the clinic, age of death, and interval between last clinic contact and death (significantly less for nonautopsied patients) were found to differ between the two groups. However, clinical diagnosis of dementia was similar in the two groups. The clinical diagnosis was confirmed in 84% of autopsied patients. These results suggest that there are no major differences between clinical diagnoses for autopsied and non-autopsied patients and that the frequency of occurrence of various dementias obtained through autopsied series are representative of the demented population.

Black or African American↗
PubMed1992

Cholinergic denervation alters [3H]phorbol-12,13-dibutyrate binding to rat hippocampal membranes.

Cholinergic denervation of the rat hippocampus caused by electrolytic lesions of the medial septum (MS) results in a time-bound ingrowth of peripheral sympathetic noradrenergic fibers from the superior cervical ganglion to the dentate gyrus and CA3 region of the hippocampus. To determine the functional significance of hippocampal sympathetic ingrowth (HSI), [3H]phorbol-12,13-dibutyrate (PDBu) binding was assessed 4 weeks after MS lesions. In control animals, affinity for [3H]PDBu binding was found to be greater in the dorsal compared to ventral hippocampus, while the number of binding sites (Bmax) was similar between regions. Regardless of the presence of HSI, MS lesions resulted in increased affinity in the dorsal hippocampus, while the Bmax was found to 'normalize' in the ventral hippocampus by HSI. These results suggest that HSI is functional and can alter important cellular events.

Animals↗
PubMed1992

Hippocampal phosphoinositide turnover is altered by hippocampal sympathetic ingrowth and cholinergic denervation.

Cholinergic denervation of the hippocampus, by medial septal (MS) lesions, results in an unusual neuronal rearrangement in which peripheral sympathetic nerves, which originate from the superior cervical ganglia, grow into the hippocampal formation. To assess the functional significance of hippocampal sympathetic ingrowth (HSI), hydrolysis of phosphoinositides was examined in three groups: control, MS lesions + sham ganglionectomy (HSI group); and MS lesions + ganglionectomy (MSGx; no ingrowth). Four months after surgery, both norepinephrine (NE) and carbachol were found to produce a dose-dependent increase in the hydrolysis of hippocampal phosphoinositides in all groups. However, the presence of HSI, when compared to control and MSGx groups, significantly enhanced the turnover of phosphoinositides when stimulated by carbachol, but not NE. In further studies, the time course of this effect was studied. One week after surgery, carbachol-stimulated phosphoinositide turnover was equivalent among all groups; by 2 weeks, phosphoinositide turnover was enhanced in the HSI and MSGx group; by 4 weeks, PI turnover was markedly diminished in the MSGx group when compared to both the HSI and control groups, which were equivalent to each other. To ensure that the ganglionectomy alone did not alter phosphoinositide turnover, a ganglionectomy-alone group was studied at the 4-week time point. In this group, phosphoinositide turnover was equivalent to controls, suggesting no influence of the superior cervical ganglia on this response. In all groups, atropine inhibited carbachol-stimulated phosphoinositide turnover. These results suggest that both cholinergic denervation (i.e., MSGx group) and HSI produce marked functional alterations in hippocampal metabolic activity.

Animals↗
PubMed1991

The relationship of high-intensity signals on magnetic resonance images to cognitive and psychiatric state in Alzheimer's disease.

In Alzheimer's disease (AD), the relationship between white-matter changes on magnetic resonance images and behavior are unclear. Therefore, magnetic resonance images, cognition, and psychiatric state were assessed in patients with AD with depression (AD/DEP; n = 18) and without depression (AD; n = 45), older depressed patients (n = 12) and older normal individuals (n = 25). High-intensity signals in the cortex and subcortical regions were similar in number and proportions among all groups, even when hypertensive patients were excluded. No correlations to cognitive or psychiatric state were found. Periventricular signals were categorized using a 1- (absent) to 6- (thick, irregular caps and stripes) point scale. The categories were similar among groups except that patients with AD exhibited more category 5 changes than did normal subjects, neuropsychological performance was significantly worse in patients with AD who had category 5 and 6 changes when compared to those in category 1. These results suggest that periventricular changes may predict poor neuropsychological performance in patients with AD. However, neither deep white-matter lesions nor periventricular changes are useful for diagnostic purposes.

Aged↗
PubMed1991

Interaction of neurotransmitter systems in the hippocampus: a study of some behavioral effects of hippocampal sympathetic ingrowth.

Recent research has suggested that normal learning/memory may depend upon the balance between central noradrenergic and cholinergic systems. This hypothesis has particular relevance to the study of the neuronal rearrangement that follows cholinergic denervation of hippocampus. In this, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus in response to lesions of the medial septal (MS) cholinergic cell bodies. To understand further the influence of hippocampal sympathetic ingrowth (HSI) on behavior, gustatory neophobia, passive avoidance (PA) learning, and open field activity were studied. Male Sprague-Dawley rats underwent one of four surgical procedures: MS lesions and sham ganglionectomy (ingrowth group; MS/HSI group), sham MS lesions and ganglionectomy (Gx group), MS lesions and ganglionectomy (no-ingrowth group; MS/Gx group), or sham MS lesions and sham ganglionectomy (CON group). Behavioral testing began 4 weeks following surgery. The time to acquire the PA task was similar among all groups; however, the initial latency to enter the dark chamber of the PA apparatus was longer, and the number of partial reentries greatest, for MS/HSI animals. Retention testing at 24 hr revealed that MS/HSI animals were significantly impaired when compared to the CON and MS/Gx groups. The MS/Gx and the CON groups demonstrated gustatory neophobia, preferring water to saccharin solution, while gustatory neophobia was absent in the MS/HSI and Gx groups. MS/HSI animals were found to be more active in the open field than the other groups. Biochemical studies revealed the expected loss of ChAT activity in the dorsal and ventral hippocampi of lesioned animals along with elevated levels of norepinephrine (NE) in the dorsal hippocampus of MS/HSI animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The effect of gonadal steroids on the behavioral and biochemical effects of hippocampal sympathetic ingrowth.

Following cholinergic denervation of the hippocampal formation, via medial septal lesions, sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previous studies have demonstrated a detrimental effect of these fibers on recovery of a spatial-learning task in male but not female animals. In this study we assessed the role of circulating male sex hormones on the behavioral and biochemical effects of hippocampal sympathetic ingrowth (HSI). For the behavioral studies male Sprague-Dawley rats underwent either sham gonadectomy or gonadectomy and were taught a standard radial 8-arm maze task. Following attainment of criterion animals underwent one of three surgical procedures: sham surgery, MS lesions, MS lesions + ganglionectomy. MS lesions, regardless of the presence of HSI, were found to severely impair reacquisition of the task in both sham-gonadectomized and gonadectomized animals. As expected, in the sham-gonadectomized group, MSGx animals reacquired the task faster than the MS group. However, gonadectomy was found to block the detrimental effect of HSI on behavior. For the biochemical studies hippocampal norepinephrine (NE) and choline acetyltransferase (ChAT) were measured eight weeks after surgery in sham-gonadectomized and gonadectomized animals. MS lesions were found to significantly reduce the ChAT activity, regardless of circulating sex hormones. Gonadectomy was found to significantly reduce the level of NE associated with HSI, while having no effect on central NE in CON or MSGx animals. These studies suggest that circulating male sex hormones can influence both the behavioral and biochemical processes associated with HSI.

Acetylcholinesterase↗
PubMed1990

Adrenoreceptor antagonist treatment influences recovery of learning following medial septal lesions and hippocampal sympathetic ingrowth.

Previous studies have demonstrated that in male rats hippocampal sympathetic ingrowth (HSI), which is induced by medial septal lesions (MS), is detrimental to recovery of spatial learning. The present study was performed in an attempt to determine if this effect was mediated through adrenergic receptor activity. Adult male Sprague-Dawley rats underwent training on a modified version (i.e., 4 arms baited) of a radial-8-arm maze task. Following attainment of learning criterion animals underwent one of three surgical procedures: CON (sham surgeries); MSGx (MS + superior cervical ganglionectomy--to prevent HSI); MS (MS + sham ganglionectomy). Reacquisition trials were performed in the same manner as initial acquisition except animals were treated with vehicle, propranolol (20 mg/kg), or phentolamine (20 mg/kg) 30 minutes prior to testing. As expected, vehicle-treated MS animals took longer to reacquire the task than MSGx animals, who were in turn more impaired than CON animals. Propranolol (beta-adrenergic antagonist) treatment impaired performance of both the MS and MSGx group, but did not alter the CON group. Phentolamine (alpha-adrenergic antagonist) increased the number of trials to reattain criterion in the CON group, had no effect in the MSGx group, and markedly improved performance in the MS group. The results suggest that HSI mediates its detrimental effects through alpha-receptors, while beta-blockade, in the setting of brain injury, is detrimental to performance regardless of the presence or absence of HSI.

Animals↗
PubMed1990

Biological and neuropsychological characterization of physostigmine responders and nonresponders in Alzheimer's disease.

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

Activities of Daily Living↗
PubMed1990

The effect of long-term physostigmine administration in Alzheimer's disease.

We assessed the effect of chronic long-term physostigmine in 20 patients with probable Alzheimer's disease. Initially, all patients went through a dose-finding phase and a double-blind crossover period, and were subsequently classified as physostigmine responders or nonresponders based on an a priori classification system. We then offered all patients long-term treatment with physostigmine regardless of their initial classification. Results revealed that responders spent significantly (p less than 0.0005) longer time periods on drug (36.1 +/- 4.6 months) than nonresponders (10.8 +/- 3.2). During a 2nd crossover period, 18 months into treatment, responders still demonstrated behavioral improvement, as assessed with the Sandoz Clinical Assessment-Geriatric Scale, whereas there were no behavioral changes observed in nonresponders. There were no effects on formal neuropsychological assessment. The results suggest that a subgroup of Alzheimer's patients benefits from long-term physostigmine therapy.

Alzheimer Disease↗
PubMed1989

Reversal of an aluminum-induced behavioral deficit by administration of deferoxamine.

Administration of aluminum sulfate in the drinking water of male Sprague-Dawley rats for 30 days resulted in a reduction in the number of days to reach extinction criterion on a passive avoidance task (38% control level). The behavioral deficit was not due to nonspecific effects caused by lower fluid consumption. Partial reversal of the deficit was produced by discontinuing aluminum treatment 2 weeks prior to testing (p less than .05). Injection of the aluminum chelator deferoxamine returned the performance of the aluminum-treated animals to control levels in a dose-dependent manner but had no effect on control animals. No differences in open-field activity were evident across groups. These results indicate that the behavioral impairment is a specific, reversible, toxic effect of the aluminum administration.

Alum Compounds↗
PubMed1989

HTLV-I-associated myelopathy and polymyositis in a US native.

A patient who had always lived in the United States had an HTLV-I infection and a chronic myelopathy clinically mimicking amyotrophic lateral sclerosis. Needle EMG and nerve conduction studies were consistent with anterior horn cell disease but muscle biopsy showed denervation and an inflammatory myopathy. Serum HTLV-I antibody tests were positive and HTLV-I DNA was present in peripheral leukocytes. This is the 1st reported US native with HTLV-I-associated myelopathy and polymyositis.

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