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Biomedical subjects

T Sunderland

Publications and source records attributed to T Sunderland.

At least 55 records · Page 3Linked to original sources
PubMed1997

Cognitive and behavioral effects of cholinergic, dopaminergic, and serotonergic blockade in humans.

The purpose of this study was to investigate the cognitive and behavioral effects of anticholinergic, antidopaminergic, and antiserotonergic agents given alone and in combination to normal volunteers. Twelve young male volunteers took part in this double-blind, randomized, placebo-controlled, crossover study of six drug conditions, each administered on separate days [haloperidol (2 mg p.o.) +/-scopolamine (0.5 mg i.v.), metergoline (4 mg p.o.) +/-scopolamine (0.5 mg i.v.), placebo, and scopolamine alone (0.5 mg i.v.)]. Scopolamine-induced sedation (p < .01), slowed information processing (p < .01) and impaired new learning and memory (p < .01), but did not affect attention or retrieval from semantic memory. Given alone, haloperidol selectively impaired the ability to rapidly switch cognitive sets (p < .05), and metergoline decreased pupil size (p < .01) but did not induce cognitive deficits. In combination with scopolamine, neither haloperidol nor metergoline produced a worsening of the subjects' cognitive performance above and beyond that seen with scopolamine alone. On the contrary, a trend (p < .10) for haloperidol to reverse some of the scopolamine-induced exacerbation of verbal short-term forgetting was observed. The data indicate that scopolamine and haloperidol can independently and selectively affect cognition and that at the doses tested in this study no synergistic exacerbation of cognitive functioning was found when cholinergic blockage was coupled with dopaminergic or serotonergic blockade.

Adult↗
PubMed1997

Assessment of motor and process skills as a measure of IADL functioning in pharmacologic studies of people with Alzheimer's disease: a pilot study.

The purpose of this pilot study was to evaluate the usefulness of the Assessment of Motor and Process Skills (AMPS) as an outcome measure of instrumental activities of daily living (IADL) in pharmacologic studies of people with Alzheimer's disease. The AMPS simultaneously measures motor and process skills and their effect on the ability of the person to perform familiar IADL tasks. We administered the AMPS to 11 Alzheimer inpatients in a 3 1/2-month, double-blind, placebo-controlled, crossover study of fluoxetine and selegiline administered as single agents and in combination with physostigmine. Results indicated that there was a significant difference in IADL ability among study conditions for process skills, but not for motor skills, thereby suggesting that the AMPS is useful as a sensitive outcome measure of IADL ability in drug trials with this population.

Activities of Daily Living↗
PubMed1997

Monitoring frequency of occurrence without awareness: evidence from patients with Alzheimer's disease.

People are surprisingly accurate at judging how often an event occurs. Patients with Alzheimer's disease (AD), however, perform poorly on such tasks, suggesting that this ability is compromised when episodic memory is impaired. The tasks used to assess this ability in previous studies, however, placed demands on retrieval that could obscure whether frequency of occurrence was adequately encoded. We developed an indirect test of frequency monitoring based on changes in reading time as a function of item repetition. Using this procedure, patients with AD showed normal frequency monitoring for novel information (Turkish words) even though they were unable to remember the words or judge how often individual words had been presented. These findings suggest the existence of a mechanism that automatically monitors frequency of occurrence and operates outside of conscious awareness.

Aged↗
PubMed1997

Depression in the elderly: biologic considerations.

Although support for the biologic basis and effective somatic therapy of geriatric depression is increasing, both patients and clinicians are reluctant to identify and treat the symptoms associated with late-life depression, a broad-based problem in the geriatric population. There is much clinical and biologic overlap between depression and other organic brain disorders such as dementia, with evidence that late-onset depression may sometimes be a prodrome for other organic disorders. These and other issues surrounding geriatric depression are reviewed with a focus on future research questions.

Age Factors↗
PubMed1997

The ratio of mesial to neocortical temporal lobe blood flow as a predictor of dementia.

OBJECTIVE: The hypothesis tested was that an increased ratio of cerebral blood flow (rCBF) in the mesocortical temporal lobe to that of the neocortical temporal lobe (MES/ NEO ratio) would be related to clinical measures of dementia severity and would help distinguish Alzheimer's patients from normal controls. DESIGN: The rCBF of nine Alzheimer's patients (5 males and 4 females; age = 65.9 +/- 6.0 years, range 55-71; Folstein Mini-Mental Status Examination = 18.6 +/- 7.4, range 9-28) and 10 age-matched normal controls (7 males, 3 females; age = 66.0 +/- 5.7 years, range 58-75) was determined by positron emission tomography (PET) using H2(15)0 and the method of Alpert et al. RESULTS: Alzheimer's disease patients had a significantly higher MES/NEO ratio (1.19 +/- .17) than the age-matched normal controls (.854 +/- .14; t = .-4.74, df = 17, P = .0002). Using a MES/NEO ratio of 1 as the cutoff point for discrimination between Alzheimer's patients and normal controls, the ratio demonstrated 100% sensitivity (no. of correctly identified Alzheimer's patients/no. of Alzheimer's patients) and 90% specificity (no. of correctly identified unaffected subjects/no. of unaffected subjects). Further, those patients with the highest MES/NEO ratios had the lowest overall measures of cognitive function (Folstein Mini-Mental Status Examination: r = -.75, P < .02, 1-tail; Mattis Dementia Rating Scale: r = -0.655, P = .028, 1-tail) scores. CONCLUSIONS: The findings are consistent with other in vivo and postmortem studies, suggesting that functional and structural changes of the lateral temporal lobe in Alzheimer's disease occur relatively early in the disease process and appear to be distinguishable from those changes accompanying normal aging. In contrast, the memory loss and pathology of the mesial temporal lobe that is characteristic of the early stages of Alzheimer's patients do not appear to be associated with a reduction in cerebral blood flow in the resting Alzheimer's patient. Nevertheless, the clinical significance of the results must await findings of longitudinal studies of larger numbers of Alzheimer's patients and controls.

Aged↗
PubMed1997

Lateralization and behavioral correlation of changes in regional cerebral blood flow with classical conditioning of the human eyeblink response.

Laterality of changes in regional cerebral blood flow (rCBF) during classical conditioning of the human eyeblink response was studied and changes in rCBF were correlated with conditioned responses. In 10 normal volunteers, rCBF was mapped with positron emission tomography and H2(15)O during pairings of a binaural tone conditioned stimulus and an air puff unconditioned stimulus to the left eye. Control conditions consisted of explicitly unpaired presentations of the tone and air puff before (control) and after (extinction) pairings. During pairings, rCBF increased significantly in right primary auditory cortex (contralateral to air puff) and decreased significantly in left and right cerebellar cortex. There were also increases in rCBF in right auditory association cortex and left temporoccipital cortex. Decreases in rCBF were noted bilaterally in the temporal poles and in the left prefrontal cortex. Positive correlations between changes in rCBF and percent conditioned responses were located in middle cerebellum, right superior temporal cortex, left dorsal premotor cortex, right middle cingulate, and right superior temporal cortex. There were negative correlations in left inferior prefrontal cortex, left middle prefrontal cortex, and right inferior parietal cortex. The data replicate our previous findings of lateralized changes in rCBF following presentations of a binaural tone and air puff to the right eye and indicate that there are pairing-specific changes in primary auditory cortex and cerebellum that are not unique to the left or right hemisphere but are a function of the side of training. The commonalities as well as differences in regional involvement in our present and previous experiment as well as in other eyeblink studies illustrate the advantage of functional neuroimaging to quantify different strategies used by the brain to perform seemingly similar functions. Indeed, the data support the notion that learning-related changes can be detected in a number of specific, but not necessarily invariant, brain regions, and that the involvement of any one region is dependent on the characteristics of the particular learning situation.

Acoustic Stimulation↗
PubMed1997

Durable power of attorney and informed consent with Alzheimer's disease patients: a clinical study.

OBJECTIVE: Experience with a new surrogate consent system for patients with Alzheimer's disease is reviewed. It was hypothesized that as patients' cognitive status deteriorated, surrogate consent through a durable power of attorney would become necessary to facilitate continued involvement in clinical research. METHOD: The authors retrospectively reviewed the charts of inpatients with Alzheimer's disease who participated in research between January 1989 and December 1994 at the Geriatric Psychiatry Unit of the National Institute of Mental Health. Seventy-nine patients were included. The main outcome measures were the Clinical Dementia Rating, Global Deterioration Scale for primary degenerative dementia, and Mini-Mental State. RESULTS: Most patients were in the mild-to-moderate stage of the illness when they chose to participate in research and assign a durable power of attorney (96% scored 2 or less on the Clinical Dementia Rating, and 92% scored 5 or less on the Global Deterioration Scale). On average, the subjects participated in 3.8 (SD = 2.6) studies. For 35 patients with multiple admissions over this period (average = 3.1 years), scores on the Clinical Dementia Rating and Global Deterioration Scale declined by 1.0 and 1.5 points, respectively. CONCLUSIONS: The durable power of attorney allows research participation for subjects with Alzheimer's disease at all stages. The linchpin is assignment of a durable power of attorney in the early-to-moderate stage of Alzheimer's disease, before subjects lose the capacity to give informed consent. This approach could also be adapted to patients with cognitive decline due to other debilitating diseases.

Advance Directives↗
PubMed1997

Late-life depression: how to make a difficult diagnosis.

Approximately 15% of persons age 65 and older have major depression. Risk factors include a recent loss (eg, widowhood or mastectomy), living alone, co-morbidities (eg, hypertension, stroke, cognitive deficits), and drug interactions. Warning signs of depression may include weight loss, sleep problems, feelings of guilt or worthlessness, loss of interest in sexual relations, or changes in activities of daily living. The diagnosis of depression is easy to miss if the physician doesn't look for it, because older persons often don't mention feeling depressed. Yet undetected depression can be deadly for older patients, who have the highest rate of suicide among all Americans. Plans for suicide may be direct or covert, as in not eating or not taking heart medication.

Age Distribution↗
PubMed1997

Late-life depression: treatment strategies for primary care practice.

Most patients age 65 and older with symptoms of depression respond well to treatment. Choices of therapy include medications, electroconvulsive therapy (ECT), and psychotherapy. Every primary care physician should be comfortable with using at least two or three medicines from different drug classes. The likelihood of side effects depends on the antidepressant prescribed and other medications the patient might be taking. The combination of medication with psychotherapy appears more effective than one or the other alone. ECT is the treatment of choice when rapid results are needed (eg, if the patient is suicidal or losing weight quickly and in danger of a medical crisis). The physician/patient relationship can be a strong antidepressant.

Aged↗
PubMed1997

Pharmacologic challenges in Alzheimer disease and normal controls: cognitive modeling in humans.

Alzheimer disease (AD) is a progressive disorder characterized by cognitive and behavioral dysfunction, central to which are deficits in the cholinergic and other neurotransmitter systems. These results in the essential symptoms of dementia, including impairment of memory, judgment, and abstract thinking. The pharmacologic relationships among the various neurotransmitters (e.g., cholinergic, serotonergic, nicotinic, and dopaminergic) are highly complex and are still being investigated. Information on the pharmacologic basis of cognitive and behavioral dysfunction in AD has applications to drug therapy. One method of obtaining this information is by pharmacomodeling, using individual or combined drugs. Joint cholinergic antagonism with both muscarinic and nicotinic blockade combines to produce short-term memory impairment, which approximates to mild AD in normal elderly people. This effect is better than that achieved with either agent alone. Mixed cholinergic and serotonergic antagonism has an effect on the cognitive function of AD patients and on depression-related behavior. Dopaminergic dysfunction is linked with the development of hallucinatory and psychotic symptoms and may also be involved in dysfunction of verbal fluency. Combination pharmacomodeling allows the various behavioral and cognitive deficits in AD to be studied and allows models for drug trials to be developed.

Aged↗
PubMed1997

[Psychodynamic treatment in Alzheimer's disease].

The psychodynamic approach to a patient's experience of having Alzheimer's disease requires more research. It is a therapeutic objective to allow a patient with Alzheimer disease to obtain a realistic perception of his own condition, particularly since this is frequently unusual for this group of patients.

Adaptation, Psychological↗
PubMed1996

Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.

Overexpression of the familial Alzheimer's disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved. A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity. This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimer's disease, leading to the earlier age of onset characteristic of familial Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Physiological levels of beta-amyloid peptide promote PC12 cell proliferation.

Alzheimer's beta-amyloid peptide (A beta) is normally present at a subnanomolar (225-625 pM) concentration in body fluids and in the medium of cultured cells. The potential actions of physiologic levels of A beta are being investigated. We have recently shown that nanomolar doses of A beta can stimulate tyrosine phosphorylation and activate phosphatidylinositol-3-kinase in neuronal cells. Here we show evidence that A beta at nanomolar levels promotes cell growth determined by [3H]thymidine incorporation, protein content and cell counts. Physiological levels of A beta peptides, including 1-40, 1-42, 25-35, all promote growth of PC12 cells in low serum medium with doubling times of 71 h to around 30 h. Although the promotion of cell proliferation can be detected at nanomolar levels of A beta, it's potency is less than that of serum. This suggests that A beta may normally play a neurotrophic/mitogenic role in neuronal biology.

Amyloid beta-Peptides↗
PubMed1996

Differential regulation of APP secretion by apolipoprotein E3 and E4.

The apolipoprotein E isozyme, apolipoprotein E4, has been implicated as a risk factor for Alzheimer's disease. One reason for the increased risk may be that apolipoprotein E binds to the A beta peptide, but there may be other factors as well. We show that apolipoprotein E is a potent regulator of the secretion of amyloid precursor protein. In cultures of PC12 cells, nanomolar levels of apolipoprotein E3 induce a rapid decrease in the secretion of APP, being observable in 30 min. and stable over 24 hours. Apolipoprotein E4, in contrast, increases secretion of APP over a similar time course. Reciprocal changes occur in cellular amyloid precursor protein. Differential characteristics are also seen in apo E binding to the cells, where apo E4 binds over a slower time course than apo E3. These results suggest a novel mechanism by which apolipoprotein E may be influencing the metabolism of amyloid precursor protein.

Amyloid beta-Protein Precursor↗
PubMed1996

Human olfactory neuroepithelial cells: tyrosine phosphorylation and process extension are increased by the combination of IL-1beta, IL-6, NGF, and bFGF.

Olfactory neuroepithelial cells (ONC) grown from biopsies of human donors are a novel cell culture system that may facilitate studies into normal and disease-related human neurobiology. We further characterized the expression of cell surface markers and intermediate filaments, and responses to neurotrophic factors by ONC. ONC are positive for cell surface markers N-CAM, PSA-N-CAM, neutral endopeptidase, N-aminopeptidase, NGF low-affinity receptor homologue (CD40), and transferrin receptor by flow cytometry for the intermediate filament proteins peripherin, vimentin, and NF-H by immunocytochemistry. Responses to neurotrophic factors measured were process outgrowth, cytoskeletal protein expression, and protein phosphorylation. Process outgrowth was increased by interleukin-beta 164-171 (IL-1beta) or by the combination of IL-1beta, interleukin-6 (IL-6), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). This combination of IL-1beta, IL-6, NGF, and bFGF (16NF) increased expression of two cytoskeletal proteins, NF-H protein and microtubule-associated protein tau. Application of the individual neurotrophic factors IL-1beta, IL-6, NGF, and bFGF increased protein phosphorylation, while 16NF produced an immediate increase in tyrosine phosphorylation of several proteins (MW of 40-80, 120, 150, and 190 kDa). The 16NF combination appears to act through a tyrosine-kinase-mediated pathway to induce process extension and increase NF-H expression. The ONC culture has the potential to be further explored to examine the relationship among process outgrowth, protein phosphorylation, and synergy between neurotrophin and cytokine receptor systems.

Antigens, CD↗
PubMed1996

Physiologic levels of beta-amyloid activate phosphatidylinositol 3-kinase with the involvement of tyrosine phosphorylation.

The beta-amyloid protein (A beta) peptide plays an important role in Alzheimer's disease, but the potential actions of physiologic levels of A beta (225-625 pM) have not been explored. We recently showed that picomolar doses of A beta can stimulate tyrosine phosphorylation of neuronal cells and now show that leads to the activation of the lipid kinase phosphatidylinositol 3-kinase (PI3 kinase). Three independent lines of evidence support the hypothesis that A beta is activating PI3 kinase through a tyrosine kinase-mediated mechanism. Immunoblotting studies show that A beta induces tyrosine phosphorylation of p85 as well as association of the p85 subunit of PI3 kinase with tyrosine-phosphorylated proteins. Studies of membrane proteins show that A beta induces a translocation of p85 to membrane-bound glycoproteins, which are likely to be receptors. Finally, direct studies of PI3 kinase activity in both anti-phosphotyrosine immunocomplexes and wheat germ agglutinin precipitates show that A beta increases formation of the product of PI3 kinase. Wortmannin, a selective inhibitor of PI3 kinase, blocks this A beta-stimulated PI3 kinase activity. Thus, physiologic levels of A beta stimulate tyrosine phosphorylation and PI3 kinase activity.

Amyloid beta-Peptides↗