Decreased CSF inositol monophosphatase activity after lithium treatment.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
T Sunderland
Publications and source records attributed to T Sunderland.
A double FDG/PET study of the effects of scopolamine in older adults.
Two consecutive positron emission scans were done in one session using a double injection method of [18F]2-fluoro-2-deoxyglucose administration to examine the effects of the antimuscarinic drug scopolamine on cerebral glucose metabolism in ten older adults. Scopolamine causes temporary memory impairment, and its effects have been used to model aspects of the cognitive impairment that occur in Alzheimer's disease (AD). Cortical metabolic rates of patients with AD have been reported to be depressed, especially in parietal, temporal, and frontal association areas. After scopolamine administration to the elderly volunteers, absolute and normalized glucose metabolic rates were depressed in prefrontal and occipital regions and increased in parietal-occipital cortical regions and a left middle temporal region. These changes in the older volunteers are generally not consistent with changes seen in AD. We conclude that deficits in muscarinic system function may contribute to some but not all of the hypometabolic changes seen in AD patients.
Brain↗
Oral administration of heptylphysostigmine in healthy volunteers: a preliminary study.
Heptylphysostigmine (HP) is a reversible cholinesterase (ChE) inhibitor with greater lipophilicity and longer inhibitory action than the parent compound, physostigmine (Phy). Single (0.1-0.6 mg/kg) and multiple 5-day (0.1-0.3 mg/kg) doses of HP were administered to 21 young normal volunteers. The relationship between logarithmic dose (mg/kg) and peak inhibition of red blood cell (RBC) ChE was linear with dose. In one subject given 0.6 mg/kg of HP, concentration in plasma was 0.68 ng/ml at 2 h and gradually declined to below the detection limit by 4 h. Peak plasma and RBC ChE inhibitions of 31.2% and 55.8% were achieved at 2 h for both with a 0.6 mg/kg dose. Chronic studies did not result in any accumulation of ChE inhibition up to 0.2 mg/kg b.i.d., whereas at 0.3 mg/kg b.i.d. 10-15% RBC ChE inhibition was maintained. Higher levels of ChE inhibition can be achieved with HP than with its parent compound, Phy. Red blood cell ChE inhibition recovered more slowly than plasma even though the maximum inhibition was similar for both enzymes.
Administration, Oral↗
A.E. Bennett Research Award 1993. Olfactory neuroblasts from Alzheimer donors: studies on APP processing and cell regulation.
Cell lines of continuously dividing human olfactory neuroblasts can be propagated using olfactory epithelium obtained from human donors at biopsy or autopsy. The expression of neuronal proteins in these cells, such as neurofilament protein and tau protein, can be increased using a combination of factors including nerve growth factor, fibroblast growth factor, interleukin 1 and interleukin 6. These cells also express aspects of human disease. Olfactory neuroblasts generated from donors with the common, sporadic forms of Alzheimer's disease, show elevated levels of the direct precursor to beta-amyloid, the amyloid precursor protein C-terminal derivative (CTD). When treated with the lysosomal inhibitor chloroquine, immunoblots of Alzheimer olfactory neuroblasts show seven-fold higher levels of CTDs than immunoblots from age-matched control neuroblasts. The disease related increases in CTDs can be reversed by treatment with agents that increase intracellular cyclic adenosine monophosphate (cAMP), such as dibutyryl-cyclic-AMP, theophylline, and isoproterenol.
Adenosine Monophosphate↗
Effects of chronic lithium treatment on platelet PKC isozymes in Alzheimer's and elderly control subjects.
Patients with Alzheimer's disease (AD) have been reported to have abnormalities in peripheral cells similar to some of those found in the brain, including decreased levels of protein kinase C (PKC) in fibroblasts. Since increasing evidence suggests that lithium affects PKC function, we investigated the effects of 3 weeks of lithium administration on the immunolabeling of 4 PKC isozymes (alpha, beta, epsilon, and zeta) in particulate and soluble fractions from platelets of 7 patients with probable AD and 6 age-matched controls. AD patients had significantly less particulate or membrane-associated PKC zeta than normals during the placebo phase (P < 0.003). After 3 weeks of lithium treatment, AD patients had significantly less membrane-associated PKC alpha (P < 0.002), epsilon (P < 0.003), and zeta (P < 0.001) than normals. This is the first report of a difference in PKC in blood cells between AD and control subjects. These findings appear to indicate that some PKC isozymes may be differentially regulated in AD versus elderly controls, at least as evidenced in this peripheral cellular system.
Aged↗
Autonomic dysfunction in patients with dementia of the Alzheimer type.
Abnormalities of the noradrenergic system have been documented in the central nervous system of patients with dementia of the Alzheimer's type (DAT). To evaluate the autonomic sympathetic system in DAT, we measured lying and standing blood pressure (BP), pulse, and plasma epinephrine (E) and norepinephrine (NE) in 60 DAT patients (mean age +/- SD = 65 +/- 8 years), and 20 normal elderly controls. DAT patients had normal baseline findings (BP, pulse, NE, and E). Upon standing, plasma NE and E significantly increased in both DAT patients and controls, without group differences. However, the systolic BP response to standing was reduced in DAT patients compared with the normal controls (repeated measures ANOVA, p < 0.01). This impaired response of the systolic BP on standing was particularly evident in DAT patients with symptoms of depression. Severely impaired DAT patients did not differ in E, NE, BP, pulse, or in orthostatic changes from mild-to-moderately impaired patients. These results suggest that the sympathetic response to the stress of standing is functionally impaired in DAT. This deficit was especially evident when DAT was accompanied by depression, consistent with prior studies in non-demented depressed patients.
Aged↗
CSF somatostatin in Alzheimer's disease and major depression: relationship to hypothalamic-pituitary-adrenal axis and clinical measures.
Patients with Alzheimer's disease (AD) and major depression have been shown to have overlapping clinical symptoms and biological markers, including decreased concentrations of cerebrospinal fluid (CSF) somatostatin-like immunoreactivity (SLI), which may be related to alterations in the hypothalamic-pituitary-adrenal axis activity. As in prior studies, we found that CSF SLI was significantly decreased in a group of AD patients (N = 49) and a group of elderly patients with major depression (N = 18), as compared with 13 age-matched controls (F[2, 77] = 12.9, p < .001). In the present study, CSF SLI and CSF corticotropin-releasing factor correlated significantly within the group of AD patients (r = 0.49, p < .0004) and almost attained significance in the depressed patients (r = 0.47, p < .07). CSF SLI correlated significantly with urinary free cortisol within each patient group (r = -0.51, p < .03). Clinical measures of dementia severity and depression did not consistently correlate with CSF SLI in either patient group.
Aged↗
A single oral dose challenge of buspirone does not affect memory processes in older volunteers.
Explore the source record for details and available documents.
Administration, Oral↗
Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines.
Understanding the pathway for amyloid percursor protein (APP) catabolism has become an important line of investigation. APP is a ubiquitous membrane bound protein that is rapidly cleaved at the membrane, yielding a secreted protein identical to protease nexin II and an internalized 11.5 kDa 100 residue C terminal derivative (CTD). The levels of CTDs in a variety of cell lines have been examined and were found to differ. Cell types associated with the pathology of Alzheimer's disease (AD), such as olfactory neuroblasts (ON) and cortical vascular endothelial cells, have higher levels of CTDs than lymphoblasts and melanoma cells. The mechanism of CTD catabolism appears to involve the lysosome because blockade of lysosomal but not endosomal or mitochondrial function results in increased levels of CTDs. Under these conditions, production of larger, amyloidogenic CTDs is also seen. In cells possessing higher levels of CTDs we find that the mechanism for production of amyloidogenic CTDs may involve the internalization of intact full-length APP. Thus, inhibition of the lysosomal system appears capable of generating amyloidogenic peptides. The amount of amyloidogenic peptides appears to vary among cell lines. Such variation may shed light on why amyloid accumulates around specific cell types such as vascular endothelial cells, neurons, and glia. Finally, disfunction of the lysosomal system may play a role in the pathogenesis of Alzheimer's disease.
Alzheimer Disease↗
Beta/A4 domain of APP: antigenic differences between cell lines.
The expression of amyloid precursor protein (APP) in olfactory neuroblasts has been examined with a panel of antibodies directed against varied regions of the APP molecule. The pattern of reactivity was compared to that in the transformed human glial cell line SVG, human cortical brain tissue, and in kidney epithelial 293 cells containing stably transfected and overexpressed human APP751. Antibodies directed against the C-terminus and extracellular domains of amyloid precursor protein (APP) react more strongly on immunoblot with transfected 293 cells and brain tissue than with olfactory neuroblasts (ON) or SVG cells. Antibodies directed against the beta/A4 region of APP show a contrasting pattern of reactivity, yielding greater reactivity with ON and SVG cells than with transfected 293 cells or brain tissue. Analysis of the APP transcripts using polymerase chain reaction indicates that ON and SVG both make predominantly APP770 and 751, as does the transfected 293 cell line. In the absence of any differences in APP transcripts among the cell lines, the difference in availability of the beta/A4 region appears likely to be due to posttranslational modification. These data therefore indicate that processing of APP varies among cell lines and thus may vary from tissue to tissue.
Amyloid beta-Protein Precursor↗
Continuous culture of neuronal cells from adult human olfactory epithelium.
Cells from the olfactory epithelium of adult human cadavers have been propagated in primary culture and subsequently cloned. These cells exhibit neuronal properties including: neuron-specific enolase, olfactory marker protein, neurofilaments, and growth-associated protein 43. Simultaneously, the cells exhibit nonneuronal properties such as glial fibrillary acidic protein and keratin, the latter suggesting properties of neuroblasts or stem cells. These clonal cultures contain 5-10% of cells sufficiently differentiated to show odorant-dependent cyclic adenosine 3',5'-monophosphate (cAMP) or calcium-release responses when challenged with submicromolar concentrations of odorants. The potential of culturing neuronal cells from patients with neuropsychiatric disorders, such as Alzheimer's disease or schizophrenia, could enable the study of the pathophysiology of these neurons in the culture dish and allow new approaches to the study of mental illness.
Adult↗
Distribution of peripheral lymphocytes in Alzheimer patients and controls.
Deficient immunoregulation has been postulated to play a role in the pathogenesis of Alzheimer's dementia. Recently, lymphopenia was reported to be more prevalent in Alzheimer patients than in control subjects. In addition, a decreasing number of total lymphocytes was found to be significantly correlated with increasing severity of dementia. In an attempt to replicate these findings, we studied 55 Alzheimer patients and 41 healthy controls of comparable age and gender, but found no significant difference in the distribution of total lymphocytes between these groups. Furthermore, total lymphocytes were not significantly correlated with dementia severity. Our findings, therefore, do not lend further support to an immune hypothesis for Alzheimer's dementia.
Adult↗
Dissociation of mechanisms of reading in Alzheimer's disease.
The role of spelling-to-sound correspondence rules in oral word reading was investigated by asking patients with Alzheimer's Disease (AD) and normal controls to read aloud pronounceable letter strings that do not happen to be real words. These pseudowords were of two types: those that have orthographically similar "neighbors," and those that have no neighbors. The patients with AD were mildly impaired relative to the normal controls in reading pseudowords with neighbors, but were markedly impaired in reading pseudowords with no neighbors. The results are interpreted as favoring a model of reading in which words and pseudowords are normally read via the same lexical mechanism. An ancillary route involving the conscious application of spelling-to-sound rules is available only to cognitively intact readers.
Aged↗
Alzheimer's disease and feeling-of-knowing for knowledge and episodic memory.
The metamemory (knowledge of the veracity of memories) of moderately impaired Alzheimer's patients was compared to that of aged controls. Despite their profoundly impaired recall of information from both long-term (knowledge) and recent (episodic) memory, Alzheimer's patients were as accurate as controls in assigning confidence ratings related to the probability that their recalls were correct. They were impaired, however, at predicting the likelihood that they would subsequently recognize correct answers (feeling-of-knowing) to knowledge memory questions which they had been unable to recall correctly. Nevertheless, their performance on this task did exceed chance. Thus, the moderately impaired Alzheimer's patient demonstrates intact awareness of the veracity of recall from knowledge and episodic memory but shows impaired feeling-of-knowing for knowledge memory.
Aged↗
Management of behavior disturbance in Alzheimer disease: current knowledge and future directions.
Assessment and treatment of behavior problems in patients with Alzheimer disease and related disorders is a seriously neglected area of study. Despite the fact that such problems are integral to the disorder, little is known about effective management. This article summarizes the current thinking on five areas of prime importance to patients, care providers, and health care professionals: agitation, assault/aggression, screaming, wandering, and depression/apathy/withdrawal. Methodological guidelines for studying these disorders are provided. Emphasis is on recognizing that behavior problems are important areas of study in their own right as well as in conjunction with studies of cognition.
Activities of Daily Living↗
In vivo imaging of cerebral muscarinic receptors with I-123 QNB and SPECT: studies in normal subjects and patients with dementia.
Explore the source record for details and available documents.
Alzheimer Disease↗
A strategy of "combination chemotherapy" in Alzheimer's disease: rationale and preliminary results with physostigmine plus deprenyl.
Although the central cholinergic deficits are still considered to be of primary importance in Alzheimer's disease, there is great need for an expansion of the pharmacological approach in this illness beyond the simple cholinergic replacement hypothesis. This report focuses on the concept of "combination chemotherapy" in Alzheimer's disease as the next generation of therapeutic strategies. Based on earlier positive findings in Alzheimer patients with the monoamine oxidase B inhibitor, 1-deprenyl, the authors speculate that a combination of physostigmine, the short-acting cholinesterase inhibitor, and 1-deprenyl might be more beneficial than either agent alone. The authors outline a sample paradigm for such combination studies, report preliminary data on the first 16 Alzheimer subjects to have received an initial combination of physostigmine and deprenyl, and point to other possible "combination chemotherapy" strategies for future study.
Aged↗
Measurement and interpretation of changes in memory in response to drug treatments.
Drug-induced changes in cognitive functions such as memory are generally domain specific rather than general effects, that is, only some components of memory are altered. Changes in memory can be secondary to alterations in other cognitive domains such as attention, or non-cognitive domains (mood and arousal), or the direct result of alterations on those neurobiological systems that determine memory functions. The selective memory impairing effects of benzodiazepines are used to illustrate how cognitive neuroscience methods and theory can be useful in assessing the memory changes produced by psychoactive drugs.
Animals↗