Detection of a deletion polymorphism of the human alpha(2)-macroglobulin gene (A2M-2) by a semi-automated PCR-single-stranded conformational polymorphism method.
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Humans↗
Biomedical subjects
T Sunderland
Publications and source records attributed to T Sunderland.
A validation study of the daily activities questionnaire: an activities of daily living assessment for people with Alzheimer's disease.
The Daily Activities Questionnaire (DAQ) was developed to assess activities of daily living (ADL) independence in people with Alzheimer's disease. After administering it to 276 people diagnosed with Alzheimer's disease, we examined the quality of the rating scale and its structure using a Rasch measurement approach. Results indicated that the original 10-point rating scale should be restructured to a 5-point rating scale to improve the quality of the instrument. In addition, we found that all but two ADL items defined the same construct and could be combined into a single summary measure of ADL independence. The remaining items were positioned along a hierarchical continuum, with IADL tasks more difficult than PADL tasks. Furthermore, the tasks were logically ordered by difficulty. We therefore report that the DAQ is a valid scale and conclude that it is a viable measure of ADL independence for studies of Alzheimer's disease.
Activities of Daily Living↗
The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls.
BACKGROUND: There is evidence from animal and human experiments that learning and memory come under the separate influence of both cholinergic and serotonergic pathways. We were interested in learning whether serotonergic drugs could attenuate or exacerbate the memory-impairing effects of anticholinergic blockade in humans. METHODS: The selective serotonin 5-HT3 receptor antagonist ondansetron (0.15 mg/kg i.v.) and the serotonergic agent m-chlorophenylpiperazine (m-CPP; 0.08 mg/kg i.v.) were administered in combination with the anticholinergic agent scopolamine (0.4 mg PO) and compared to scopolamine alone in 10 young, healthy volunteers. Testing occurred on three separate days. RESULTS: As expected, i.v. administration of scopolamine induced significant impairments in episodic memory and processing speed; however, these scopolamine-induced cognitive deficits were not attenuated by pretreatment with i.v. ondansetron (0.15 mg/kg), nor were they exacerbated by administration of i.v. m-CPP (0.8 mg/kg) in addition to scopolamine; however, administration of i.v. m-CPP was followed by a significant increase of self-rated functional impairment, altered self-reality, and dysphoria ratings, and scopolamine's effect on pupil size was potentiated. CONCLUSIONS: Together, these results suggest that in young, healthy volunteers scopolamine-induced changes of cognitive performance are only minimally modulated by the serotonergic effects on ondansetron and m-CPP. Further studies with older controls are needed to test whether these findings may be influenced by age.
Adult↗
Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer's disease.
The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.
Age of Onset↗
Apolipoprotein E epsilon 4 allele in association with global cognitive performance and CSF markers in Alzheimer's disease.
To better define the influence of apolipoprotein E (ApoE) epsilon 4 genotype on the cognitive and biochemical features of Alzheimer's disease (AD), cross-sectional analysis of global cognitive measures and cerebrospinal fluid studies gathered on AD subjects at a tertiary care facility between 1986 and 1997 was carried out. The 112 AD patients examined included 62 women and 50 men with a mean (SD) age of 64.2 (9.2) years. Patient demographics; illness onset age and duration, education level and global cognitive measures were recorded systematically. Genetic analysis for ApoE allele type and biochemical characterization of CSF, including total tau concentration, was performed. Descriptive statistics of demographics, cognitive and CSF measures were performed by chi-square, ANOVA and Tukey's tests. Overrepresentation of the epsilon 4 allele was found, with 45.5% of AD patients heterozygous and 20.5% homozygous for ApoE epsilon 4. Overall, ApoE epsilon 4 status had no effect on mean onset age of AD (F = 1.56; p = 0.214), but an earlier mean onset age of AD (F = 4.10; p = 0.02) was seen in the late-onset subjects. No differences were found with regard to ApoE epsilon 4 status and measures of disease, duration of illness or global cognitive performance. Although CSF tau was elevated in our sample (575.4 +/- 290.3 pg/ml), ApoE epsilon 4 status did not influence total CSF tau or neurotransmitter metabolite levels. ApoE epsilon 4 genotype had no impact on a variety of illness severity, cognitive and CSF examinations in the largest cross-sectional analysis of AD subjects yet reported.
Aged↗
Differential trace amine alterations in individuals receiving acetylenic inhibitors of MAO-A (clorgyline) or MAO-B (selegiline and pargyline).
Marked, dose-dependent elevations in the urinary excretion of phenylethylamine, para-tyramine, and meta-tyramine were observed in depressed patients treated for three or more weeks with 10, 30, or 60 mg/day of the partially-selective inhibitor of MAO-B, selegiline (l-deprenyl). In comparative studies with other, structurally similar acetylenic inhibitors of MAO, pargyline, an MAO-B > MAO-A inhibitor used in doses of 90 mg/day for three or more weeks, produced elevations in these trace amines which were similar to those found with the highest dose of selegiline studied. Clorgyline, a selective inhibitor of MAO-A used in doses of 30 mg/day for three or more weeks (a dose/time regimen previously reported to reduce urinary, plasma, and cerebrospinal fluid 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) > 80%, indicating a marked inhibitory effect on MAO-A in humans in vivo) produced negligible changes in trace amine excretion. In comparison to recent studies of individuals lacking the genes for MAO-A, MAO-B, or both MAO-A and MAO-B, the lack of change in trace amine excretion in individuals with a mutation affecting only MAO-A is in agreement with the observed lack of effect of clorgyline in the present study. Selegiline produced larger changes in trace amines--at least at the higher doses studied--than found in individuals lacking the gene for MAO-B, in agreement with other data suggesting a lesser selectivity for MAO-B inhibition when selegiline was given in doses higher than 10 mg/day. Overall, trace amine elevations in individuals receiving the highest dose of deprenyl or receiving pargyline were approximately three to five-fold lower than the elevations observed in individuals lacking the genes for both MAO-A and MAO-B, suggesting that these drug doses yield incomplete inhibition of MAO-A and MAO-B.
Biogenic Amines↗
Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses.
Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg i.v.), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone.
Aged↗
Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants.
The beta-amyloid (A beta) peptide is present both in serum and in platelets, however it is unclear whether A beta plays a role in platelet function. We have now investigated the effects of soluble A beta on platelet function and have found that low levels (0.1-1 nM) of soluble A beta augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A beta to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A beta ratios. The structure activity requirements for A beta activity showed intriguing constraints. Only full length A beta has significant activity. Truncated A beta peptides, such as A beta(1-16) or A beta(25-35), or reverse A beta(40-1) all show little or no activity. We also examined the activity of mutant A beta peptides, corresponding with the APP(692A-G) and APP(693E-Q) (at A beta21 and A beta22, respectively) which are found in familial Alzheimer's disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A beta interacts with platelets in a highly specific manner and may play a role in regulating platelet function.
Adenosine Diphosphate↗
Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease.
Tacrine is widely used for the treatment of Alzheimer's disease, but data are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheimer's disease who were receiving tacrine at doses of 40 to 140 mg/day as a part of a double-blind trial were studied. After 6 weeks of tacrine therapy, concomitant plasma and CSF samples were collected 30 minutes after the morning dose of tacrine. Although this time point is before the peak oral absorption in most patients, the critical issue for this study is that the plasma and CSF samples were collected concomitantly so that a percentage of tacrine penetration could be derived. The morning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01+/-7.07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21+/-6.00 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50+/-0.45, with wide interindividual variability. No relationship between dose and percentage of penetration was observed. Plasma concentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dose, suggesting erratic oral absorption and/or rapid metabolism. CSF concentrations ranged from not detectable to 15.92 ng/mL. The authors support that penetration of tacrine into CSF is highly variable in patients with Alzheimer's disease and that disparity in tacrine concentrations at the site of action may be one reason for conflicting results from studies of the efficacy of tacrine in Alzheimer's disease.
Aged↗
Alzheimer's disease. Cholinergic therapy and beyond.
While much of the Alzheimer's disease (AD) research community turns its spotlight on genetics, molecular biology, and the neurotoxicity of beta-amyloid, there is a more subtle but equally significant shift in focus emerging within AD therapeutic circles. Once devoid of specific treatment options, the field now enjoys a choice of two Food and Drug Administration (FDA)-approved cholinesterase inhibitors and the prospect of several more in the near future. In addition, therapy for AD is rapidly expanding beyond the central cholinergic hypothesis to include neuroprotective agents and the possibility of interfering with basic mechanisms involved in the pathogenesis of this disorder. Clinically, we have entered the era of viable cholinergic therapies, and we are already moving beyond that starting point to an era of effective combination approaches. This article provides a clinical framework for these current and potential new therapies.
Age Distribution↗
Newer psychotropic medication use in nursing home residents.
OBJECTIVE: To evaluate the use of newer psychotropic agents in nursing home residents in the era of new Health Care Financing Administration (HCFA) guidelines. DESIGN: Retrospective chart review of referrals to an on-site geriatric psychiatry service in seven Eastern Massachusetts facilities during 1995-1996. SUBJECTS: The 298 patients examined included 226 women and 72 men with a mean (SD) age of 81.9 (9.4) years. MEASUREMENTS: Patient demographics, psychiatric history and medical diagnoses, prescribed medication information, and mental status examination results were recorded systematically. Descriptive statistics of demographics, medication use, and dosing were generated, and comparative analyses were performed by chi-square, ANOVA, and Tukey's tests. RESULTS: Overall, 69% of subjects were taking at least one psychotropic medication. Although benzodiazepines (32%) and antipsychotics (42%) were used by a large portion of subjects, antidepressants (61%) were the most commonly prescribed psychotropic, with 53% taking serotonin reuptake inhibitors. The atypical antipsychotic, risperidone, accounted for more than 30% of antipsychotic prescriptions. Low rates of anticholinergic use and low doses and rates of tricyclic antidepressant use were found in Alzheimer's disease patients. Mean dosing of the psychotropic agents fell within HCFA guidelines. CONCLUSIONS: Newer-generation psychotropics have had a significant impact on the prescribing practices of primary physicians in treating nursing home residents. Of clinical importance is the high rate of antidepressant use in a population that has traditionally received inadequate pharmacotherapy for depression. More studies are needed to examine a shift to the use of other psychotropic drugs in this population in the post-HCFA area.
Aged↗
Psychosis Secondary to Encephalitis and Encephalopathies.
Psychosis due to encephalitis and encephalopathies is common and has been reported in multiple case reports or anecdotal observations. There are, however, few prospective studies or careful reviews summarizing this body of knowledge. In this review, we list a number of causes of psychosis that have been reported secondary to encephalitis and encephalopathies and focus in more detail on brain infections, inflammatory or demyelinating disease, temporal lobe epilepsy, and certain endocrine, metabolic, and nutritional deficiency states. Depending on the underlying etiology, the clinical features, course of illness, and treatment of these disturbances are quite variable. As systematic studies in these areas are lacking, there is a need for increased research to aid in the identification and management of psychotic conditions secondary to underlying encephalitis and encephalopathies.
Journal Article↗
New cholinergic therapies: treatment tools for the psychiatrist.
This article reviews the current status of therapy with acetylcholine-enhancing compounds in the management of patients with Alzheimer's disease. The focus is on pivotal articles investigating the role of cholinergic augmentation strategies, including precursor loading and acetylcholinesterase (AChE) inhibitors, in the management of cognitive and noncognitive symptoms of Alzheimer's disease. Precursor loading strategies have been for the most part unimpressive. By contrast, studies with AChE inhibitors--tacrine and donepezil--have been promising. For patients in whom hepatotoxicity and gastrointestinal side effects were not problematic, tacrine improves cognitive performance and selected secondary psychiatric symptoms and significantly delays nursing home placement. Donepezil, recently approved for use in mild to moderate Alzheimer's disease, appears to be less toxic and better tolerated than tacrine. It improves performance on cognitive testing and, in one preliminary investigation, demonstrated a sustained drug effect over several years. Therapy with AChE inhibitors provides modest significant symptomatic improvement in patients with mild to moderate Alzheimer's disease.
Alzheimer Disease↗
Physiological levels of beta-amyloid peptide stimulate protein kinase C in PC12 cells.
Alzheimer's beta-amyloid peptide (A beta) is normally present at nanomolar concentrations in body fluids and in the medium of cultured cells. In vitro experiments have shown that A beta has neurotrophic effects and can promote neuronal adhesion and elongation of axon-like processes. In an attempt to understand the molecular mechanisms underlying such effects, we have recently reported that nanomolar doses of A beta can stimulate protein tyrosine phosphorylation and activate phosphatidylinositol-3-kinase in neuronal cells. Here we show evidence that A beta can also activate protein kinase C, a serine/threonine kinase, in PC12 cells. First, using a serine-containing S6 peptide as an exogenous substrate, we found that nanomolar levels of A beta peptides 1-40 or 1-42 significantly stimulated an S6 phosphorylating kinase activity, whereas the A beta40-1 reverse sequence peptide had no effect. Down-regulation of PKC by prolonged (18 h) treatment with 1 microM PMA prevented the A beta-induced S6 phosphorylation. Using a more specific PKC substrate, N-terminal acetylated peptide (4-14) from myelin basic protein, we then demonstrated that A beta indeed increased PKC activity and that this activity could be blocked by the PKC inhibitor, staurosporine. Finally, immunoblotting experiments showed that A beta induced translocation of PKCgamma from cytosol to membrane and also significantly reduced cytosolic PKCalpha levels. Taken together, these data suggest that physiological levels of A beta can regulate PKC activity.
Amyloid beta-Peptides↗
Interleukin-6 is not altered in cerebrospinal fluid of first-degree relatives and patients with Alzheimer's disease.
We investigated interleukin-6 (IL-6) levels in cerebrospinal fluid (CSF) of 25 patients with clinically diagnosed sporadic Alzheimer's disease (AD) and 19 healthy control subjects (HC). For comparison 19 clinically healthy subjects with at least one first-degree relative with clinical or autopsy confirmed AD (CF/AD) were examined. CSF levels of IL-6 did not show statistically significant differences between AD patients, CF/AD and HC subjects. There was no correlation between age, gender, age of onset, degree of cognitive impairment, blood-brain barrier dysfunction and IL-6 values. We could not demonstrate altered CSF concentrations of IL-6 that may indicate an inflammatory response or capability to support neuronal survival in the central nervous system (CNS) of first-degree relatives and patients with AD. We suggest that combined measurement of all parameters of the IL-6-receptor complex could yield more insight in a probably altered IL-6 function.
Adult↗
Opiate receptor avidity and cerebral blood flow in Alzheimer's disease.
Positron emission tomography was performed on 12 Alzheimer's patients and 12 age-matched normal controls following the administration of the opiate receptor antagonist 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF). Tracer kinetic analysis was used to determine the volume of distribution of CF, a measure of unoccupied mu and kappa receptor density, i.e. opiate receptor avidity in 34 brain regions. Regional cerebral blood flow rates (CBF) were determined on the same day with H2[15O]. Global gray CF avidity and global gray CBF were found to be lower in the Alzheimer's patients and correlated (r=0.73, P<0.03). Regional CBF differences were superimposed on global CBF changes in the Alzheimer's patients, with the subcortex relatively spared. Multivariate statistical analyses, however, failed to demonstrate regional specificity for the CF avidity changes. Furthermore, percent changes in regional CF avidity were not correlated with percent changes in regional CBF (r=0.12, P=NS). These findings demonstrate involvement of the opiate system in Alzheimer's disease. Although, neurodegeneration is the likely underlying process responsible for both the changes in CF avidity and CBF in Alzheimer's disease, the differences with respect to the patterns of these losses suggest that the intermediate mechanisms leading from neurodegeneration to loss are distinct.
Aged↗
Plasma levels of m-chlorophenylpiperazine following single oral dose administration of m-chlorophenylpiperazine and trazodone in human volunteers.
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Antidepressive Agents, Second-Generation↗
Minimal effects of dextroamphetamine on scopolamine-induced cognitive impairments in humans.
The central anticholinergic drug scopolamine has been used to model aspects of the memory impairment that occurs in Alzheimer's disease and in aging. To determine whether nonspecific stimulant effects can attenuate the cognitive impairment induced by scopolamine, we studied the effects of scopolamine and the stimulant dextroamphetamine in 17 young normal volunteers. After a baseline day of cognitive testing, subjects participated in two study days, in which they received dextroamphetamine (d-AMP) (0.25 mg/kg p.o.) + scopolamine (0.5 mg i.v.) and placebo + scopolamine, in randomized order under double-blind conditions. There were no statistically significant differences in cognitive test performance between the two drug conditions with the exception of one of the category retrieval tasks. Stimulant effects were documented to occur by other measures. We conclude that d-AMP at the dose used does not attenuate the memory impairment induced by scopolamine.
Adult↗