Effects In Alzheimer's Disease Research Articles

Short-Term Effects of β-Amyloid25-35Peptide Aggregates on Transmitter Release in Neuromuscular Synapses

The beta-amyloid (AB) peptide25-35 contains the functional domain of the AB precursor protein that is both required for neurotrophic effects in normal neural tissues and is involved in the neurotoxic effects in Alzheimer disease. We demonstrated the presence of the amyloid precursor protein/AB peptide in intramuscular axons, presynaptic motor nerve terminals, terminal and myelinating Schwann cells, and the postsynaptic and subsarcolemmal region in the Levator auris longus muscle of adult rats by immunocytochemistry. Using intracellular recording, we investigated possible short-term functional effects of the AB fragment (0.1-10 micromol/L) on acetylcholine release in adult and newborn motor end plates. We found no change in evoked, spontaneous transmitter release or resting membrane potential of the muscle cells. A previous block of the presynaptic muscarinic receptor subtypes and a previous block or stimulation of protein kinase C revealed no masked effect of the peptide on the regulation of transmitter release. The aggregated form of AB peptide25-35, however, interfered acutely with acetylcholine release (quantal content reduction) when synaptic activity was maintained by electric stimulation. The possible relevance of this inhibition of neurotransmission by AB peptide25-35 to the pathogenesis of Alzheimer remains to be determined.

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation: EFFECTS OF ALZHEIMER DISEASE AND IDENTIFICATION OF LIPOXIDATION TARGETS

Diverse oxidative pathways, such as direct oxidation of amino acids, glycoxidation, and lipoxidation could contribute to Alzheimer disease pathogenesis. A global survey for the amount of structurally characterized probes for these reactions is lacking and could overcome the lack of specificity derived from measurement of 2,4-dinitrophenylhydrazine reactive carbonyls. Consequently we analyzed (i) the presence and concentrations of glutamic and aminoadipic semialdehydes, N(epsilon)-(carboxymethyl)-lysine, N(epsilon)-(carboxyethyl)-lysine, and N(epsilon)-(malondialdehyde)-lysine by means of gas chromatography/mass spectrometry, (ii) the biological response through expression of the receptor for advanced glycation end products, (iii) the fatty acid composition in brain samples from Alzheimer disease patients and age-matched controls, and (iv) the targets of N(epsilon)-(malondialdehyde)-lysine formation in brain cortex by proteomic techniques. Alzheimer disease was associated with significant, although heterogeneous, increases in the concentrations of all evaluated markers. Alzheimer disease samples presented increases in expression of the receptor for advanced glycation end products with high molecular heterogeneity. Samples from Alzheimer disease patients also showed content of docosahexaenoic acid, which increased lipid peroxidizability. In accordance, N(epsilon)-(malondialdehyde)-lysine formation targeted important proteins for both glial and neuronal homeostasis such as neurofilament L, alpha-tubulin, glial fibrillary acidic protein, ubiquinol-cytochrome c reductase complex protein I, and the beta chain of ATP synthase. These data support an important role for lipid peroxidation-derived protein modifications in Alzheimer disease pathogenesis.

Conventional Trial Designs Offer Limited Clinical Understanding of Cholinesterase-Inhibitor Treatment Effects in Alzheimer Disease

Conventional Trial Designs Offer Limited Clinical Understanding of Cholinesterase-Inhibitor Treatment Effects in Alzheimer Disease

On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease

The surprisingly beneficial effects in Alzheimer disease (AD) of ion channel blockers (ICB) like memantine that act on NMDA- and other aminergic transmitter receptors are yet poorly understood. NMDA receptor levels and binding were shown to be significantly decreased in AD, in which highly NMDA receptor and Ca(2+) dependent synaptic plasticity and re-modelling are severely compromised. Thus, how could one expect to improve AD by further suppressing NMDA channels with antagonists. Nevertheless, clinical trials with NMDA blockers revealed in moderate to advanced AD surprisingly positive effects. The present paper tries to provides a hypothetical explanation of that paradoxical success of ICBs. Based on evidence from current data, emphasis is put on a profound impairment in the AD brain of the inhibition-excitation balance in the neuronal circuitry to the advantage of excitation. This imbalance is conceived to result from a degeneration of four modulatory aminiergic transmitter systems (serotonin, noradrenalin, acetylcholine, histamine) and related peptidergic systems, the decline of which causes a profound loss of inhibitory impact in the forebrain neuronal circuitry leading to disinhibition of principal neurones ("aminergic disinhibition"). Subsequent Ca(2+) excito-toxicity and its sequelae are suggested to be the basic promotors of the neuro-degeneration and the related mental decline in AD. Re-adjustment of the inhibition-excitation imbalance by decreasing excitation is conceived to be the mechanism that renders ion channel blockade therapeutically successful. Putatively, attempts to increase inhibition, e.g., by application of GABA mimetics that stimulate the production GABA from preserved but "lazy" GABA neurones lacking aminergic facilitation, might be an even better way to achieve the re-balance.

Effects of Alzheimer disease on memory for verbal emotional information

In healthy young and older adults, emotional information is often better remembered than neutral information. It is an open question, however, whether emotional memory enhancement is blunted or preserved in Alzheimer disease (AD). Prior studies of emotional memory in AD have included small samples of patients. In addition, studies that failed to find an enhancement effect in AD used stimuli lacking semantic coherence (e.g. lists of unrelated words, some that were emotional and others that were neutral). To circumvent these limitations, the present study examined a large number of AD patients ( N=80) and investigated whether AD patients would show better memory for a verbal description of an emotional event as compared to a neutral one. AD patients were equivalent to young and older control participants in rating the emotional descriptions for valence and arousal. Unlike the control groups, however, memory in AD patients did not benefit from the emotional narratives. We conclude that AD disrupts memory enhancement for at least some types of verbal emotional information.

Evidence for parent of origin effect in late-onset Alzheimer disease.

Evidence for a parent of origin effect in Alzheimer disease was obtained from a sample of 148 sibships on which affection status of the parents was sought using family history interviews. The parent study recruited families with two or more affected sibs for late onset AD utilizing rigorous diagnostic criteria. In 74 families, there was evidence of an affected parent, 49 maternal and 25 paternal. Genome scan data were analyzed for the sample as a whole and for the maternal and paternal families separately, using Genehunter-ASM. Seven regions with Z(lr) scores >or=2 were identified, four in maternal families (chr. 10,12,19,20) and three in paternal families (chr. 1,7,13). With the exception of the chromosome 10 finding, analysis by parent of origin greatly increased evidence of linkage in areas showing no linkage in the overall analyses. For example, a chr. 12 region reached a LOD = 2.29 among maternal families whereas the same region showed a LOD = 0.3 when all families were analyzed together. The strongest findings among maternal families (chr. 10 and 12) were followed up with fine mapping that resulted in an increase in maximum LOD scores from 2.7-3.2 on chr. 10, and 2.29-2.42 on chr. 12. These analyses highlight the importance of parent of origin effects in late-onset AD families and identify several genomic regions that may include genes linked to late-onset AD specific to disease transmission from the mother and require further investigation.

Effect of Alzheimer disease on the cost of treating other diseases.

The authors' objective is to determine the effect of diagnosed Alzheimer disease (AD) on cost to Medicare of treating other diseases. Using the 1994 National Long-Term Care Survey merged with Medicare claims and death data, the authors assessed the relative cost to Medicare of covering beneficiaries over 1994-1995 with diagnosed AD relative to other elderly population. They focused on hospitalizations during 1994-1995 for hip fracture, stroke, coronary heart disease, congestive heart failure, and pneumonia. The authors determined whether differences in Medicare payments by AD status mainly reflected differences in rates of occurrence of hospitalizations for the five primary diagnoses, other primary diagnoses, or death during 1994-1995 or in spending given the adverse events. During 1994-1995, an average of $15,700 was spent by Medicare, per person, for those with diagnosed AD, nearly twice the amount spent on others. The difference in Medicare payments was attributable to more adverse events occurring to AD group. Such persons had higher death rates than other elderly population (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.07-1.62), higher hospitalization rates for hip fracture (OR, 1.96; 95% CI, 1.34-2.87), stroke (OR, 1.71; 95% CI, 1.10-2.68), pneumonia (OR, 1.46; 95% CI, 1.07-1.99), and for other reasons than the five conditions (OR, 1.65; 95% CI, 1.38-1.98), but they also had lower hospitalization rates for the cardiac diseases. There were no differences in Medicare payments according to AD diagnosis, controlling for frequency of deaths, hospitalizations, and other factors. Persons with diagnosed AD cost Medicare more because of more adverse health events rather than in intensity of care, given event occurrence.

Estrogen replacement therapy for cognitive benefits: viable treatment or forgettable "senior moment"?

The perceived benefits of estrogen on cognitive function are one of the few remaining potential roles for estrogen replacement therapy. The justification for such a role has a strong biologic basis and is easily shown in animal models. Purported benefits for estrogen on cognitive function include neuroprotective, neurostimulating, and neurotrophic effects. The objective of this study was to review the literature and to evaluate the role of estrogen replacement therapy in improving cognition in Alzheimer disease, vascular dementia, premenopausal women, and postmenopausal women without dementia. Additionally, the authors separately looked at the neuroprotective effects of estrogen replacement therapy on the subsequent risk of dementia. The available data fail to show a therapeutic benefit of estrogen replacement therapy in Alzheimer disease. Surprisingly, limited data allow consideration of a possible role of estrogen in the management of vascular dementia. Additionally, younger females with low estrogen levels secondary to primary ovarian failure and Turner syndrome benefit from estrogen replacement therapy. Despite the limited role of estrogen replacement therapy in cognitive enhancement, neuroprotective properties are likely because several prospective studies indicate a reduced risk of Alzheimer disease. A critical window of opportunity seems to exist for this protective effect in Alzheimer disease because once established, the course of the disease is not affected by concomitant estrogen replacement therapy. The authors conclude that the use of estrogen replacement therapy is not substantiated for the treatment of patients with Alzheimer disease. Alternatively, because of the evidence for a possible neuroprotective effect, women at high risk for the development of Alzheimer disease may be appropriate candidates for estrogen replacement therapy. Such a decision should be made on a case-by-case basis, after careful consideration of the risks and benefits.

The Effect of Brain Atrophy on Cerebral Hypometabolism in the Visual Variant of Alzheimer Disease

Brain glucose metabolic rates measured by positron emission tomography can be more affected by partial volume effects in Alzheimer disease (AD) than in healthy aging because of disease-associated brain atrophy. To determine whether the distinct distribution of cerebral metabolic lesions in patients with the visual variant of AD (AD + VS) represents a true index of neuronal/synaptic dysfunction or is the consequence of brain atrophy. Government research hospital. Resting cerebral metabolic rate for glucose was measured with positron emission tomography in a cross-sectional study of AD and AD + VS groups and in healthy control subjects. Segmented magnetic resonance images were used to correct for brain atrophy. Patients with AD + VS had prominent visual and visuospatial symptoms. There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control subjects. Measurement of the rate of cerebral glucose metabolism. Before atrophy correction, the AD + VS group, compared with the control subjects, showed hypometabolism in primary and extrastriate visual areas and in parietal and superior temporal cortical areas. Compared with the AD group, the AD + VS group showed hypometabolism in visual association areas. After atrophy correction, hypometabolism remained significantly different between patients and controls and between the 2 AD groups. The reductions in cerebral hypometabolism represent a true loss of functional activity and are not simply an artifact caused by brain atrophy. The different patterns of hypometabolism indicate the differential development of the lesions between the AD and AD + VS groups.

Review: Tacrine has some benefits and many adverse effects in Alzheimer disease

Source Citation Arrieta JL, Rodriguez Artalejo F. Methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease: a systematic review of the literature. Age ...

Gangliosides -- A new therapeutic agent against stroke and Alzheimer's disease

Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. The highest ganglioside concentration of any organ is found in the mammalian brain, where the gangliosides are enriched in the neuronal membrane, particularly in the synapses. There are four major brain gangliosides with the same neutral tetrasaccharide core to which one to three sialic acids are linked - the simplest being the GM1-ganglioside. These gangliosides have been shown to have neuritogenic and neuronotrophic activity and to facilitate repair of neuronal tissue after mechanical, biochemical or toxic injuries. Mixtures of native bovine brain gangliosides were adopted for pharmacological use in the treatment of peripheral nerve damage, and GM1-ganglioside has been applied for the treatment of CNS injuries and diseases. Beneficial effects of GM1 have been documented in the treatment of stroke and spinal cord injuries, particularly when the treatment has been initiated within a few hours of the acute event. Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).

The effects of Alzheimer disease on driving-related abilities.

Ten Alzheimer disease (AD) patients and 12 healthy elderly controls were evaluated on two tests of driving-related abilities: the Driver Performance Test (DPT) and the Driving Advisement System (DAS). Subjects were administered a battery of neuropsychological tests to determine if severity of dementia in AD correlates with driving performance. On the DPT, the AD patients scored in the average range in two of five skill areas (predicting the effects of a hazard, deciding how to avoid it); below average in two areas (searching for a hazard, executing evasive actions); and poorly in one area (identifying hazards). The elderly controls scored at an average level in all five skill areas. On the DAS, AD patients were significantly slower than the elderly controls on simple, two-choice, and conditional reaction time tests and were much slower than drivers in general. The AD patients' performances on two cognitive tests, the Mini-Mental State Examination (MMSE) and the Category Fluency Test, correlated significantly with aspects of performance on the DPT and the DAS. Although these are preliminary results from a pilot investigation, they suggest that AD patients' driving-related abilities are adversely affected by the disease and that driving-related performance tests and neuropsychological tests may be useful in assessing the impact of AD on driving.

Precipitation and Characterization of an Aluminosilicate from ALCL3-Na2SiO3-HCL in Serum, of Interest for Alzheimer Disease

A precipitation experiment was performed with human serum to model aluminosilicate formation in brains of patients with Alzheimer disease. Aluminum and (or) silicate ions were added to serum in a 1:2 molar ratio at pH 7.4. Precipitates formed immediately and were left for 24 h at 37 degrees C before filtration. Silicate and aluminosilicate formed precipitates with human serum proteins albumin, transferrin, and IgG. In untreated samples, the IgG/albumin ratio increased slightly compared with the ratio in dried serum. Diethylbarbiturate-washed precipitates had a significantly lower protein content than did untreated ones. The IgG/albumin ratio increased considerably in the sample containing aluminosilicate. We conclude that IgG is the sodium dodecyl sulfate-soluble human protein most firmly bound to the aluminosilicate matrix. From 27Al magic-angle-spinning nuclear magnetic resonance (MAS NMR), a pronounced peak was found at 52.79 ppm and a minor peak at 0.53 ppm, suggesting that 4-coordinated aluminum predominates and that 6-coordinated aluminum is present in a smaller proportion. The 29Si MAS NMR spectrum shows a poorly ordered structure. The aluminosilicate formed also contains the cations Na+ > K+ > Ca2+ > Mg2+ and anions Cl- > PO4(3-). Rather than looking for aluminum toxicity to explain the effects of Alzheimer disease, one should consider that by precipitating such a composite phase, the balance of cations, anions, and proteins in human serum is changing.