Amyloid beta protein and Alzheimer disease

Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view of evidence that NSAID therapy may interfere with the hydrolysis of phospholipids, the researchers will focus on finding an NSAID-related compound effective against Alzheimer disease.     

Use of cholinesterase inhibitors in Alzheimer disease

According to the cholinergic theory of Alzheimer's disease, the cognitive failure depends on a deficit in acetylcholine. The study reported above examines the efficacy and tolerability of cholinesterase inhibitors, such as tetrahydroamino acridine (THA), for the management of this pathology.     

Predicting the course of disease

The ability to predict the course of disease and the effect of interventions is critical to effective medical practice and health care management. In this analysis, we sought to test whether available clinical data and analytic methodologies can be used to accurately predict the time course of the probability of death after hospital admission and the probability of readmission following discharge for patients with acute myocardial infarction or pulmonary disease. We grouped patients by selected physiologic characteristics and made time-to-event predictions using multiple regression models. These predictions were compared with observed probabilities calculated using the actuarial or life-table method. Predictions made with the Bailey-Makeham model generally replicated observed experience. They accurately accounted for substantial differences in the patterns of death and readmission and accurately delineated the effects of therapies, after adjustment for patient risk. These results were validated by analyses of resampled populations that differed in case mix from the source population. We believe that using such models to project the course of disease and the effects of treatment on that course in defined classes of patients should facilitate the development of practice guidelines for patient care and the management of health care resources.     

Abnormalities of mitochondrial enzymes in Alzheimer disease

Abundant evidence, including critical information gathered by Prof. Siegfried Hoyer and his colleagues, indicates that abnormalities of cerebral metabolism are common in neurodegenerative diseases, including Alzheimer's Disease (AD). Alterations in mitochondrial enzymes likely underlie these deficits. Replicable reductions in AD brain occur in the pyruvate dehydrogenase complex (the link of glycolysis to the Kreb's cycle), the alpha-ketoglutarate dehydrogenase complex (KGDHC; the link of Kreb's cycle to glutamate metabolism) and cytochrome oxidase (the link of the Kreb's cycle to oxygen utilization). Available evidence suggests that deficiencies in KGDHC may be genetic in some cases, whereas evidence that the other two enzyme systems have a genetic component is lacking. Additional results indicate that the reductions can also be secondary to other causes including oxidative stress. A variety of data suggest that the mitochondrial insufficiencies contribute significantly to the pathophysiology of AD.     

Genetics, ethics, and Alzheimer disease

This article considers the emerging research on Alzheimer disease (AD) genetics in relation to ethical questions surrounding presymptomatic and prenatal genetic testing. Given the rapid advance in AD genetics over the past 8 years, it is likely that the attention of clinicians and ethicists will increasingly turn to genetic issues. After a survey of current genetic knowledge, this article addresses 3 areas of likely ethical concern. While AD genetic screening programs are currently rare and restricted to specific pedigrees, they will become more common in the future. It is, therefore, imperative that society and clinicians begin to consider the ethical issues this raises.     

Tissue segmentation of the brain in Alzheimer disease

Cytomegalovirus-based mammalian expression vectors are widely used to drive the expression of transfected genes in cultured cells. Immunofluorescent staining of the WT1 protein in 3T3 and 293 cell clones, stably transfected with a cyomegalovirus (CMV) expression vector carrying a cDNA coding for the tumour suppressor protein WT1, showed extreme cell to cell variation in the amount of recombinant protein expressed, indicative of cell cycle dependence. This was investigated further by Western blot and FACS analysis which showed that WT1 protein expression was highest in S phase and almost absent in G0/G1. Northern blot analysis of cell clones expressing sense or antisense WT1 cDNAs regulated by the CMV promoter/enhancer showed that RNA expression was also cell cycle-dependent. Western blotting of cells expressing a luciferase reporter gene driven by the CMV promoter/enhancer also showed apparent cell cycle-dependent expression. We further demonstrated that the expression of these gene constructs was serum responsive with a 10-fold increase in expression occurring 2 h after the addition of serum. These results show that the CMV promoter/enhancer system varied in its response to serum and the cell cycle state. Therefore, care must be taken when interpreting any phenotypic alterations (or lack of them) produced in cells transfected with CMV-based expression vectors.     

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.     

Studies of the enteric nervous system in Alzheimer disease and other dementias of the elderly: enteric neurons in Alzheimer disease

Nitric oxide is a biological mediator. In nervous system it acts like neurotransmitter and also modulate acute inflammation. In the peripheral nervous system it blocks the nociceptive stimulus through an increase in postsynaptic neurone GMPc level. Nitro-vasodilator drugs like nitroglycerin are metabolised in the cell given rise to short lived intermediates, which liberating nitric oxide that activate the guanylate cyclase enzyme, increasing the GMPc in smooth muscle cell. This study show that nitroglycerin produces an analgesic action. The pain sensitivity to pinprick test in forearm with nitroglycerin has shown a decrease in a significative manner against placebo. We speculate that nitroglycerin could have a similar action as endogenous nitric oxide in nervous system.     

Alzheimer disease and frontotemporal dementias. Behavioral distinctions

BACKGROUND: Frontotemporal dementia (FTD) is a syndrome produced by lobar degeneration of the temporal and/or frontal lobes. OBJECTIVES: To quantify the behavioral disturbances of FTD and compare them with behavioral changes observed in Alzheimer disease (AD). DESIGN: Cross-sectional comparison of 2 groups defined by research diagnostic criteria and single photon emission computed tomography. Behaviors were assessed using a standardized rating scale-Neuropsychiatric Inventory. Groups were matched for dementia severity. SETTING: Patients were seen at 2 university-based outpatient dementia clinics and a Veterans Affairs medical center. PARTICIPANTS: Twenty-two patients with FTD and 30 patients with AD. RESULTS: Patients with FTD had significantly greater total Neuropsychiatric Inventory scores than patients with AD and exhibited more apathy, disinhibition, euphoria, and aberrant motor behavior. The Neuropsychiatric Inventory accurately assigned 77% of patients with FTD and 77% of patients with AD to the correct diagnostic group using disinhibition, apathy, and depression. Patients with FTD had higher levels of disinhibition and apathy with relatively lower levels of depression compared with patients with AD. CONCLUSIONS: The Neuropsychiatric Inventory provides a behavioral profile that differentiates patients with FTD from patients with AD. Patients with FTD are more behaviorally disturbed but are often less depressed than patients with AD relative to their level of apathy.     

Predicting coronary aneurysms in Kawasaki disease

Intravenous immunoglobulin is used to prevent coronary artery involvement in patients with acute Kawasaki disease. In this issue of the journal, Beiser et al provide a scoring system that is invoked 24 hours after gamma globulin therapy to predict risk for coronary involvement. This instrument would be useful for pediatric cardiologists and pediatricians in planning later management of patients with Kawasaki disease and counseling parents regarding long-term outcome.     

Familial Alzheimer disease: first report from India

Kept under observation were eight patients with Sweet's syndrome--six men and 2 women aged 25-60. The syndrome was accompanied by fever in 8 patients; in 6 it was preceded by common cold, respiratory diseases; neutrophilia was present in 7 patients. Rash presented as inflammatory spots, 10 am in diameter, was located predominantly in the upper part of the body. Helpful in the treatment of the condition were corticosteroid therapy and potassium iodide.     

Alzheimer disease: protein-protein interaction and oxidative stress

Alzheimer disease, the most prevalent dementia of the aged, is defined by the concurrence of two filamentous brain lesions: neurofibrillary tangles and senile plaques. The lesions are temporally and spatially correlated to each other and to cognitive impairment suggesting that is a interaction between neurofibrillary tangles and senile plaques that might play a role in disease pathogenesis. Here we present findings demonstrating specific interactions between the major protein components of the lesions. Such an interaction is likely important to lesion genesis and to the overall cognitive deficits seen clinically. Also important are forces that stabilize and cement abnormal interactions and protect them form removal. Oxidative post-translational modifications is probably one of the major mediators that by disrupting cellular homeostatic balance both promotes abnormal interactions and makes them resistant to proteolytic removal. Overall, these findings support the view that the lesions of Alzheimer disease are intimately involved in neuronal destructions.