Interaction of tacrine and velnacrine with neocortical synaptosomal membranes: relevance to Alzheimer's disease

The acridine-based, potential Alzheimer's disease therapeutic agents, tacrine and velnacrine, were incubated with rat or gerbil neocortical synaptosomal membranes. Electron paramagnetic resonance employing a protein-specific spin label was used to monitor this interaction. Analogous to their effects in erythrocyte membranes [Butterfield and Rangachari (1992) Biochem. Biophys. Res. Commun. 185: 596-603], in the present studies both agents decreased segmental motion of spin labeled synaptosomal membrane proteins, consistent with increased cytoskeletal protein-protein interactions (0.001 < P < 0.005), and tacrine was more potent than velnacrine. These results are discussed with possible relevance to molecular actions of the agents and molecular alterations in Alzheimer's disease.     

The cardinal features of cognitive and noncognitive dysfunction and the differential efficacy of tacrine in Alzheimer's disease patients

The Alzheimer's Disease Assessment Scale (ADAS), frequently used in clinical trials to assess overall pathology of Alzheimer's disease (AD), comprises two subscales. The cognitive subscale (ADAS-COG) consists of 11 items, and the noncognitive subscale consists of 9 items. Factor analyses were carried out on ADAS-COG and ADAS-NONCOG item scores from the most recent and largest (n = 663) placebo-controlled, multicenter, 30-week study (970-61) of tacrine in patients with AD conducted by the clinical research group at Parke-Davis Pharmaceutical Research. Through factor analyses the primary dimensions of variation in the ADAS-COG and ADAS-NONCOG were defined. Obliquely rotated three principal factors of ADAS-COG and three principal factors of ADAS-NONCOG have been interpreted as three cardinal features of cognitive function corresponding to memory, language, and praxis, and three cardinal features of noncognitive function corresponding to agitation, depression, and lack of concentration. Reliably defined factors of ADAS-COG enabled comparisons of longitudinal changes in cognitive dysfunction. Factor scores at week 30, adjusted to baseline factor scores, were used to compare the effects of tacrine with those of placebo on cognitive cardinal features. Additionally, the effect of concurrent depression on cardinal features of cognitive dysfunction was evaluated by gender.     

Retrieval monitoring and anosognosia in Alzheimer's disease.

This study explored the relationship between episodic memory and anosognosia (a lack of deficit awareness) among patients with mild Alzheimer's disease (AD). Participants studied words and pictures for subsequent memory tests. Healthy older adults made fewer false recognition errors when trying to remember pictures compared with words, suggesting that the perceptual distinctiveness of picture memories enhanced retrieval monitoring (the distinctiveness heuristic). In contrast, although participants with AD could discriminate between studied and nonstudied items, they had difficulty recollecting the specific presentation formats (words or pictures), and they had limited use of the distinctiveness heuristic. Critically, the demands of the memory test modulated the relationship between memory accuracy and anosognosia. Greater anosognosia was associated with impaired memory accuracy when participants with AD tried to remember words but not when they tried to remember pictures. These data further delineate the retrieval monitoring difficulties among individuals with AD and suggest that anosognosia measures are most likely to correlate with memory tests that require the effortful retrieval of nondistinctive information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interleukin-6-associated inflammatory processes in Alzheimer's disease: new therapeutic options

The cytokine interleukin-6 is consistently detected in the brains of Alzheimer's disease patients but not in the brains of nondemented elderly persons. Until recently it was unclear whether an interleukin-6-associated inflammatory mechanism is an early or late event in the pathological cascade of Alzheimer's disease. We investigated whether interleukin-6 could be detected in plaques of Alzheimer's disease patients prior to the onset of neuritic degeneration. We found interleukin-6 mostly in plaques where neuritic pathology has not yet developed. This indicates that the appearance of interleukin-6 may precede neuritic changes and is not just a consequence of neuritic degeneration. Therefore, one may hypothesize that activation of inflammatory mechanisms may cause neuritic degeneration in plaques. A suppression of interleukin-6 synthesis could, therefore, be of therapeutic value. Upon screening a number of substances, we found that a small number of nonsteroidal antiinflammatory drugs, including tenidap, were able to inhibit interleukin-6 synthesis in cultured human astrocytoma cells. These substances may be therapeutically useful in Alzheimer's disease and should be evaluated in clinical studies.     

The Alzheimer's Disease Assessment Scale: patterns and predictors of baseline cognitive performance in multicenter Alzheimer's disease trials

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is used as an efficacy measure in clinical drug trials of Alzheimer's disease (AD). We used data from 1,648 AD participants in two identical 26-week multicenter drug trials to examine the distribution of baseline ADAS-Cog scores in relation to selected demographic and clinical variables, Mini-Mental State Exam (MMSE), Global Deterioration Scale (GDS), and Geriatric Evaluation by Relative's Rating Instrument (GERRI) scores. At baseline, the mean (+/-SD) MMSE score was 18 +/- 4, the ADAS-Cog score was 28 +/- 11, and most subjects were in GDS stage 4 or 5. The ADAS-Cog score was statistically significantly correlated with MMSE (R = -0.76, p < 0.0001) and GERRI (R = 0.40, p < 0.0001) total scores. Correlations among the ADAS-Cog items ranged from 0.19 to 0.59 and all were statistically significant (p < 0.0001). In a multiple regression model, younger age, male gender, older age at onset of dementia, use of concurrent estrogen, and use of concurrent anti-inflammatory agents were statistically significantly associated with superior cognitive performance. We also present data on the distribution of ADAS-Cog scores in relation to subjects' age, level of education, MMSE score, and GDS stage. Because age, MMSE score, and GDS stage (and not the ADAS-Cog) are commonly used to select subjects for AD clinical trials, our data should improve the ability of sponsors to predict ADAS-Cog scores of the subjects in their trials on the basis of the inclusion criteria used. Our data also suggest that age, gender, age at onset of dementia, level of education, and use of estrogen (in women) or anti-inflammatory drugs are related to cognitive abilities in AD. Further studies are needed to assess how and when cognitive differences related to these variables arise.     

Treatment of Alzheimer disease with tacrine: a cost-analysis model

In a cost-analysis model, the effect on the costs of Alzheimer disease of tacrine (tetrahydroaminoacridine) treatment was studied. A model of the survival of the Swedish Alzheimer disease population was constructed in which the placement of patients with Alzheimer disease in care organization was assumed to be influenced by the use of tacrine. Based on this model, the cost analysis was performed. Fifty-two percent of the Alzheimer disease population with an initial Mini-Mental State Examination (MMSE) score of 10 to 24 points are in the main alternative of the model treated with 160 mg tacrine with an initial improvement in MMSE of 2.6 points. The benefit of tacrine was a cost reduction of 1.3% when the results were calculated for the entire Alzheimer disease population. This corresponds to a benefit of 1.3 billion Swedish kronor (SEK) (with 3% discount rate) for the entire estimated survival period. The annual benefit per patient was estimated as 2,900 SEK [approximately U.S. $320 (1993)]. In the sensitivity analysis, the range was between -0.6% and 5.2%. Beginning treatment in the early stages of Alzheimer disease results in lower costs than a later start. The main conclusion is that tacrine, according to the model, has beneficial but modest effects on the costs of Alzheimer disease in Sweden.     

Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75(NTR), both of which are produced by CBF neurons. This review focuses on NGF/receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.     

Bioavailability and pharmacokinetic disposition of tacrine in elderly patients with Alzheimer''s disease

PURPOSE: The Baerveldt glaucoma implant is an aqueous shunting device with large surface area that is installed through a single-quadrant conjunctival incision. A rabbit model of the Baerveldt implant was created to obtain serial histology and clinical information over 1 year. METHODS: Modified versions of the Baerveldt implant (110 or 160 mm2) were implanted in 18 normal New Zealand white rabbit eyes. The rabbits were examined periodically and their intraocular pressures (IOPs) recorded. They were killed at monthly intervals to obtain histology of the bleb capsules. RESULTS: Thin capsules were present at 1 month, which consisted of lamellar collagen deposition surrounded by a granulomatous reaction with multinucleate giant cells. Inflammatory cells (probably macrophages) were scattered on the inner bleb surface. The granulomatous reaction resolved after 4 months. Subsequently, capsule thickness and cellularity remained relatively stable, although the collagen stroma became less compact over time. Sixteen rabbit eyes had initial IOP reductions of > or = 3 mm Hg compared with fellow eyes, which persisted up to 4 weeks postoperatively. Seven eyes (39%) exhibited a hypertensive phase (IOP exceeded that of fellow eye by > or = 3 mm Hg) from 2 weeks to 3 months postoperatively. CONCLUSION: The Baerveldt explant is surrounded by a fibrous capsule that matures over time. The bleb histology in the rabbit model is similar to that described with the Molteno implant in primates and humans, except for the eventual development of a fibroblastic inner lining in the rabbit model. This contrasts with primate and human models, in which the inner lining remains an open mesh.     

Advances in the treatment of Alzheimer's disease

Management of the most common type of dementia--Alzheimer's disease--is becoming increasingly sophisticated. Differentiation of Alzheimer's disease from vascular dementia has become therapeutically important, since the choice of treatments depends on the diagnosis. Two cholinesterase inhibitors, donepezil and tacrine, are labeled for use in patients with Alzheimer's disease. Other therapies, such as estrogen, nonsteroidal anti-inflammatory drugs and vitamin E, are sometimes used and show promise in delaying the progression of this dementia. Behavior problems, which often accompany the disease, can be managed using environmental modification, alterations in caregiving and medication. In the terminal phase of the illness, quality care involves implementing advance directives, communicating with the family, individualizing care and attending to patient comfort.     

Improving the use of therapeutic drug monitoring

A search for serum factors that modulate the mutability of human cells has been attempted in the peripheral blood of lung cancer patients. Factors were separated by dye-ligand chromatography and first identified as those exhibiting the ability to enhance the frequency of drug-resistance mutations in human RSa cells. The frequency was assessed by estimation of the cloning efficiency of mutant cells resistant to ouabain-mediated cell killing (OuaR) after irradiation with far-ultraviolet light (UV, mainly 254-nm wavelength). Pre-culture of cells with medium containing the factors prior to UV irradiation led to about a 19- to 37-fold increase in the OuaR mutation frequency compared with that of cells irradiated but not treated with the factors. The enhancing activity was detected in the serum of all 7 lung cancer patients, although the serum itself, which had not been treated with chromatography, had little or no enhancing activity in all patients. No enhancing activity was detected in serum preparations from healthy donors. The enhancing activity of lung cancer serum factors on UV-induced mutagenicity was next confirmed by detecting an enhancement of K-ras codon 12 base substitution mutations in human RSb cells, as analyzed by polymerase chain reaction (PCR) and differential dot-blot hybridization. Our results, together with previous findings on suppression of mutagen-induced mutagenicity by human interferons, suggest the existence of extracellular factors that modulate the mutability of human cells.     

Recent advances in the genetics of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common cause of dementia in the elderly. It is a clinical-pathologic entity characterized by progressive dementia associated with the neuropathologic hallmarks of Abeta amyloid plaques, neurofibrillary tangles (NFTs), neuronal loss, and amyloid angiopathy. Three "causative" AD genes (i.e., genes in which a mutation is sufficient to result in clinical AD) for early-onset familial Alzheimer's disease (FAD) and one "susceptibility" gene that affects risk and age of onset of AD in familial and sporadic late-onset AD have been identified. The three causative genes are the amyloid precursor protein (APP gene) on chromosome 21, the presenilin-1 gene on chromosome 14, and the presenilin-2 gene on chromosome 1. The susceptibility gene is the apolipoprotein E (APOE) gene on chromosome 19. Investigations of the normal and aberrant function of these genes will provide insights into the mechanisms underlying AD and will suggest new strategies for therapeutic intervention.     

Affective disorders in Alzheimer's disease

The links between depressive syndrome and Alzheimer's disease are problematic concerning the diagnosis and the therapeutic choice. The concepts of pseudo-dementia and late onset depression are shortly discussed. The hypothesis concerning the relationship between depression and Alzheimer's disease are summarized. The clinical data relevant for the diagnosis and the therapeutic guidelines are discussed.     

Mental-behavioral disorders in Alzheimer's disease

Behavioural and psychological disorders are often observed in Alzheimer's disease. Some are common, such as symptoms of depression, apathy, aggressivity, agitation, psychotic disturbances, disorders of sleep rhythm, etc. Many factors contribute to the aetiology of these disorders, mainly cerebral lesions, environmental changes, somatic illnesses, iatrogenic factors and psychological reaction mechanisms. Management must take each into account. Treatment comprises medication (symptomatic treatment of the various disorders, cholinergic treatment) and other means (adaptation of the inhabitation, informing family and friends, psychotherapy, etc.).     

Prognostic value of ECG changes detected by Holter monitoring in silent ischemic heart disease in the aged

Ischemic Cardiomiopathy (IC) is the main cause of morbidity and mortality in the elderly and its incidence increases progressively with age. Holter monitoring (HM) is used to study IC which reveals asymptomatic ischemic episodes identifiable with the depression of the ST tract. It has been demonstrated that these electric manifestations have the same unfavourable diagnostic value as those accompanied by pain. In order to evaluate the prevalence and prognostic significance of episodes of silent myocardial ischemia in the elderly patient, we examined 99 consecutive patients with stable clinical symptoms of myocardial ischemia and a positive ergometric test (ET). The patients were randomly divided according to age (< or = 65 years, >65 years) into two groups with homogeneous clinical feature, except for a higher prevalence of women in the second group. The HM analysis, carried out for 24 hours during common every day activities and after suspending anti-ischemic therapy, showed that 62 patients (63%) had 289 episodes of electric ischemia; 216 (75%) of these were asymptomatic, and, in the group of elderly there was a higher incidence of ST depression unaccompanied by pain (A vs B = 86 vs 132 episodes, p < 0.001). Comparing the patients with and without anamnestic evidence of myocardial infarction it was found that the first group presented a higher prevalence of ST depression both asymptomatic and symptomatic (147 vs 71 silent episodes, p < 0.001, and 49 vs 24 symptomatic episodes, p = 0.015 respectively), while no statistically significant differences were found between the two age groups. Electric alterations of the asymptomatic ischemic kind were more often found in subjects with stable angina, above all if elderly; this is important from a prognostic point of view as few elderly patients are capable of performing a maximal TE and it is thus significant of reduced coronary reserve. From our data we observed that in patients with stable angina, especially if elderly, Holter revealed asymptomatic ST depression analyzed considering both its length and magnitude, is able to give prognostic evidence of subsequent coronary events.     

Oxidative alterations in Alzheimer's disease

The expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), an EGF receptor ligand, was investigated in rat forebrain under basal conditions and after kainate-induced excitotoxic seizures. In addition, a potential neuroprotective role for HB-EGF was assessed in hippocampal cultures. In situ hybridization analysis of HB-EGF mRNA in developing rat hippocampus revealed its expression in all principle cell layers of hippocampus from birth to postnatal day (P) 7, whereas from P14 through adulthood, expression decreased in the pyramidal cell layer versus the dentate gyrus granule cells. After kainate-induced excitotoxic seizures, levels of HB-EGF mRNA increased markedly in the hippocampus, as well as in several other cortical and limbic forebrain regions. In the hippocampus, HB-EGF mRNA expression increased within 3 hr after kainate treatment, continued to increase until 24 hr, and then decreased; increases occurred in the dentate gyrus granule cells, in the molecular layer of the dentate gyrus, and in and around hippocampal pyramidal CA3 and CA1 neurons. At 48 hr after kainate treatment, HB-EGF mRNA remained elevated in vulnerable brain regions of the hippocampus and amygdaloid complex. Western blot analysis revealed increased levels of HB-EGF protein in the hippocampus after kainate administration, with a peak at 24 hr. Pretreatment of embryonic hippocampal cell cultures with HB-EGF protected neurons against kainate toxicity. The kainate-induced elevation of [Ca2+]i in hippocampal neurons was not altered in cultures pretreated with HB-EGF, suggesting an excitoprotective mechanism different from that of previously characterized excitoprotective growth factors. Taken together, these results suggest that HB-EGF may function as an endogenous neuroprotective agent after seizure-induced neural activity/injury.