Anti-Alzheimer's, Anti-Dementia Agents

Oxidative stress is a key factor involved in the development and progression of Alzheimer's disease, and it is well documented that free radical oxidative damage, particularly of neuronal lipids, proteins, nucleic acids and sugars, is extensive in brains of Alzheimer's disease patients. However, oxidative stress may elicit compensatory responses and downstream adaptations such as amyloid-beta deposition and neurofibrillary tangle formation, which may function as "shields" to ensure that neuronal cells do not succumb to oxidative injuries. Although during the past several years our understanding of the mechanisms leading to neuronal damage and death in the course of Alzheimer's disease has improved significantly, we have not found an effective therapeutic to fight this devastating disorder. However, the results obtained in clinical trials with antioxidants are promising and propel us in the search of new and more effective antioxidant therapies.

The authors examined the relationship between hypertension and cognitive performance in 34 African-American patients with probable Alzheimer disease. Multiple regression analyses indicated that hypertension was associated with poorer overall performance on the Mattis Dementia Rating Scale, particularly the Initiation/Perseveration and Conceptualization subscales, after controlling for gender, age, and education. The findings suggest that African-American patients with hypertension exhibit greater cognitive impairment, possibly reflecting executive dysfunction.

Oxidative stress is important in the pathogenesis of Alzheimer's disease (AD). The brain contains high levels of oxidizable lipids that must be protected by antioxidants. Low concentrations of vitamin E, quantitatively the major lipophilic antioxidant in the brain, are frequently observed in cerebrospinal fluid (CSF) of AD patients, suggesting that supplementation with vitamin E might delay the development of AD. In a placebo-controlled trial, vitamin E (2000 IU/day, 2 years) slowed (-53%) functional deterioration in patients with moderate AD (Sano et al., N. Engl. J. Med. 336: 1216-1222, 1997). Recently, use of vitamin E and vitamin C supplements in combination was found to be associated with reduced prevalence (-78%) and incidence (-64%) of AD in elderly population (Zandi et al., Arch. Neurol. 61: 82-88, 2004). These results are consistent with the ability of the supplementation with vitamin E (400 IU/day, 1 month) to increase its levels in CSF (123%) and plasma (145%) of AD patients and, in combination with vitamin C (1000 g/day), to decrease the susceptibility of CSF lipoproteins (up to -32%) to in vitro oxidation (Kontush et al., Free Radic. Biol. Med. 31: 345-354, 2001). In addition, vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mice model of AD (Sung et al., FASEB J. 18: 323-325, 2004). Computer modeling of the influence of vitamin E on lipoprotein oxidation reveals that the vitamin develops antioxidative activity in CSF lipoproteins in the presence of physiologically relevant, low amounts of oxidants. By contrast, under similar conditions, vitamin E behaves as a pro-oxidant in plasma lipoproteins, consistent with the model of tocopherol-mediated peroxidation (Stocker, Curr. Opin. Lipidol. 5: 422-433, 1994). This distinction is related to major differences in the levels of vitamin E (50 nM vs. 30 muM) and oxidizable lipids (4 muM vs. 2.5 mM) between CSF and plasma, which result in major differences in oxidative conditions (per unit of vitamin E) between CSF and plasma in the presence of similar amounts of oxidants. Altogether, these data suggest that vitamin E may be effective against in vivo oxidation of CSF lipoproteins and brain lipids, and offer new perspectives in the treatment of AD and other neurodegenerative disorders.

The aim of this article is to provide evidence-based recommendations for early diagnosis of Alzheimer's disease (AD) and hereby to give clinican guidelines for optimal detection of patients with AD. Our intention is also to unify diagnostic schemes in accordance with our objective and specific possibilities. Basic diagnostic procedures primarily are anamnesis and clinical examination with rational usage of neuroimaging, electrophysiological and laboratory procedures. Using these guidelines in medical practice in Croatia would be a good basis for future epidemiological and clinical multicentric studies.

Alzheimer's disease is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal destruction, particularly in cholinergic neurons. Drugs that inhibit the degradation of acetylcholine within synapses are the mainstay of therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially troublesome cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weight loss. These adverse reactions are often self-limited and can be minimized by slow drug titration. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefit may be greater in clinical trials than in practice. The drugs clearly improve cognition, but evidence is less robust for benefits in delaying nursing home placement and improving functional ability and behaviors. Benefit for vitamin E or selegiline has been suggested, but supporting evidence is not strong. Most guidelines for monitoring drug therapy in patients with Alzheimer's disease recommend periodic measurements of cognition and functional ability. The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitors when dementia becomes severe.

This phase III trial was conducted to evaluate the safety and efficacy of donepezil in Alzheimer's disease (AD) patients with a greater range of comorbid conditions and concomitant medication use than those previously evaluated in placebo-controlled studies. Patients (n = 1,035) with mild to moderate probable or possible AD were enrolled from 255 sites in the USA; 894 (86%) completed the trial. Mean age was 74.9 years (+/- 7.8); baseline standardized Mini-Mental State Examination (sMMSE) score was 19.77 (+/- 5.4). Nearly all patients had at least 1 prior or comorbid medical condition (97%) or were taking at least 1 concomitant medication (93%). Safety assessments included recording treatment-emergent adverse events (AEs). To confirm comparability with past studies, efficacy was measured using the sMMSE. Over the 12-week study period, the mean sMMSE score increased by 1.54 points over baseline (p < 0.0001) in donepezil-treated patients. Most AEs (64%) were mild, and the occurrence of cholinergic-induced AEs was significantly lower after a dose increase at 4 weeks than that seen with a dose increase after 1 week in previous trials. Risk ratios for gastrointestinal side effects were not significantly increased by the use of aspirin or nonsteroidal anti-inflammatory drugs. Risk ratios for bradycardia were not significantly increased by the use of beta-blockers, nondihydropyridine calcium channel blockers or digoxin. Therefore, donepezil improved cognition, as measured by the sMMSE, and was well tolerated despite high concomitant medication use and extensive comorbidity. These results highlight donepezil as a safe and effective treatment for AD patients typically seen by community-based physicians.