X. Antón Alvarez

Blood levels of histamine, IL-1β, and TNF-α in patients with mild to moderate alzheimer disease

In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1β), and plasma tumor necrosis factor-alpha (TNF-α) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 agematched control subjects (C). AD patients showed higher concentrations of histamine (AD=452.9±237.9 pmol/mL; C=275.3±151.5 pmol/mL;p<0.05) and IL-1β (AD=211.2±31.1 pg/mL; C=183.4±24.4 pg/mL;p<0.01), and lower values of TNF-α (AD=3.59±2.02 pg/mL; C=9.47±2.64 pg/mL;p<0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-α were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1β values compared with age-matched controls. Age negatively correlated with histamine (r=−0.57;p<0.05) and positively with IL-1β levels (r=0.48;p<0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-α scores and age was only found in AD patients (r=0.46;p<0.05). Furthermore, histamine and TNF-α values correlated negatively in AD (r=−0.50,p<0.05). In addition, cognitive impairment increased in patients with lower TNF-α and higher histamine and IL-1β levels, as indicated by the correlations between mental performance scores and histamine (r=−0.37, ns), IL-1β (r=−0.33, ns) and TNF-α levels (r=0.42,p<0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r=−0.63,p<0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.

Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.

According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimers disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.

Persistence of the effects of Cerebrolysin on cognition and qEEG slowing in vascular dementia patients: results of a 3-month extension study.

The maintenance of the effects of Cerebrolysin, a peptidergic compound with neurotrophic activity, on cognitive performance and qEEG activity was investigated through a 12-week, open-label extension of a 4-week, randomised, placebo-controlled pilot study. Thirty-three out of 41 patients with mild-to-moderate severe probable vascular dementia (VaD) according to NINDS-AIREN participating in the double-blind phase of the study were also assessed at the follow-up visit at week 16. Patients received i.v. infusions of Cerebrolysin (10 or 30 mL) or placebo (saline) 5 days/week for 4 weeks. Neuropsychological evaluations and qEEG recordings were done at baseline, week 4 and week 16. The mean change in score from baseline in the ADAS-cog+ and the slow-to-fast qEEG power ratio (PR), used as an index of qEEG slowing, were the two primary endpoints. Correlations between changes in cognition and qEEG induced by the treatment were also assessed. At the week 16 follow-up visit, Cerebrolysin improved (p<0.05) cognitive performance at the 10-mL and 30-mL doses and reduced qEEG slowing significantly (p<0.05) at the 30-mL dose with respect to the placebo. In addition, a significant (p<0.05) positive correlation between the change from the baseline qEEG PR and ADAS-cog+ variables was observed at week 16. These results indicate a persistence of the beneficial effects of Cerebrolysin on cognition and qEEG activity in VaD patients for at least 12 weeks after treatment cessation, and they suggest the potential utility of qEEG parameters as biomarkers for VaD clinical trials.

Citicoline antagonizes bromazepam-induced amnesia in rats

Citicoline is an endogenous intermediate in the biosynthesis of brain phospholipids and acetylcholine used for the treatment of neurodegenerative processes associated with head trauma, stroke, brain aging, cerebrovascular pathology and Alzheimers disease. In this study we have investigated the effects of citicoline on acquisition and retention in passive avoidance and spatial discriminative learning tasks in control rats and in bomazepam‐treated animals. Interactions of citicoline with bromazepam on exploratory behaviour (anxiolytic/sedative activity) and motor co‐ordination (myorelaxing activity) were also evaluated to test the specificity of the cognitive effects of citicoline. Our results indicate that citicoline reverses bromazepam‐induced amnesia, improves retention in control rats, and has no significant effects on spontaneous activity and motor co‐ordination when given alone or in combination with bromazepam. According to these results we conclude that citicoline acts as a promnesic and anti‐amnesic drug with no sedative‐myorelaxing activity in rats. Therefore, this compound might be of use for the specific treatment of cognitive impairments associated with the chronic use of benzodiazepines.

Anapsos: New Therapeutic Strategies for Neurodegeneration and Brain Aging with Neuroimmunotrophic Factors

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by an heterogeneous etiopathogenesis on a genetic basis. The most prominent neuropathological findings in AD are senile plaques, neurofibrillary tangles (NFT), amyloid deposition in neural tissues and vessels, synaptic loss and subsequent neuronal death (Cacabelos et al., 1993, 1995; Hardy and Allsop, 1991; Terry et al., 1991). However, other neurochemical mechanisms may also account for cell death and neurodegeneration in AD, including neuroimmune dysfunction, free radical formation, neurotransmitter deficits and alterations in brain calcium homeostasis (Cacabelos et al., 1994, 1995; Richardson, 1993). So, new approaches to AD treatment are oriented to search for agents acting on etiopathogenic events and pleiotropic compounds displaying multifactorial effects.

Combination Drug Therapy for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder resulting in continuous deterioration of cognition, daily living abilities and motor functions and consequently has a huge social and familial burden. To date, the drugs approved for AD treatment provide only modest symptomatic effects. At present, the combined therapy with memantine plus one cholinesterase inhibitor (ChEI) is the best option for the treatment of moderate-to-severe AD. This combination has demonstrated higher clinical efficacy than monotherapy with ChEIs, with similar safety and tolerability in several randomised-controlled clinical trials (RCTs). Recent long-term observational studies have shown that combination therapy slows the rate of cognitive and functional deterioration, delays the placement of patients in nursing homes and also provides evidence that it is more effective when initiated early. None of the drugs for AD tested in Phase III trials show evidence of disease modification. A few studies have shown that the newer drugs, particularly anti-amyloid and neurotrophic agents, may provide improved disease-modifying treatments of AD in the near future. Meanwhile, combination therapy with available drugs is the most effective AD treatment.

APOE Genotype-Related Blood Pressure in Senile Dementia

Both senile dementia (SD) and hypertension (HBP) are pathologies with a high prevalence (Applegate, 1989; Cacabelos, 1995). SD is the third health problem in developed countries after cardiovascular disease and cancer (with a prevalence of 5–15 % after the age of 65 (Cacabelos, 1995). Hypertension is a risk factor classically associated with SD of the vascular type (Sokoog, 1994, 1996, Strandgaard, 1994). Genetic factors, and particularly Apolipoprotein E (APOE), have been associated with SD (Saunders, 1993; Basun, 1995; Cacabelos, 1996; Beyer, 1996) although no specific factors correlating SD and HBP have yet been identified.