Manuel Aleixandre

Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease

Tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-I (IGF-I) have been involved in the pathogenesis of Alzheimers disease (AD) as neurotoxic and survival factors, respectively. Recent experimental studies suggest that the signalling pathways of TNF-alpha and IGF-I are functionally interrelated. In order to investigate the possible interaction of TNF-alpha and IGF-I in AD and mild cognitive impairment (MCI), the serum levels of total IGF-I, free IGF-I and TNF-alpha were determined in 141 AD patients, 56 MCI cases and 30 controls. As compared with controls, AD patients showed increased TNF-alpha and decreased IGF-I levels in serum, as well as a significant negative correlation between TNF-alpha and free IGF-I values. MCI patients also exhibited significantly higher TNF-alpha levels than controls. The present results suggest that increased TNF-alpha levels are involved in the pathogenesis of AD and MCI, and might antagonize the neurotrophic activity of IGF-I in these medical conditions. In addition, the combined determination of TNF-alpha and IGF-I might be useful to monitor anti-inflammatory and/or neurotrophic drug effects in AD.

Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease.

Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimers disease (AD), but the influence of apathy and apolipoprotein E ε4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI), and control subjects. Baseline BDNF levels were similar in AD, MCI, and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p < 0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p < 0.01) and MMSE scores (p < 0.01) than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p < 0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers.

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.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele.

Combined treatment with cerebrolysin and donepezil in mild to moderate alzheimer's disease: Results of a double-blind, randomized clinical trial

P1-244 COMBINED TREATMENT WITH CEREBROLYSIN AND DONEPEZIL IN MILD TO MODERATE ALZHEIMER’S DISEASE: RESULTS OF A DOUBLEBLIND, RANDOMIZED CLINICAL TRIAL Anton Alvarez, Ramon Cacabelos, Manuel Aleixandre, Carlos Linares, Elias Granizo, Edith Doppler, Herbert Moessler, Euroespes Biomedical Research Centre, A CoruÑA, Spain; Granada University, Granada, Spain; Memory Clinic, Malaga, Spain; Ebewe Neuro Pharma, Unterach, Austria. Contact e-mail: xantonal@yahoo.es

SERUM VEGF LEVELS ARE ASSOCIATED WITH COGNITION AND FUNCTIONING IN AD: INFLUENCE OF TREATMENT WITH CEREBRLYSIN AND DONEPEZIL

Serum VEGF levels, cognitive and functional performance were evaluated in AD patients treated with Cerebrolysin (n=52), donepezil (n=52), or a combination of both drugs (n=53) in a 28-week doubleblind, randomized clinical trial. VEGF levels were measured in serum samples by using specific ELISA kits for VEGF165 in serum samples obtained at baseline, at week-16 (end of active Cerebrolysin treatment) and at week-28 (endpoint). MATERIALS AND METHODS

Neurotrophic and cholinergic treatment in Alzheimer's disease: Results of a randomized clinical trial

P3-448 NEUROTROPHIC AND CHOLINERGIC TREATMENT IN ALZHEIMER’S DISEASE: RESULTS OF A RANDOMIZED CLINICAL TRIAL Anton Alvarez, Carolina Sampedro, Veronica Couceiro, Ramon Cacabelos, Manuel Aleixandre, Carlos Linares, Elias Granizo, Edith Doppler, Philipp Novak, Herbert Moessler, Euroespes Biomedical Research Centre, a Coruña, Spain; Faculty of Psychology, Granada University, Granada, Spain; Memory Clinic, Malaga, Spain; Ever Neuro Pharma, Unterach, Austria. Contact e-mail: xantonal@yahoo.es

O2-03-08: Hyperactivity of peripheral TNF-alpha system in Alzheimer's disease: Interaction with serum IGF-I

with amyloid -peptide (A ) has been proposed as a treatment for AD. Experimental models have shown that A accumulation in the brain, a key feature of the disease, can be reversed by immunotherapy mediated, at least in part, by phagocytosis by microglia (cells of the monocyte/macrophage lineage). Methods: We are co-ordinating a collaborative clinical and neuropathological follow-up of the patients who where in the first trial of active A immunization (Elan Pharmaceuticals). To date we have neuropathology on 9 immunized AD patients (iAD) who died between 4 and 64 months after first immunization dose. In these cases we have quantified the expression of microglial proteins, compared with unimmunized AD controls. Results: CD68 is a component of the wall of lysosomes and its presence is therefore an indication of phagocytic activity. A similar amount of CD68 immunostaining was observed in cerebral cortex of both the iAD cases and AD controls indicating phagocytic activity in both groups. The iAD cases showed variable degrees of plaque clearance associated with A within the lysosomes of activated microglia, indicating that A had been phagocytosed. However, the phagocytic activity in the AD controls was not associated with A within microglia, suggesting that microglia are qualitatively different after immunization. Conclusions: These observations highlight the point that, rather than simply demonstrating that microglia have been activated, it is the specific way in which microglia are activated that is important in determining their role in AD pathology. To what extent the changes in the activation of microglia are reflected in changes in cognitive function, remains to be determined. Indeed despite evidence of plaque removal, mediated at least in part by microglia, all except one of the iAD patients studied at post mortem had severe end stage dementia prior to death.