Current Alzheimer Research - Volume 7, Issue 5, 2010

Background: This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimer's disease (AD). Methods: Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and ≥90% power to compare SB-742457 35 mg with placebo. Results: 371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB- 742457 vs 15% for placebo. Comments: SB-742457 was generally safe and well tolerated and may be efficacious in AD.

Cholinesterase activity associated with neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains exhibit altered histochemical properties, such as requiring lower pH (6.8) for optimal cholinesterase staining compared to the pH (8.0) for best visualization of cholinesterases in neurons. Furthermore, visualization of NPs and NFTs can be prevented by agents like the peptidase inhibitor/metalloantibiotic bacitracin. The anomalous behavior of cholinesterases associated with pathological lesions needs to be elucidated because of the putative links between these enzymes and the disease process in AD. In this study, cholinesterases were extracted from AD and normal brain tissue to determine whether the differences observed in histochemical analyses in the two sources were reflected in kinetic properties measured in solubilized enzymes. Isolated brain enzymes from both these sources exhibited comparable kinetic parameters with respect to pH dependence, substrate affinity and inhibitor sensitivity and were not significantly affected by other agents that blocked cholinesterase histochemical visualization, such as the structurally diverse metalchelating antibiotics bacitracin, doxycycline, minocycline and rifampicin. Although the cholinesterases from AD brain tissue examined here represented a total pool of these enzymes from AD brain, rather than enzymes specifically from NPs and NFTs, their kinetic behavior being comparable to cholinesterases isolated from normal brain tissues implies that these enzymes do not undergo disease-related modification in their primary structures. This suggests that the atypical histochemical behavior of cholinesterases in NPs and NFTs may result from interaction of cholinesterases with other molecules within these lesions, mediated by transition metal ions known to be present in AD pathology lesions.

Although it is well established that aluminum (Al) is neurotoxic, the potential role of this element in the etiology of Alzheimer's disease (AD) is not well established. In this study, we evaluated the effects of oral Al exposure on spatial learning, memory and neurogenesis in Tg2576 mice, an animal model of AD in which Abeta plaques start to be deposited at 9 months of age. Aluminum was given as Al lactate (11 mg/g of food) for 6 months. At 11 months of age a water maze test was carried out to evaluate learning and memory. Subsequently, mice were injected with bromodeoxyuridine (BrdU) and sacrificed 24 hours or 28 days after the last injection in order to assess proliferation, survival and differentiation of neurons. We observed impaired acquisition in the water maze task in Al-treated Tg2576 mice, as well as worse memory in the Al-exposed groups. In terms of neurogenesis, no effects of aluminum were observed in proliferation, survival and differentiation. The results of this investigation suggest that Tg2576 mice fed for 210 days with rodent chow supplemented with Al lactate at 11 mg/g of food have impaired spatial learning although their neurogenesis remains unmodified.

Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that activates microglial cells, involved in phagocytosis of amyloid-beta (Aβ) in the brain. In the present study, we found in 50 patients with Alzheimer's disease (AD) significantly increased M-CSF plasma levels compared to 22 patients with mild cognitive impairment (MCI) and 35 age-matched healthy controls. In contrast, MCI patients showed significantly decreased M-CSF levels in cerebrospinal fluid (CSF) compared to AD patients and 20 patients with other non-inflammatory neurological disease (NIND). Analyzing the impact of Beta-amyloid 1-42 (Aβ 1-42), tau protein and M-CSF for differentiation between the groups we found that M-CSF, but not Aβ 1-42 and tau-protein is a significant parameter for distinction between MCI and NIND patients with 68.8% sensitivity and 75.0% specificity. M-CSF CSF levels ≤ 357.8 pg/ml yielded 73.7% sensitivity and 75.0% specificity for diagnosing MCI patients in comparison with control subjects. In conclusion, our data indicate that M-CSF in CSF could be a putative biomarker for MCI.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.

One mechanism leading to neurodegeneration during Alzheimer's Disease (AD) is amyloid β peptide (Aβ)- induced neurotoxicity. Among the factors proposed to potentiate Aβ toxicity is its covalent modification through carbohydrate- derived advanced glycation endproducts (AGEs). Other experimental evidence, though, indicates that certain polymeric carbohydrates like the glycosaminoglycan (GAG) chains found in proteoglycan molecules attenuate the neurotoxic effect of Aβ in primary neuronal cultures. Pretreatment of the 42-residue Aβ fragment (Aβ1-42) with the ubiquitous brain carbohydrates, glucose, fructose, and the GAG chondroitin sulfate B (CSB) inhibits Aβ1-42-induced apoptosis and reduces the peptide neurotoxicity on neuroblastoma cells, a cytoprotective effect that is partially reverted by AGE inhibitors such as pyridoxamine and L-carnosine. Thioflavin T fluorescence measurements indicate that at concentrations close to physiological, only CSB promotes the formation of Aβ amyloid fibril structure. Atomic force microscopy imaging and Western blot analysis suggest that glucose favours the formation of globular oligomeric structures derived from aggregated species. Our data suggest that at short times carbohydrates reduce Aβ1-42 toxicity through different mechanisms both dependent and independent of AGE formation.

Processes of demographic change are leading to decreasing human resources in professional as well as lay care; this decrease necessitates new concepts of care, especially for the growing number of people with dementia (p.w.d.). Since the amendment to the German Care Insurance Law (2002), family carers have been entitled to regular weekly relief, provided by volunteers who have been given a thirty-hour-training. As difficulties in information processing in p.w.d. form an important part of the symptoms in dementia sufferers - with a high impact on communication as well as competent functioning in activities associated with daily life -, we wanted to establish how much awareness and sensitivity voluntary attendants show in “tuning in” to the p.w.d. and her/his individual capacity to interact. In an exploratory study the authors analyzed videotaped interactions between volunteer caregivers and dementia-sufferers which were recorded in everyday situations during the process of ongoing care. Using methods of Video Interaction Analysis and Grounded Theory, we developed categories which describe how in tune the helpers are with the timing skills — or lack of them — of p.w.d.. We think that understanding the different ways in which p. w. d. structure their time can improve their communication and interaction. The categories — “speed and adjustment of speed”, “mutuality” and “time control” — seemed crucial in understanding the subsequent course of the interactions. In a second step, these categories have recently been used by students and staff of the Lausitz University of Applied Sciences to provide training that sensitizes volunteer attendants to the topic and to learn about volunteers' judgement on the importance of continuing education in this field.

Background: Several studies have shown that religiosity has beneficial effects on health, mortality and pathological conditions; little is known about religiosity in Alzheimer's disease and the progression of its cognitive, behavioral and functional symptoms. Our aim was to identify any relationship between religiosity and the progression of cognitive impairment and behavioral disorders in mild-moderate Alzheimer's disease, and any relationship between the patient's religiosity and the stress in caregivers. Materials and Methods: 64 patients with Alzheimer's disease were analyzed at baseline and 12 months later using the Mini-Mental State Examination (MMSE), the Behavioral Religiosity Scale (BRS) and the Francis Short Scale (FSS). Caregivers were also questioned on the patient's functional abilities (ADL, IADL), the behavioral disturbances (NPI), and on their stress (NPI-D, CBI). Patients were divided into 2 groups according to BRS: a score of <24 meant no or low religiosity (LR), while a score of ≥24 meant moderate or high religiosity (HR). Findings: LR patients had worsened more markedly after 12 months in their total cognitive and behavioral test scores. Stress was also significantly higher in the caregivers of the LR group. Global BRS and FSS scores correlated significantly with variations after 1 year in the MMSE (r: 0.50), NPI (r:-0.51), NPI-D (r:-0.55) and CBI (r:-0.62). A low religiosity coincided with a higher risk of cognitive impairment, considered as a 3-point decrease in MMSE score (OR 6.7, CI: 1.8- 24.7). Interpretation: Higher levels of religiosity in Alzheimer's dementia seem to correlate with a slower cognitive and behavioral decline, with a corresponding significant reduction of the caregiver's burden.

Soluble amyloid β (Aβ) oligomers might trigger early cognitive deficit in Alzheimer's Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Aβ25-35 affects the spontaneous activity in hippocampal slices, when was added to the bath, at high nanomolar concentrations. In the present study, we aimed to characterize the effects of the oligomerized full length sequence Aβ1-42 on the spontaneous network activity in the CA1 hippocampal area testing whether such effects are age dependent. By performing extracellular field recordings of spontaneous network activity of hippocampal slices, we found that an oligomerized solution of Aβ1-42 (osAβ) potently inhibit, in a dose-dependent manner, the spontaneous hippocampal network activity with an IC50 of 0.4 ± 3.2 nM and a maximal effect reached around 10 nM. While spontaneous hippocampal network activity is unaffected by age, the sensitivity of spontaneous hippocampal network activity to osAβ (10 nM) appears to be increased in slices from older animals. Moreover, to see a significant reduction in spontaneous network activity in slices from animals in their second week of life 100nM osAβ was needed. The osAβ-induced reduction in hippocampal network activity is accompanied by a presynaptic reduction in both spontaneous and miniature synaptic potentials. Finally, we demonstrated that the effect produced by osAβ on spontaneous network activity was specific, reversible and unrelated with cell death. In conclusion, our data show that osAβ alters hippocampal network activity at concentrations commonly observed in AD patients and that such effect of osAβ increases with age.

Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to evaluate the serum oxidation marker levels in patients with AD. Both untreated patients (n: 15) and patients who received treatment (n: 62) had higher Malondialdehyde (p<0.01 and p<0.001), Oxidized LDL (ox-LDL; p<0.0001 and p<0.0001), F2-isoprostane (p<0.0001 and p<0.001), and Nitric oxide (NOx; p<0.0001 and p<0.0001) levels compared with those of age-matched controls (n: 15). Protein Carbonyl and Asymmetrical Dimethyl-L-Arginine levels in Alzheimer patients were not found to be different from the controls. Short-term cholinesterase inhibitor (ChEIs) therapy (7, 5 ±1, 5 months, n: 12) resulted in a reduction in ox-LDL and NOx levels (p<0.05 and p<0.01) from baseline. Long-term ChEItherapy group (50, 4± 30, 5 months, n: 33) has higher ox-LDL, NOx and F2-isoprostane levels than short-term treated group (p<0.01, p<0.001 and p<0.05, respectively). Ox-LDL levels were also found to be lower in ChEI patients who were given antipsychotic treatment (n: 15) than in the group who were ChEIs-alone treatment group (p<0.0001). MMSE scores showed negative correlation with both NOx (p<0.05) and ox-LDL (p<0.05) levels. There was positive correlation between NOx and both MDA (p<0.05) and ox-LDL (p<0.05), and between F2-isoprostane and 3-NT (p<0.05). In conclusion, our results suggest that serum NOx-induced lipid oxidation levels were increased in AD and use of antipsychotic drugs may cause lower ox-LDL levels in patients having combination therapy with ChEi's. However, it is required further studies for the determination of clinical importance of these markers.

Background: Amyloid β40 (Aβ40) is the most abundant Aβ peptide in the brain. The cerebrospinal fluid (CSF) level of Aβ40 might therefore be considered to most closely reflect the total Aβ load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Aβ load in the brain has a large inter-individual variability. Relating Aβ42 to Aβ40 levels might consequently provide a more valid measure for reflecting the change in Aβ metabolism in dementia patients than the CSF Aβ42 concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Objective: To investigate the diagnostic value of the CSF Aβ42/Aβ40 ratio in differentiating AD from controls, VaD, DLB and FTD. Methods: We analysed the CSF Aβ42/Aβ40 ratio, phosphorylated tau181 and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls. Results: Mean Aβ40 levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Aβ40 levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Aβ42/Aβ40 ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Aβ42/Aβ40 ratio was used instead of Aβ42 concentrations alone (p<0.01) The Aβ42/Aβ40 ratio performed equally well as the combination of Aβ42, phosphorylated tau181 and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Aβ42/Aβ40 ratio was used instead of Aβ42 alone. Conclusion: The CSF Aβ42/Aβ40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Aβ42 alone, and is a more easily interpretable alternative to the combination of Aβ42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.