Alzheimer's disease - input of vitamin D with mEmantine assay (AD-IDEA trial): study protocol for a randomized controlled trial

BACKGROUND: Current treatments for Alzheimer\u27s disease and related disorders (ADRD) are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol) with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine. METHODS: The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20), hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] < 30 ng/mL), normocalcemia (i.e., serum calcium < 2.65 mmol/L) and receiving no antidementia treatment at time of inclusion are being recruited. All participants receive memantine 20 mg once daily -titrated in 5 mg increments over 4 weeks- and each one is randomized to one of the two treatment options: either cholecalciferol (one 100,000 IU drinking vial every 4 weeks) or placebo (administered at the same pace). One hundred and twenty participants are being recruited and treatment continues for 24 weeks. Primary outcome measure is change in cognitive performance using Alzheimer\u27s Disease Assessment Scale-cognition score. Secondary outcomes are changes in other cognitive scores (MMSE, Frontal Assessment Battery, Trail Making Test parts A and B), change in functional performance (Activities of Daily Living scale, and 4-item Instrumental Activities of Daily Living scale), posture and gait (Timed Up & Go, Five Time Sit-to-Stand, spatio-temporal analysis of walking), as well as the between-groups comparison of compliance to treatment and tolerance. These outcomes are assessed at baseline, 12 and 24 weeks, together with the serum concentrations of 25OHD, calcium and parathyroid hormone. DISCUSSION: The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01409694

IL-6-174 G/C and -572 C/G Polymorphisms and Risk of Alzheimer’s Disease

Associations between interleukin 6 (IL-6) polymorphisms and Alzheimer’s disease (AD) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations for the relationship between IL-6-174 G/C and -572 C/G polymorphisms and risk for AD. Electronic searches for all publications in databases PubMed and EMBASE were conducted on the associations between IL-6 polymorphisms and risk for AD until January 2012. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. Twenty-seven studies were included with a total of 19,135 individuals, involving 6,632 AD patients and 12,503 controls. For IL-6-174 G/C polymorphism, the combined results showed significant differences in recessive model (CC vs. CG+GG: OR = 0.65, 95%CI = 0.52–0.82). As regards IL-6-572 C/G polymorphism, significant associations were shown in dominant model (CG+GG vs. CC: OR  = 0.73, 95% CI = 0.62–0.86) and in additive model (GG vs. CC, OR  = 0.66, 95% CI = 0.46–0.96). In conclusion, genotype CC of IL-6-174 G/C and genotype GG plus GC of IL-6-572 C/G could decrease the risk of AD

Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscle

Distinct interrelationships between inflammation and β-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-γ, TNF-α and IL-1β in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-γ. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β co-localized to β-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β caused upregulation of APP with subsequent intracellular aggregation of β-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle

Resveratrol Acts Not through Anti-Aggregative Pathways but Mainly via Its Scavenging Properties against Aβ and Aβ-Metal Complexes Toxicity

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD

Jugular venous reflux and brain parenchyma volumes in elderly patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUND: To determine whether or not jugular venous reflux (JVR) is associated with structural brain parenchyma changes in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: 16 AD patients (mean (SD): 81.9 (5.8) years), 33 MCI patients (mean (SD): 81.4 (6.1) years) and 18 healthy elderly controls (mean (SD): 81.5 (3.4) years) underwent duplex ultrasonography and magnetic resonance imaging scans to quantify structural brain parenchyma changes. Normalized whole brain (WB), gray matter (GM) and white matter (WM) volumes were collected, together with CSF volume. RESULTS: JVR was strongly associated with increased normalized WB (p = 0.014) and GM (p = 0.002) volumes across all three subject groups. There was a trend towards increased WB and GM volumes, which was accompanied by decreased CSF volume, in the JVR-positive subjects in both the MCI and AD groups. When the MCI and AD subjects were aggregated together significant increases were observed in both normalized WB (p = 0.009) and GM (p = 0.003) volumes for the JVR-positive group. No corresponding increases were observed for the JVR-positive subjects in the control group. Through receiver operating characteristic analysis of the brain volumetric data it was possible to discriminate between the JVR-positive and negative AD subjects with reasonable accuracy (sensitivity = 71.4%; specificity = 88.9%; p = 0.007). CONCLUSIONS: JVR is associated with intracranial structural changes in MCI and AD patients, which result in increased WB and GM volumes. The neuropathology of this unexpected and counterintuitive finding requires further investigation, but may suggest that JVR retrogradely transmits venous hypertension into the brain and leads to brain tissues swelling due to vasogenic edema

Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and b-amyloid (Ab)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer’s disease (AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Ab1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Ab-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Ab42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Ab-related synaptic dysfunctio

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Interleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating <it>IL-6 </it>genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent.</p> <p>Methods</p> <p>This is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common <it>IL-6 </it>haplotype-tagging SNPs were selected to assess the association between <it>IL-6 </it>polymorphisms and the risk of late-onset AD (LOAD).</p> <p>Results</p> <p>Variant carriers of <it>IL-6 </it>rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in <it>ApoE e4 </it>non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (<it>p</it>_interaction= 0.03).</p> <p>Conclusions</p> <p><it>IL-6 </it>polymorphisms are associated with reduced risk of LOAD, especially in <it>ApoE e4 </it>non-carriers. This study identified genetic markers for predicting LOAD in <it>ApoE e4 </it>non-carriers.</p

Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer's Disease

Immunosuppression is a characteristic feature of Toxoplasma gondii-infected murine hosts. The present study aimed to determine the effect of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of Alzheimer's disease (AD) in Tg2576 AD mice. Mice were infected with a cyst-forming strain (ME49) of T. gondii, and levels of inflammatory mediators (IFN-γ and nitric oxide), anti-inflammatory cytokines (IL-10 and TGF-β), neuronal damage, and β-amyloid plaque deposition were examined in brain tissues and/or in BV-2 microglial cells. In addition, behavioral tests, including the water maze and Y-maze tests, were performed on T. gondii-infected and uninfected Tg2576 mice. Results revealed that whereas the level of IFN-γ was unchanged, the levels of anti-inflammatory cytokines were significantly higher in T. gondii-infected mice than in uninfected mice, and in BV-2 cells treated with T. gondii lysate antigen. Furthermore, nitrite production from primary cultured brain microglial cells and BV-2 cells was reduced by the addition of T. gondii lysate antigen (TLA), and β-amyloid plaque deposition in the cortex and hippocampus of Tg2576 mouse brains was remarkably lower in T. gondii-infected AD mice than in uninfected controls. In addition, water maze and Y-maze test results revealed retarded cognitive capacities in uninfected mice as compared with infected mice. These findings demonstrate the favorable effects of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of AD in Tg2576 mice