Safety and Efficacy of Anti-Amyloid-β Immunotherapy in Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Immunotherapeutics targeting amyloid-β (Aβ) have had mixed results in clinical trials. The present study aims to evaluate the safety and clinical efficacy of immunotherapeutic agents targeting Aβ in Alzheimer’s disease. Randomised controlled trials of at least two weeks duration were included in the review. Fourteen randomised controlled trials (n = 5554) were identified in a systematic search of eight electronic databases. Upon pooling of data, there was no increased risk of any adverse event, serious adverse events, or death with the exception of a near fivefold increase in amyloid-related imaging abnormalities (ARIA; OR 4.79, 95% CI 1.24–18.55; p = 0.02). Of the cognitive indicators, the Mini-Mental State Examination (MMSE) showed a small statistically significant improvement (diff in means =0.44; p = 0.02), while the others (ADAS-cog, ADCS-ADL, and CDR-sb) showed no change. Therefore, immunotherapeutic agents have been relatively well tolerated, with some promise for cognitive improvements if the occurrence of ARIA can be mitigated.     

Use of Benzodiazepines in Alzheimer’s Disease: A Systematic Review of Literature

Background:

Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited.

Methods:

Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific search terms in MEDLINE and PubMed Library according to the recommendations of The Strengthening the Reporting of Observational Studies in Epidemiology initiative.

Results:

Of the 657 articles found, 18 articles met predefined selection criteria and were included in this review (8 on frequency, 5 on cognitive functions, 5 on behavioral and sleep disturbances). The frequency of benzodiazepine use ranged from 8.5% to 20%. Five studies reported accelerated cognitive deterioration in association with benzodiazepine use. Two studies reported clinical efficacy for lorazepam and alprazolam to reduce agitation in Alzheimer’s disease patients. No evidence was found for an improvement of sleep quality using benzodiazepines.

Conclusion:

This systematic review shows a relatively high prevalence of benzodiazepine use but limited evidence for clinical efficacy in Alzheimer’s disease patients. However, there is a paucity of methodologically high quality controlled clinical trials. Our results underscore a need for randomized controlled trials in this area.     

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition.     

Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer’s Disease

Angiotensin converting enzyme (ACE) converts Angiotensin I to a potent vasoconstrictor angiotensin II (ANG II). ACE inhibitors (ACEIs) are widely used for the management of hypertension. All components of the renin-angiotensin system (RAS) have also been identified in the brain. In addition to cytokines, neuromodulators such as ANG II can induce neuroinflammation. Moreover, in Alzheimer’s disease (AD) models, where neuroinflammation occurs and is thought to contribute to the propagation of the disease, increased levels of ANG II and ACE have been detected. However, the specific effect of ACEIs on neuroinflammation and AD remains obscure. The present study suggests that captopril and perindopril, centrally active ACEIs, may serve as modulators for microglial activation associated with AD. Our in vitro study investigated the effect of both ACEIs on nitric oxide (NO), tumor necrosis factor- α (TNF-α) release and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 microglia. Exposure of BV2 microglia to ACEIs significantly attenuated the LPS-induced NO and TNF-α release. In vivo, short term intranasal administration of perindopril or captopril to 5 Familial AD (5XFAD) mice significantly reduced amyloid burden and CD11b expression (a microglial marker) or only CD11b expression respectively, in the cortex of 5XFAD. Long-term intranasal administration of captopril to mice reduced amyloid burden with no effect on CD11b expression. We provide evidence that intranasal delivery of ACEI may serve as an efficient alternative for their systemic administration, as it results in the attenuation of microglial accumulation and even the reduction of Amyloid β (Aβ) plaques.     

Tau-Directed Immunotherapy: A Promising Strategy for Treating Alzheimer’s Disease and Other Tauopathies

Immunotherapy directed against tau is a promising treatment strategy for Alzheimer’s Disease (AD) and tauopathies. We review initial studies on tau-directed immunotherapy, and present data from our laboratory testing antibodies using the rTg4510 mouse model, which deposits tau in forebrain neurons. Numerous antibodies have been tested for their efficacy in treating both pathology and cognitive function, in different mouse models, by different routes of administration, and at different ages or durations. We report, here, that the conformation-specific antibody MC-1 produces some degree of improvement to both cognition and pathology in rTg4510. Pathological improvements as measured by Gallyas staining for fully formed tangles and phosphorylated tau appeared 4 days after intracranial injection into the hippocampus. We also examined markers for microglial activation, which did not appear impacted from treatment. Behavioral effects were noted after continuous infusion of antibodies into the lateral ventricle for approximately 2 weeks. We examined basic motor skills, which were not impacted by treatment, but did note cognitive improvements with both novel object and radial arm water maze testing. Our results support earlier reports in the initial review presented here, and collectively show promise for this strategy of treatment. The general absence of extracellular tau deposits may avoid the opsonization and phagocytosis mechanisms activated by antibodies against amyloid, and make anti tau approaches a safer method of immunotherapy for Alzheimer’s disease.     

Repurposing of Kinase Inhibitors to Target c-Abl as Potential Therapeutics for Alzheimer’s Disease

Alzheimer’s disease (AD) represents a major public health concern and has been considered as a research priority. Recently, the tyrosine kinase c-Abl has been shown as a new and potential target of AD therapy. In the current study, sophisticated molecular docking and empirical scoring functions were integrated to develop a bioinformatics predictor based on 52 kinase–inhibitor complexes with solved crystal structures and known biological activities. The predictor was then used to identify those potential c-Abl binders from a commercially available kinase inhibitor library. A total of 18 promising candidates with top scores were raised; their intermolecular interactions with c-Abl were further examined in detail by using molecular dynamics simulations and binding energy analysis. Seven out of the 18 candidates were selected and tested in vitro for their inhibitory activities against c-Abl, and, consequently, two compounds, namely S2882 and TAE684, were identified as high-activity agents (IC₅₀?=?28?±?5 and 12?±?3 nM, respectively). The two compounds possess long-chain structures with multiple rings that are structurally similar to the FDA-approved drugs imatinib and nilotinib. Visual examination of molded complex structures revealed that the S2882 and TAE684 can be readily bound within the active cleft of c-Abl kinase domain, exhibiting an extended conformation. In addition, an intensive network of nonbonded interactions across the complex interfaces of c-Abl with S2882 and TAE684 was also highlighted, which confers substantial stability and specificity for the complex systems.     

Anti-Oxidants in Parkinson’s Disease Therapy: A Critical Point of View

Parkinson’s disease (PD) is a degenerative neurological syndrome, which is characterized by the preferential death of dopaminergic (DAergic) neurons in the Substantia Nigra. The pathogenesis of this disorder remains poorly understood and PD is still incurable. Current drug treatments are aimed primarily for the treatment of symptoms to improve the quality of life. Therefore, there is a need to find out new therapeutic strategies that not only provide symptomatic relief but also halt or reverse the neuronal damage hampering PD progression. Oxidative stress has been identified as one of the major contributors for the nigral loss in both sporadic and genetic forms of PD. In this review we first evaluate the current literature that links oxidative stress and mitochondrial dysfunction to PD. We then consider the results obtained through the treatment of animal models or PD patients with molecules that prevent oxidative stress or reduce mitochondrial dysfunction.     

Imaging Microglial Activation During Neuroinflammation and Alzheimer’s Disease

Microglial activation is an important pathogenic component of neurodegenerative disease processes. This state of increased inflammation is associated not only with neurotoxic consequences but also neuroprotective effects, e.g., phagocytosis and clearance of amyloid in Alzheimer’s disease. In addition, activation of microglia appears to be one of the major mechanisms of amyloid clearance following active or passive immunotherapy. Imaging techniques may provide a minimally invasive tool to elucidate the complexities and dynamics of microglial function and dysfunction in aging and neurodegenerative diseases. Imaging microglia in vivo in live subjects by confocal or two/multiphoton microscopy offers the advantage of studying these cells over time in their native environment. Imaging microglia in human subjects by positron emission tomography scanning with translocator protein-18 kDa ligands can offer a measure of the inflammatory process and a means of detecting progression of disease and efficacy of therapeutics over time.     

Role of Cognitive Enhancer Therapy in Alzheimer’s Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study

Background

Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.

Objective

In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.

Methods

We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.

Results

Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (−0.04, p = 0.007), and the decrease was similar for both diagnosis groups (−0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.

Conclusion

Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.     

Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

Journal of Neuroimmune Pharmacology - This study examines the link between peripheral immune changes in perpetuation of the Alzheimer’s disease (AD) neuropathology and cognitive deficits. Our...     

How to Optimize the Effectiveness and Safety of Parkinson’s Disease Therapy? – A Systematic Review of Drugs Interactions with Food and Dietary Supplements

Background: Despite increasing worldwide incidence of Parkinson’s disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient treatment, the poor adherence in advanced patients, and varied response. Proper intake of medications regarding food and managing drug-food interactions may optimize Parkinson’s disease treatment.Objectives: We investigated potential effects that food, beverages, and dietary supplements may have on the pharmacokinetics and pharmacodynamics of drugs used by parkinsonian patients; identified the most probable interactions; and shaped recommendations for the optimal intake of drugs regarding food.Methods: We performed a systematic review in adherence to PRISMA guidelines, and included a total of 81 studies in the qualitative synthesis.Results and Conclusion: We found evidence for levodopa positive interaction with coffee, fiber and vitamin C, as well as for the potential beneficial impact of low-fat and protein redistribution diet. Contrastingly, high-protein diet and ferrous sulfate supplements can negatively affect levodopa pharmacokinetics and effectiveness. For other drugs, the data of food impact are scarce. Based on the available limited evidence, all dopamine agonists (bromocriptine, cabergoline, ropinirole), tolcapone, rasagiline, selegiline in tablets, safinamide, amantadine and pimavanserin can be taken with or without a meal. Opicapone and orally disintegrating selegiline tablets should be administered on an empty stomach. Of monoamine oxidase B inhibitors, safinamide is the least susceptible for interaction with the tyramine-rich food, whereas selegiline and rasagiline may lose selectivity to monoamine oxidase B when administered in supratherapeutic doses. The level of presented evidence is low due to the poor studies design, their insufficient actuality, and missing data.     

Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease

Purpose

To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD).

Methods

Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.

Results

The successful synthesis of DPA was demonstrated via ¹H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119?±?12 nm and zeta potential of 8.2?±?0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.

Conclusion

This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.     

Extracellular Vesicle Biology in Alzheimer’s Disease and Related Tauopathy

Extracellular vesicles (EVs) are physiological vesicles secreted from most eukaryotes and contain cargos of their cell of origin. EVs, and particularly a subset of EV known as exosomes, are emerging as key mediators of cell to cell communication and waste management for cells both during normal organismal function and in disease. In this review, we investigate the rapidly growing field of exosome biology, their biogenesis, cargo loading, and uptake by other cells. We particularly consider the role of exosomes in Alzheimer’s disease, both as a pathogenic agent and as a disease biomarker. We also explore the emerging role of exosomes in chronic traumatic encephalopathy. Finally, we highlight open questions in these fields and the possible use of exosomes as therapeutic targets and agents.     

Memantine in Japanese patients with moderate to severe Alzheimer’s disease: meta-analysis of multiple-index responder analyses

Background: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer’s disease (AD).

Research design and methods: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013.

Results: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician’s Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003).

Conclusions: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.     

Diagnostic methods and biomarkers for Alzheimer’s disease

Alzheimer’s disease (AD) is the most frequently occurring and intensively investigated neurodegenerative disorder, which is associated with extracellular senile plaques and intracellular neurofibrillary tangles. In this review, AD related diagnostic strategies and the potential biomarkers of AD will be discussed. Several proteomics methods were developed for disease diagnosis, such as ELISA, MALDI-TOF, SELDI-TOF, and 2 D-electrophoresis. Imaging technologies, such as MRI and PET analyses, are also important, since they could directly show the changes in the brain, associated with dementia progression. MRI technologies might estimate the presence and degree of neurodegeneration by identification and quantification of atrophy. PET could reflect the metabolic changes in the brain by various radioactive molecules (tracers). Along with neuropsycoanalysis of behavioral changes, the progression of dementia can be characterized with biochemical changes in brain metabolisms, in addition to fluctuations in many inflammatory mediators in the cerebral spinal fluid (CSF), blood and in other bodily fluids. These biochemical changes in the brain and other body fluids can be initiated before the appearance of AD symptoms. There is no specific marker for AD along with other dementia, but the combination of different markers may predict the disease progression more accurately. Monitoring the changes in their levels in brain, CSF, blood and body fluids with biomarkers in early disease stages might improve the diagnosis and therapies. Several molecules were established as successful biomarkers for AD diagnosis. Ratio of Abeta42/40 became an important AD marker, which could reflect the disease-associated changes in the blood plasma and CSF. Additional markers were available in blood, such as apolipoprotein E or inflammatory molecules. In CSF, the Abeta42, Tau or phospho-tau could be the most successful biomarker for AD progression. Several new biomarkers and diagnostic approaches were developed for differentiating AD from other forms of dementia. It should be important to predict the AD progression prior to the development of clinical symptoms. Above all, the improvement of above strategies, especially with diverse biomarkers, should support the precise diagnosis of AD, greatly enhancing both AD therapies and preventative measures.     

Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer’s Disease

Amyloid-β peptide (Aβ) is still best known as a molecule to cause Alzheimer’s disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. Thus, strategies on developing AD drugs have been focused on the reduc-tion of Aβ in the brain. Since accumulation of Aβ depends on the rate of its synthesis and clearance, the metabolic pathway of Aβ in the brain and the whole body should be carefully explored for AD research. Although the synthetic pathway of Aβ is equally important, we summarize primarily the clearance pathway in this paper because the former has been extensively reviewed in previous studies. The clearance of Aβ from the brain is accomplished by several mechanisms which include non-enzymatic and enzymatic pathways. Nonenzymatic pathway includes interstitial fluid drainage, uptake by microglial phagocytosis, and transport across the blood vessel walls into the circulation. Multiple Aβ-degrading enzymes (ADE) implicated in the clearance process have been identified, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II and others. A series of studies on Aβ clearance mechanism provide new insight into the pathogenesis of AD at the molecular level and suggest a new target for the development of novel therapeutics.     

Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer''s dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.Key Words: Alzheimer’s disease, neurodegeneration, inflammation, β-amyloid peptide, complement, complement regulators, CD59, complement therapeutics.     

Drug development for Alzheimer’s disease: review

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is considered as one of the most intractable medical problems with heavy social and economic costs. The current drugs for AD, including acetylcholinesterase inhibitors (AChEIs) and memantine, a NMDA receptor antagonist, only temporarily ameliorate cognitive decline, but are unable to stop or reverse the progression of dementia. This paper reviewed the recent advance in AD drug development. The drug discovery programs under clinical trials targeting cholinergic system, α7 nicotinic acetylcholine receptors (nAChRs), N-methyl-d-aspartate receptor (NMDAR), β-secretase, γ-secretase modulators, tau, inflammatory mediators and glucagon-like peptide-1 (GLP-1) were discussed. Though several drug discovery programs are ongoing, the high failure rate is an outstanding issue. Novel techniques and strategies are desperately needed to significantly accelerate this process.