Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?

Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

Electrochemical investigations of the interaction of C-reactive protein (CRP) with a CRP antibody chemically immobilized on a gold surface.

A possibility of using a range of dc and ac electrochemical techniques to probe associative interactions of C-reactive protein (CRP) with CRP antibody (aCRP) immobilized on a gold electrode surface was investigated. It was demonstrated that the investigated electrochemical techniques can be used efficiently to probe these interactions over a wide CRP concentration range, from 1.15 x 10(-5) to 1.15 mg L(-1). The measured sensitivity of the techniques is in the following decreasing order: differential pulse voltammetry, charge-transfer resistance obtained from electrochemical impedance spectroscopy (EIS), cyclic voltammetry, chronoamperometry, and double-layer capacitance deduced from EIS measurements which gave the poorest sensitivity. Measurements of kinetic parameters demonstrated that the associative interactions of CRP with the immobilized aCRP reached quasi-equilibrium after 20-30 min. The kinetics of these interactions was modeled successfully using a two-step kinetic model. In this model, the first step represents reversible CRP-aCRP associative-dissociative interactions, while the second step represents the irreversible transformation of the bound CRP into a thermodynamically stable configuration. It was demonstrated that the thermodynamically stable configuration of CRP starts prevailing after 7 min of interaction of CRP with the immobilized aCRP.

Effect of antiepileptic agent, levetiracetam, on urodynamic parameters and neurogenic bladder overactivity in chronically paraplegic rats.

OBJECTIVES: To investigate the effects of different levetiracetam (LEV) doses on urodynamic parameters in an animal model of neurogenic detrusor overactivity (NDO). METHODS: A total of 54 female rats were studied. Of the 54 rats, 6 served as normal controls, and 48 underwent T10 spinal cord transection (SCT). Of the latter 48 rats, 12 were paraplegic controls, and the remaining 36 rats were divided into 3 equal subgroups that received LEV by way of a subcutaneous osmotic minipump at a dose of 17, 54, and 108 mg/kg daily, respectively. The paraplegic control and treatment groups were further subdivided (n = 6), and cystometry was performed at 3 and 4 weeks after SCT, respectively. RESULTS: All paraplegic controls developed NDO, with spontaneous contractions. At 3 and 4 weeks after SCT, the mean frequency of the contractions was 1.6 +/- 0.3/min and 1.7 +/- 0.2/min. The contraction amplitude and bladder capacity were not significantly different. After 1 week of LEV treatment, these urodynamic parameters improved significantly in a dose-dependent manner, and the changes were more striking at 2 weeks. At a LEV dosage of 17, 54, and 108 mg/kg, respectively, the NDO frequency increased from 1.7 +/- 0.3 to 0.7 +/- 0.2 contractions/min (P = .01), 0.48 +/- 0.16 contractions/min (P = .009), and 0.5 +/- 0.17 contractions/min (P = .01). The bladder capacity increased from 0.51 +/- 0.1 mL to 1.5 +/- 0.2 mL (P = .0001), 2.5 +/- 1.7 mL (P = .006), and 2.6 +/- 0.3 mL (P = .0003), and the micturition pressure improved from 105.8 +/- 6.9 to 73.8 +/- 6.8 cm H(2)O (P = .01), 58.6 +/- 8.9 cm H(2)O (P = .006), and 49.7 +/- 8.9 cm H(2)O (P = .002). CONCLUSIONS: The results of our study have shown that LEV is an effective treatment of NDO after SCT in rats. It might prove to be a novel, alternative therapeutic approach to NDO. The follow-up of these experimental results with a clinical trial is warranted.

Intra-axonal recording from large sensory myelinated axons: demonstration of impaired membrane conductances in early experimental diabetes.

AIM/HYPOTHESIS: Diabetic neuropathy is accompanied by a range of positive (paresthaesia, dysesthaesia, pain) and negative (hypesthaesia, anesthaesia) neurological symptoms suggesting widespread alterations in axonal excitability. The nature and the mechanisms underlying these alterations in axonal excitability are not well understood. The aim of this study was to examine the extent of changes in membrane properties of an identified neuronal structure-the large myelinated sensory axons in early experimental diabetes in rats. METHODS: Intra-axonal microelectrode recordings from large sensory myelinated axons from the isolated sural nerve in short-term streptozotocin-induced diabetic rats were used to study membrane properties using standard current-clamp technique. RESULTS: In addition to decreased conduction velocity we found several differences in physiological properties of sensory axons from diabetic rats: decreased resting membrane potential, decreased single action potential amplitude associated with slower rate of rise and decrease in inward rectification associated with slight alteration in outwardly rectifying conductances indicating impaired potassium conductances. CONCLUSION/INTERPRETATION: These results extend previous indirect evidence that potassium and sodium ionic conductances, most notably the inward rectifier (IR, I(h)), are altered in large sensory axons of diabetic rats. The depression of IR could underly clinical neurological findings in diabetic patients.