Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models.

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported that obesity accelerates AD-related pathophysiology and memory impairment in mouse models of AD. However, the nature of the brain structure-behaviour relationship mediating this acceleration remains unclear. In this manuscript we evaluated the impact of adolescent obesity on the brain morphology of the triple transgenic mouse model of AD (3xTg) and a non-transgenic control model of the same background strain (B6129s) using longitudinally acquired structural magnetic resonance imaging (MRI). At 8 weeks of age, animals were placed on a high-fat diet (HFD) or an ingredient-equivalent control diet (CD). Structural images were acquired at 8, 16, and 24 weeks. At 25 weeks, animals underwent the novel object recognition (NOR) task and the Morris water maze (MWM) to assess short-term non-associative memory and spatial memory, respectively. All analyses were carried out across four groups: B6129s-CD and -HFD and 3xTg-CD and -HFD. Neuroanatomical changes in MRI-derived brain morphology were assessed using volumetric and deformation-based analyses. HFD-induced obesity during adolescence exacerbated brain volume alterations by adult life in the 3xTg mouse model in comparison to control-fed mice and mediated volumetric alterations of select brain regions, such as the hippocampus. Further, HFD-induced obesity aggravated memory in all mice, lowering certain memory measures of B6129s control mice to the level of 3xTg mice maintained on a CD. Moreover, decline in the volumetric trajectories of hippocampal regions for all mice were associated with the degree of spatial memory impairments on the MWM. Our results suggest that obesity may interact with the brain changes associated with AD-related pathology in the 3xTg mouse model to aggravate brain atrophy and memory impairments and similarly impair brain structural integrity and memory capacity of non-transgenic mice. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

Early-in-life neuroanatomical and behavioural trajectories in a triple transgenic model of Alzheimer's disease.

Animal models of Alzheimer's disease (AD) can be used to determine the progressive neurodegeneration characteristics of AD in vivo using magnetic resonance imaging (MRI). Given the need for therapeutic interventions before the onset of frank AD, it is critical to examine if AD models demonstrate neuroanatomical remodeling in an equivalent preclinical phase. This manuscript examines the trajectories of brain and behavioural changes in the Triple transgenic mouse model (3xTg) prior to the development of AD-like behaviours. The 3xTg mimics both ß-amyloid plaques and neurofibrillary tangles through three mutations associated with familial AD, namely: PS1M146V, APPSwe, and tauP301L transgenes. We performed detailed investigation using longitudinal structural MRI at 6, 8, 12, 16, 20, and 24 weeks old to assess neuroanatomical changes using volumetric and deformation-based analyses. Learning- and memory-related behaviour were assessed through the Morris water maze at 9, 17, and 25 weeks of age. There was the absence of major memory deficits with the notable exception of water maze conducted at 17 weeks old, where 3xTg group spent significantly less time in the quadrant of interest in the probe trial. Through volumetric and deformation-based analyses, we observed relative decrease over time in the 3xTg group in the third ventricle, piriform cortex, fornix, and fimbria relative to the control group. We also observed decreases over time in the control mice in the hippocampus, entorhinal cortex, cerebellum, and olfactory bulb. In many of these cases, we note a delay in the attainment of peak volume in the 3xTgs relative to the control group, suggesting a possible neurodevelopmental and maturational delay given the likely over-expression of AD-related pathology from birth. Importantly, neuroanatomical alterations are observed prior to the manifestation of AD-like behaviours, suggesting that mutated amyloid and tau are, indeed, sufficient to cause changes in the neuroanatomy in 3xTg mice, but potentially insufficient to be responsible for behavioural changes in the earlier stages of life.

Changes in the pathogenesis of alcohol-induced liver disease -- preclinical studies.

Excessive alcohol consumption presents considerable health risks in humans. A variety of morphologic and functional changes contribute to hepatic injury produced by heavy drinking. The present review summarizes the current knowledge of alcohol-induced liver disease and describes preclinical experimental approaches used to understand alcoholic liver disease (ALD), with a particular emphasis on impaired protein and lipid trafficking, disruption of proteolysis and autophagy, alterations in methionine metabolism and perturbations in metabolic signaling that cause dysfunctional gene expression and the eventual formation of aggresomal Mallory-Denk bodies (MDB) in liver cells. These changes eventually lead to some of the more severe hepatic impairments, including alcoholic hepatitis and fibrosis. Moreover the misuse of alcohol contributes to immune dysfunction and inadequate immune response to viral infections.

Drug-induced severe adverse reaction enhanced by human herpes virus-6 reactivation.

Reactivation of certain latent viruses has been linked with a more severe course of drug-induced hypersensitivity reaction (HSR). For example, reactivation of human herpes virus (HHV)-6 is associated with severe organ involvement and a prolonged course of disease. The present study discusses an HSR developed in a previously healthy male exposed to ceftriaxone, doxycycline, vancomycin, and trimethoprim/sulfamethoxazole (co-trimoxazole; TMP/SMX). Initially, the patient presented clinical manifestations of HSR, as well as clinical and laboratory measurements compatible with liver and renal failure. Moreover, the patient presented skin desquamation compatible with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis. During the reaction, it was observed HHV-6 reactivation. The severity of clinical symptoms is correlated with HHV-6 titer, as well as with results of the in vitro lymphocyte toxicity assay (LTA). Serum levels of a large panel of cytokines are compared between the patient, a large population of SJS patients, and a cohort of healthy controls, using data collected by our laboratory over the years. HHV-6 was measured in the cell culture media from lymphocytes incubated with each of the 4 drugs. Moreover, we describe a new assay using cytokines released by patient lymphocytes following in vitro exposure to the incriminated drugs as biomarkers of HSR. Based on LTA results, HHV-6 reactivation and cytokine measurements, we establish that only doxycycline and TMP/SMX were involved in the HSR. As result of this analysis, the patient could continue to use the other 2 antibiotics safely.

Adjuvant analgesics in neuropathic pain.

Conventional analgesics have limited efficacy in the management of neuropathic pain. An adjuvant analgesic is a drug that has a primary nonpain indication but which may be analgesic in certain circumstances, and many of these have established a role in the pharmacological treatment of neuropathic pain. The number needed to treat is an indirect statistical measure that can be used to compare relative efficacy of different adjuvant analgesics and, from this, there is currently insufficient evidence to suggest that any one adjuvant analgesic has absolute advantages over another. Analgesic efficacy, tolerability, safety/toxicity, drug interactions, ease of use, and cost-effectiveness are essential factors that guide the selection of an adjuvant analgesic. Cost-effectiveness data are absent for the vast majority of these drugs. Pharmacological treatments should be used as part of a multimodal therapeutic programme for the management of neuropathic pain.