Developmental Pathogenicity of 4-Repeat Human Tau Is Lost with the P301L Mutation in Genetically Matched Tau-Transgenic Mice.

Tau is a microtubule-associated protein that becomes dysregulated in a group of neurodegenerative diseases called tauopathies. Differential tau isoforms, expression levels, promoters, and disruption of endogenous genes in transgenic mouse models of tauopathy make it difficult to draw definitive conclusions about the biological role of tau in these models. We addressed this shortcoming by characterizing the molecular and cognitive phenotypes associated with the pathogenic P301L tau mutation (rT2 mice) in relation to a genetically matched transgenic mouse overexpressing nonmutant (NM) 4-repeat (4R) human tau (rT1 mice).

Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis.

Background & Aims: Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine).

Perspective: Randomized Controlled Trials Are Not a Panacea for Diet-Related Research.

Research into the role of diet in health faces a number of methodologic challenges in the choice of study design, measurement methods, and analytic options. Heavier reliance on randomized controlled trial (RCT) designs is suggested as a way to solve these challenges. We present and discuss 7 inherent and practical considerations with special relevance to RCTs designed to study diet: 1) the need for narrow focus; 2) the choice of subjects and exposures; 3) blinding of the intervention; 4) perceived asymmetry of treatment in relation to need; 5) temporal relations between dietary exposures and putative outcomes; 6) strict adherence to the intervention protocol, despite potential clinical counter-indications; and 7) the need to maintain methodologic rigor, including measuring diet carefully and frequently.

A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI.

Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.

Yohimbine-induced amygdala activation in pathological gamblers: a pilot study.

Rationale And Objectives: There is evidence that drug addiction is associated with increased physiological and psychological responses to stress. In this pilot functional magnetic resonance imaging (fMRI) study we assessed whether a prototype behavioral addiction, pathological gambling (PG), is likewise associated with an enhanced response to stress.

Methods: We induced stress by injecting yohimbine (0.

Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core.

N-terminal truncated amyloid beta (Aβ) derivatives, especially the forms having pyroglutamate at the 3 position (AβpE3) or at the 11 position (AβpE11) have become the topic of considerable study. AβpE3 is known to make up a substantial portion of the Aβ species in senile plaques while AβpE11 has received less attention. We have generated very specific polyclonal antibodies against both species.

The art and science of patient storytelling-harnessing narrative communication for behavioral interventions: the ACCE project.

Narrative communication is an emerging form of persuasive communication used in health education to solicit actual patient stories. Eliciting a narrative is an open-ended process and may or may not map to desired intervention objectives or underlying behavioral constructs. In addition, incorporating actual, unscripted narratives into multimedia interventions is challenging.

Mouse models of Huntington's disease and methodological considerations for therapeutic trials.

Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine-adenine-guanine repeat in the gene coding for the protein huntingtin. Despite great progress, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of multiple murine models that replicate many of the clinical, neuropathological, and molecular events in HD patients.

Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD.

Visual association pathology in preclinical Alzheimer disease.

The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD.

Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice.

Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials.

Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis.

A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with APP and Abeta amyloid may contribute to the Alzheimer's amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. However, poor target specificity and consequential clinical safety of current metal-complexing agents have limited their widespread clinical use. To develop the next generation of metal chelators, we have designed and synthesized a new bifunctional molecule-XH1, based on a novel 'pharmacophore conjugation' concept.

Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile.

Transgenic mice that express mutant human amyloid precursor protein (APPTg2576) develop beta-amyloid (Abeta) plaques throughout the cortex starting at 10-12 months of age. We examined the neurochemical profile of APPTg2576 mice using in vitro and in vivo magnetic resonance spectroscopy (MRS); gross abnormalities using magnetic resonance imaging (MRI) and plaque distribution; size and number using immunohistochemistry. Transgenic mice were anesthetized with halothane and scanned at 4.

Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease.

There is substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide. We found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD.

The neurotoxicity of amyloid beta protein in aged primates.

Amyloid beta protein deposition is a universal feature of Alzheimer's disease brain. To investigate the effects of amyloid beta protein in aged primates, intracerebral microinjections of solubilized amyloid beta (A beta (1-40)) and control peptides were made into the frontal cortex of 7 primates under stereotactic guidance. Control injections consisted of vehicle alone, a 37 amino acid non toxic peptide (A37), scrambled peptide (CA4), and reverse peptide (A beta (40-1)).