Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the HdhQ150/Q150 mouse model of huntington's disease

A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the "clinical horizon" of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments

Mind over milkshakes: mindsets, not just nutrients, determine ghrelin response

Objective: To test whether physiological satiation as measured by the gut peptide ghrelin may vary depending on the mindset in which one approaches consumption of food. Methods: On 2 separate occasions, participants (n ϭ 46) consumed a 380-calorie milkshake under the pretense that it was either a 620-calorie "indulgent" shake or a 140-calorie "sensible" shake. Ghrelin was measured via intravenous blood samples at 3 time points: baseline (20 min), anticipatory (60 min), and postconsumption (90 min). During the first interval (between 20 and 60 min) participants were asked to view and rate the (misleading) label of the shake. During the second interval (between 60 and 90 min) participants were asked to drink and rate the milkshake. Results: The mindset of indulgence produced a dramatically steeper decline in ghrelin after consuming the shake, whereas the mindset of sensibility produced a relatively flat ghrelin response. Participants' satiety was consistent with what they believed they were consuming rather than the actual nutritional value of what they consumed. Conclusions: The effect of food consumption on ghrelin may be psychologically mediated, and mindset meaningfully affects physiological responses to food

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease

Background: Alzheimer’s disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. Methods: We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). Results: The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer’s related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype. Conclusions: This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/1 mouse model of huntington's disease

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear. © 2013 Rattray et al

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al