Aging, Parkinson’s disease, and models: what are the challenges?

Parkinson’s disease (PD) is a chronic, neurodegenerative condition characterized by motor symptoms such as bradykinesia, rigidity, and tremor, alongside multiple nonmotor symptoms. The appearance of motor symptoms is linked to progressive dopaminergic neuron loss within the substantia nigra. PD incidence increases sharply with age, suggesting a strong association between mechanisms driving biological aging and the development and progression of PD. However, the role of aging in the pathogenesis of PD remains understudied. Numerous models of PD, including cell models, toxin-induced models, and genetic models in rodents and nonhuman primates (NHPs), reproduce different aspects of PD, but preclinical studies of PD rarely incorporate age as a factor. Studies using patient neurons derived from stem cells via reprogramming methods retain some aging features, but their characterization, particularly of aging markers and reproducibility of neuron type, is suboptimal. Investigation of age-related changes in PD using animal models indicates an association, but this is likely in conjunction with other disease drivers. The biggest barrier to drawing firm conclusions is that each model lacks full characterization and appropriate time-course assessments. There is a need to systematically investigate whether aging increases the susceptibility of mouse, rat, and NHP models to develop PD and understand the role of cell models. We propose that a significant investment in time and resources, together with the coordination and sharing of resources, knowledge, and data, is required to accelerate progress in understanding the role of biological aging in PD development and improve the reliability of models to test interventions

Increased Diacylglycerols Characterize Hepatic Lipid Changes in Progression of Human Nonalcoholic Fatty Liver Disease; Comparison to a Murine Model

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD.Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts.Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts.Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD

Motor coordination problems in children and adolescents with ADHD rated by parents and teachers: effects of age and gender

Summary. Objective. ADHD is frequently accompanied by motor coordination problems. However, the co-occurrence of poor motor performance has received less attention in research than other coexisting problems in ADHD. The underlying mechanisms of this association remain unclear. Therefore, we investigated the prevalence of motor coordination problems in a large sample of children with ADHD, and the relationship between motor coordination problems and inattentive and hyperactive/impulsive symptoms. Furthermore, we assessed whether the association between ADHD and motor coordination problems was comparable across ages and was similar for both genders. Method. We investigated 486 children with ADHD and 269 normal controls. Motor coordination problems were rated by parents (Developmental Coordination Disorder Questionnaire) and teachers (Groningen Motor Observation Scale). Results. Parents and teachers reported motor coordination problems in about one third of children with ADHD. Problems of fine and gross motor skills, coordination skills and motor control were all related to inattentive rather than hyperactive/impulsive symptoms. Relative to controls, motor coordination problems in ADHD were still present in teenagers according to parents; the prevalence diminished somewhat according to teachers. Boys and girls with ADHD were comparably affected, but motor performance in controls was better in girls than in boys. Conclusions. Motor coordination problems were reported in one third of children with ADHD and affected both boys and girls. These problems were also apparent in adolescents with ADHD. Clinicians treating children with ADHD should pay attention to co-occurring motor coordination problems because of the high prevalence and the negative impact of motor coordination problems on daily life

A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design

<p>Abstract</p> <p>Background</p> <p>The ACTION study (<it>Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) </it>is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.</p> <p>Methods</p> <p>Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo.</p> <p>Results</p> <p>The methodology for the ACTION study has been detailed.</p> <p>Conclusions</p> <p>The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment.</p> <p>Trial registration</p> <p>Australian and New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ANZCTRN12607000535471.aspx">ANZCTRN12607000535471</a>.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)