Investigation of SARS-CoV-2 infection and associated lesions in exotic and companion animals.

Documented natural infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in exotic and companion animals following human exposures are uncommon. Those documented in animals are typically mild and self-limiting, and infected animals have only infrequently died or been euthanized. Through a coordinated One Health initiative, necropsies were conducted on 5 animals from different premises that were exposed to humans with laboratory-confirmed SARS-CoV-2 infection. The combination of epidemiologic evidence of exposure and confirmatory real-time reverse transcriptase-polymerase chain reaction testing confirmed infection in 3 cats and a tiger. A dog was a suspect case based on epidemiologic evidence of exposure but tested negative for SARS-CoV-2. Four animals had respiratory clinical signs that developed 2 to 12 days after exposure. The dog had bronchointerstitial pneumonia and the tiger had bronchopneumonia; both had syncytial-like cells with no detection of SARS-CoV-2. Individual findings in the 3 cats included metastatic mammary carcinoma, congenital renal disease, and myocardial disease. Based on the necropsy findings and a standardized algorithm, SARS-CoV-2 infection was not considered the cause of death in any of the cases. Continued surveillance and necropsy examination of animals with fatal outcomes will further our understanding of natural SARS-CoV-2 infection in animals and the potential role of the virus in development of lesions.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington's disease, a 2-part study.

AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M1 -receptor partial agonist for the treatment of dementias.

AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.

Factors associated with ordering food via online meal ordering services.

OBJECTIVE: Online meal ordering services are increasing in popularity in Australia and globally. Meals ordered online for home delivery are typically less healthy than home-made meals, potentially contributing to weight gain. The aim of the present study was to identify the types of consumers who are most likely to engage in online meal ordering. DESIGN: A cross-sectional survey including items relating to demographic and lifestyle factors was disseminated via a web panel provider. SETTING: Australia. PARTICIPANTS: A total of 2010 Australian adults aged 18+ years. RESULTS: More than a quarter of respondents (28 %) engaged in online meal ordering at least once in the previous month. Younger respondents, those with a higher BMI, and those with higher education and income levels were more likely to have done so. Consuming higher levels of sugary drinks and fast-food restaurant patronage were significantly associated with ordering meals online for home delivery. CONCLUSIONS: The outcomes of this study suggest that the use of online meal ordering services is becoming a common practice in Australia, and it is therefore important to implement evidence-based strategies and policies to encourage individuals to make healthy food choices when using these services.

Anti-fat attitudes and dietary restraint within mother-daughter dyads: an Actor-Partner Interdependence Model (APIM) analysis.

PURPOSE: This study examined the association between anti-fat attitudes (fear of fat, dislike of fat, willpower) and dietary restraint within the mother-daughter relationship. METHODS: Mother-adolescent daughter dyads (Npairs = 100) were recruited from a Midwestern community to participate in a study together. They completed self-report measures of anti-fat attitudes and eating behavior. Data were analyzed with an Actor-Partner Interdependence Model (APIM). RESULTS: Significant actor effects for mothers include fear of fat (b = 0.270, B = 0.319, p < 0.05) and willpower (b = 0.228, B = 0.280, p < 0.05) predicting her own dietary restraint. For daughters, fear of fat (b = 0.554, B = 0.612, p < 0.05) and dislike (b = 0.202, B = 0.214, p < 0.05) predict her own dietary restraint. Regarding partner effects, mothers' fear of fat was related to daughters' dietary restraint (b = 0.126, B = 0.138, p < 0.05), and daughters' dislike was related to mothers' restraint (b = 0.257, B = 0.294, p < 0.05). Regarding dyad-level interaction effects, mother and daughter fear of fat interacted to predict daughter dietary restraint (b = 0.184, B = 0.201, p < 0.05), such that when both mother and daughter fear of fat is high, daughters appear to engage in more dietary restraint. CONCLUSIONS: Given the role of mothers' fear of fat in daughter eating behavior, parent-focused or parent-involved interventions may improve family culture around weight and eating, contributing to better adolescent outcomes. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

Attachment, rumination, and disordered eating among adolescent girls: The moderating role of stress.

PURPOSE: Disordered eating behaviors are prevalent and problematic in adolescent girls. Given that disordered eating has been linked to attachment insecurity and emotion dysregulation, the current study used an emotion regulation model of attachment theory to investigate pathways to disordered eating among adolescent girls. While past research has examined attachment and eating, an emotion regulation perspective is rarely used. Additionally, limited studies have investigated specific types of eating or mediators or moderators. To address these research gaps, this study examined whether rumination mediates the relationship between attachment anxiety and avoidance and three types of disordered eating and whether stress moderates this mediation. METHODS: 100 adolescent girls (Mage = 14.35 years, SD = 2.29) completed online surveys including the Relationship Structures Questionnaire, Dutch Eating Behaviour Questionnaire, Rumination Questionnaire, and Perceived Stress Scale. RESULTS: The interaction between stress and attachment anxiety on rumination was significant (b = .09, SE = .04, p < .05), and stress and attachment anxiety predicted emotional eating through rumination (b = .50, SE = .15, p < .05). Rumination also predicted external eating (b = .32, SE = .11, p < .05). The mediation was not significant for restrained eating. Attachment avoidance did not significantly predict eating behaviors. CONCLUSION: The emotion regulation model of attachment theory provides a suitable framework for studying disordered eating in adolescent girls. Future research may continue the use of this framework to examine related topics. Clinicians treating girls experiencing disordered eating may use interventions to promote healthy emotion regulation strategies. LEVEL OF EVIDENCE: Level V: cross-sectional descriptive study.

"I just don't want to be fat!": body talk, body dissatisfaction, and eating disorder symptoms in mother-adolescent girl dyads.

PURPOSE: Mothers serve as a primary socializing figure among adolescent girls at a time when they are at high risk of body image concerns and disordered eating behavior, and this influence may vary by weight status. Body talk may be one mechanisms of influence in this relationship. The current study utilized an observational measure of body talk to investigate the relationship between adolescent girls' body talk with mothers, eating disorder symptoms, and body dissatisfaction. METHODS: Participants included 100 mother-daughter dyads who completed self-report measures of body dissatisfaction and eating behavior and engaged in a 10-min discussion about the daughter's body image. RESULTS: Results indicated that the relationship between both positive and negative body talk and body dissatisfaction varied by weight status. For healthy/underweight adolescents, negative body talk is related to higher body dissatisfaction (b = 0.04, SE 0.01, p < 0.01) and positive talk is related to lower body dissatisfaction (b = - 0.06, SE 0.02, p < 0.001). No relationship was found for individuals of overweight/obese status. Body talk was unrelated to eating disorder symptoms for all adolescents. CONCLUSIONS: Given the current findings, mothers should continue to limit their engagement in body talk (particularly negative talk) within the home. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

Interactive role of weight status and fat talk on body dissatisfaction: an observation of women friends.

PURPOSE: The current study examined the interactive role of weight status and fat talk on body dissatisfaction among women friends. METHOD: Sixty pairs of women friends completed a measure of body dissatisfaction and engaged in an observed fat talk interaction with their friend. RESULTS: Women's weight status was related to their own, but not their friend's, body dissatisfaction. Observed fat talk was significantly related to individuals' own and their friend's body dissatisfaction. A significant interaction effect showed that the association between fat talk and body dissatisfaction was minimal for women with higher weight status. In contrast, fat talk was associated with more body dissatisfaction for women with lower weight status. CONCLUSION: These findings suggest the importance of examining the conjoint effect of personal (e.g., weight status) and contextual (e.g., fat talk) factors on body image issues. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

Reversal of mecamylamine-induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses.

AIMS: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor. METHODS: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine. RESULTS: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and ß power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine. CONCLUSIONS: Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.

Cognitive Performance and Apathy Predict Unemployment in Huntington's Disease Mutation Carriers.

Unemployment is common for those with Huntington's disease (HD), a genetic neurodegenerative disorder, and affects patients' quality of life. HD is characterized by motor disturbances, cognitive dysfunction, and psychiatric symptoms. The purpose of this article was to determine which clinical signs of HD are predictive of unemployment. Data for employed (N=114) and unemployed (N=106) HD mutation carriers were used to investigate group differences. Univariate logistic regression analyses, adjusted for age and gender, were performed to determine individual predictors of unemployment. Subsequently, a multivariate logistic regression analysis was performed, entering all significant results from the univariate analyses into one fully adjusted model to determine the strongest predictors. HD mutation carriers with lower cognitive performances and higher apathy scores were more likely to be unemployed than were HD mutation carriers with higher cognitive scores and no signs of apathy. Motor functioning was an independent predictor of unemployment but was not associated with unemployment in the fully adjusted model. Cognitive impairments, especially in the executive domain, and apathy were independent determinants of unemployment in HD mutation carriers. Motor disturbances, the clinical hallmark of HD, did not appear to be the most important predictor for work cessation. These results should be taken into consideration in clinical practice when evaluating HD patients' ability to work.

Body talk, weight status, and pathological eating behavior in romantic relationships.

This study examined whether engagement in body talk would interact with weight status (body mass index; BMI) to predict pathological eating behaviors among romantically involved adults. Adults (N = 137, females = 86.86%, average age = 23.50) involved in a romantic relationship were recruited to complete an online survey about their body image, dietary behaviors, and engagement in body talk. Results indicated that engagement in negative body talk was directly related to higher pathological eating (i.e., drive for thinness, dieting, and bulimia symptoms). Positive body talk, on the other hand, had a significant interaction effect with BMI to predict pathological eating. For individuals with a high BMI, high engagement in positive body talk was associated with increased drive for thinness, dieting, and bulimia symptoms. However, for those with a low BMI, high engagement in positive body talk was protective against pathological eating. These findings suggest that while negative body talk is harmful in general, positive body talk is uniquely problematic for individuals of a higher weight status.

Interdependence of attachment styles and relationship quality in parent-adolescent dyads.

The current study examined how attachment styles of parents and adolescents may jointly influence the quality of their relationship. Parent-adolescent (Ndyads = 77) pairs were recruited from a Midwestern town in the United States. The mean of adolescents' age was 16.25. Both members reported their attachment styles, relationship closeness, and relationship discord. The Actor-Partner Interdependence Model (APIM) showed that both members' attachment avoidance was associated with self-report lower levels of closeness. Parents' attachment anxiety was related to relationship discord. Parents with higher avoidant attachment reported lower closeness when adolescents were higher in avoidant attachment. Higher parents' anxious attachment was related to higher relationship closeness when adolescents were higher on anxious attachment. Such an association was negative when adolescents had lower anxious attachment. Higher parents' anxious attachment was related to greater discord when adolescents were lower on anxiety attachment. This study reveals the complex dyadic dynamics of relationship quality in parent-adolescent pairs.

The relationship between alcohol consumption and related harm among young university students.

Issue addressed Research has shown that Australian university students consume alcohol at a higher level than their peers from the general population and are therefore more likely to witness and experience alcohol-related harm. This study measured the prevalence of alcohol consumption among 18-24-year-old university students and the association between alcohol consumption and witnessed and experienced harms. Methods A random cross-sectional sample of university students aged 18-24 years (n=2466) was recruited via the University Survey Office and through random intercept at campus market day. All participants completed an online survey that included the Alcohol Use Disorders Identification Test, Alcohol Problems Scale and an additional scale measuring witnessed harm. Results Principal Components Analysis revealed three factors within the Alcohol Problems Scale; i.e. Criminal and Aggressive Behaviour, Health and Emotional Harms and Sexual Harms. Students who consume alcohol at high-risk levels were significantly more likely to score highly on each factor, 1.6 times more likely to experience harm and 1.1 times more likely to witness harm than students who consume alcohol at low-risk levels. Conclusions The positive association between alcohol consumption and alcohol-related harm supports previous findings. This study adds previous research through the categorisation of harm into factors. So what? Integrated and comprehensive interventions addressing alcohol consumption among young university students that are informed by evidence-based research can be tailored to ensure that they meet the needs of the target group.

Longitudinal resting state fMRI analysis in healthy controls and premanifest Huntington's disease gene carriers: a three-year follow-up study.

BACKGROUND: We previously demonstrated that in the premanifest stage of Huntington's disease (preHD), a reduced functional connectivity exists compared to healthy controls. In the current study, we look at possible changes in functional connectivity occurring longitudinally over a period of 3 years, with the aim of assessing the potential usefulness of this technique as a biomarker for disease progression in preHD. METHODS: Twenty-two preHD and 17 healthy control subjects completed resting state functional magnetic resonance imaging (fMRI) scans in two visits with 3 years in between. Differences in resting state connectivity were examined for eight networks of interest using FSL with three different analysis types: a dual regression method, region of interest approach, and an independent component analysis. To evaluate a possible combined effect of gray matter volume change and the change in blood oxygenation level dependent signal, the analysis was performed with and without voxel-wise correction for gray matter volume. To evaluate possible correlations between functional connectivity change and the predicted time to disease onset, the preHD group was classed as preHD-A if ≥10.9 years and preHD-B if <10.9 years from predicted disease onset. Possible correlations between burden of pathology score and functional connectivity change in preHD were also assessed. Finally, longitudinal change in whole brain and striatal volumetric measures was assessed in the studied cohort. RESULTS: Longitudinal analysis of the resting state-fMRI (RS-fMRI) data revealed no differences in the degree of connectivity change between the groups over a period of 3 years, though a significantly higher rate of striatal atrophy was found in the preHD group compared to controls in the same period. DISCUSSION: Based on the results found in this study, the provisional conclusion is that RS-fMRI lacks sensitivity in detecting changes in functional connectivity in HD gene carriers prior to disease manifestation over a 3-year follow-up period.

Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease.

Motor disturbances can be present in both manifest and premanifest Huntington's disease (HD). We aimed to investigate the role of motor functioning on executive functioning to better understand the progression of cognitive dysfunction in HD. Forty patients with manifest HD, 21 patients with premanifest HD, and a group of 28 controls were tested twice with a 1-year interval. For the Symbol Digit Modalities Test and the Figure Fluency Test, extra conditions were designed to measure motor involvement. Subtraction of this motor score from the original test score resulted in isolation of the cognitive component. Groups were compared on motor, cognitive, and original test scores using multilevel regression analysis. Manifest patients had lower baseline scores of 0.53 standard deviations (SD) on the original Symbol Digit Modalities Test (P = 0.03) and 0.71 SD on the motor isolation part (P = 0.006), and they showed a deterioration of 0.47 SD over 1 year of follow-up on the original Symbol Digit Modalities Test (P = 0.001) compared with controls. Premanifest patients had lower baseline scores of 0.67 SD on the Symbol Digit Modalities motor part (P = 0.008) and deterioration of 0.48 SD on the original (P = 0.001) and cognitive isolation (P = 0.02) parts. Secondary analyses revealed that the premanifest deterioration resulted from the close-to-predicted-onset group. Motor disturbances have a negative influence on performance on the Symbol Digit Modalities Test. Isolation of the cognitive component of this test revealed cognitive deterioration in the premanifest group only, caused by deteriorating scores for patients who were close to their predicted clinical disease onset. The Figure Fluency Test did not prove sensitive to cognitive change.

Better global and cognitive functioning in choreatic versus hypokinetic-rigid Huntington's disease.

BACKGROUND: Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. METHODS: In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n=528) or hypokinetic-rigid (n=432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. RESULTS: Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P<.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P<.001). CONCLUSIONS: Patients with a predominantly choreatic motor phenotype performing better in all areas than patients with a hypokinetic-rigid motor phenotype.

Elevated brain iron is independent from atrophy in Huntington's Disease.

Increased iron in subcortical structures in patients with Huntington's Disease (HD) has been suggested as a causal factor of neuronal degeneration. The present study examines iron accumulation, measured using magnetic resonance imaging (MRI), in premanifest gene carriers and in early HD patients as compared to healthy controls. In total 27 early HD patients, 22 premanifest gene carriers and 25 healthy controls, from the Leiden site of the TRACK-HD study, underwent 3T MRI including high resolution 3D T(1)- and T(2)-weighted and asymmetric spin echo (ASE) sequences. Magnetic Field Correlation (MFC) maps of iron levels were constructed to assess magnetic field inhomogeneities and compared between groups in the caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, accumbens nucleus, and thalamus. Subsequently the relationship of MFC value to volumetric data and disease state was examined. Higher MFC values were found in the caudate nucleus (p<0.05) and putamen (p<0.005) of early HD compared to controls and premanifest gene carriers. No differences in MFC were found between premanifest gene carriers and controls. MFC in the caudate nucleus and putamen is a predictor of disease state in HD. No correlation was found between the MFC value and volume of these subcortical structures. We conclude that Huntington's disease patients in the early stages of the disease, but not premanifest gene carriers, have higher iron concentrations in the caudate nucleus and putamen. We have demonstrated that the iron content of these structures relates to disease state in gene carriers, independently of the measured volume of these structures.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease.

BACKGROUND: Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. METHODS: There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. RESULTS: 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. CONCLUSIONS: The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.