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

Altered Intracortical T1-Weighted/T2-Weighted Ratio Signal in Huntington’s Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder that is characterized by neuronal cell death. Although medium spiny neurons in the striatum are predominantly affected, other brain regions including the cerebral cortex also degenerate. Previous structural imaging studies have reported decreases in cortical thickness in HD. Here we aimed to further investigate changes in cortical tissue composition in vivo in HD using standard clinical T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance images (MRIs). 326 subjects from the TRACK-HD dataset representing healthy controls and four stages of HD progression were analyzed. The intracortical T1W/T2W intensity was sampled in the middle depth of the cortex over 82 regions across the cortex. While these previously collected images were not optimized for intracortical analysis, we found a significant increase in T1W/T2W intensity (p < 0.05 Bonferroni-Holm corrected) beginning with HD diagnosis. Increases in ratio intensity were found in the insula, which then spread to ventrolateral frontal cortex, superior temporal gyrus, medial temporal gyral pole, and cuneus with progression into the most advanced HD group studied. Mirroring past histological reports, this increase in the ratio image intensity may reflect disease-related increases in myelin and/or iron in the cortex. These findings suggest that future imaging studies are warranted with imaging optimized to more sensitively and specifically assess which features of cortical tissue composition are abnormal in HD to better characterize disease progression

Altered Intracortical T1-Weighted/T2-Weighted Ratio Signal in Huntington’s Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder that is characterized by neuronal cell death. Although medium spiny neurons in the striatum are predominantly affected, other brain regions including the cerebral cortex also degenerate. Previous structural imaging studies have reported decreases in cortical thickness in HD. Here we aimed to further investigate changes in cortical tissue composition in vivo in HD using standard clinical T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance images (MRIs). 326 subjects from the TRACK-HD dataset representing healthy controls and four stages of HD progression were analyzed. The intracortical T1W/T2W intensity was sampled in the middle depth of the cortex over 82 regions across the cortex. While these previously collected images were not optimized for intracortical analysis, we found a significant increase in T1W/T2W intensity (p < 0.05 Bonferroni-Holm corrected) beginning with HD diagnosis. Increases in ratio intensity were found in the insula, which then spread to ventrolateral frontal cortex, superior temporal gyrus, medial temporal gyral pole, and cuneus with progression into the most advanced HD group studied. Mirroring past histological reports, this increase in the ratio image intensity may reflect disease-related increases in myelin and/or iron in the cortex. These findings suggest that future imaging studies are warranted with imaging optimized to more sensitively and specifically assess which features of cortical tissue composition are abnormal in HD to better characterize disease progression

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD

The varved succession of Crawford Lake, Milton, Ontario, Canada as a candidate Global boundary Stratotype Section and Point for the Anthropocene series

An annually laminated succession in Crawford Lake, Ontario, Canada is proposed as the Global boundary Stratotype Section and Point (GSSP) for the Anthropocene as a series/epoch with a base dated at 1950 CE. Varve couplets of organic matter capped by calcite precipitated each summer in alkaline surface waters reflect environmental change at global to local scales. Spheroidal carbonaceous particles and nitrogen isotopes record an increase in fossil fuel combustion in the early 1950s, coinciding with fallout from nuclear and thermonuclear testing—239+240Pu and 14C:12C, the latter more than compensating for the effects of old carbon in this dolomitic basin. Rapid industrial expansion in the North American Great Lakes region led to enhanced leaching of terrigenous elements by acid precipitation during the Great Acceleration, and calcite precipitation was reduced, producing thin calcite laminae around the GSSP that is marked by a sharp decline in elm pollen (Dutch Elm disease). The lack of bioturbation in well-oxygenated bottom waters, supported by the absence of fossil pigments from obligately anaerobic purple sulfur bacteria, is attributed to elevated salinities and high alkalinity below the chemocline. This aerobic depositional environment, unusual in a meromictic lake, inhibits the mobilization of 239Pu, the proposed primary stratigraphic guide for the Anthropocene

White matter predicts functional connectivity in premanifest Huntington's disease

Objectives The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD. The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trial

Risk Factors, Molecular Epidemiology and Outcomes of Ertapenem-Resistant, Carbapenem-Susceptible Enterobacteriaceae: A Case-Case-Control Study

Background: Increasing prevalence of ertapenem-resistant, carbapenem-susceptible Enterobacteriaceae (ERE) in Singapore presents a major therapeutic problem. Our objective was to determine risk factors associated with the acquisition of ERE in hospitalized patients; to assess associated patient outcomes; and to describe the molecular characteristics of ERE. Methods: A retrospective case-case-control study was conducted in 2009 at a tertiary care hospital. Hospitalized patients with ERE and those with ertapenem-sensitive Enterobacteriaceae (ESE) were compared with a common control group consisting of patients with no prior gram-negative infections. Risk factors analyzed included demographics; co-morbidities; instrumentation and antibiotic exposures. Two parallel multivariate logistic regression models were performed to identify independent variables associated with ERE and ESE acquisition respectively. Clinical outcomes were compared between ERE and ESE patients. Results: Twenty-nine ERE cases, 29 ESE cases and 87 controls were analyzed. Multivariate logistic regression showed that previous hospitalization (Odds ratio [OR], 10.40; 95 % confidence interval [CI], 2.19–49.20) and duration of fluoroquinolones exposure (OR, 1.18 per day increase; 95 % CI, 1.05–1.34) were unique independent predictors for acquiring ERE. Duration of 4 th-generation cephalosporin exposure was found to predict for ESE acquisition (OR, 1.63 per day increase; 95 % CI, 1.05– 2.54). In-hospital mortality rates and clinical response rates were significantly different between ERE and ESE groups