[Show abstract][Hide abstract] ABSTRACT: Background
Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM.Methods
We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles.ResultsThe degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P < 0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P < 0.01), with most prominent axonal abnormalities observed in the frontal WM (P < 0.05). The SIs of arterioles in CADASIL were increased by 25–45% throughout the regions assessed, with the highest change in the mid-frontal region (P = 0.000).Conclusions
Our results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures.
Neuropathology and Applied Neurobiology 08/2014; 40(5).
[Show abstract][Hide abstract] ABSTRACT: To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release.
We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package.
The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Overexpression of TIMP-1 was much less effective than that of TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK-1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition.
Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting.
[Show abstract][Hide abstract] ABSTRACT: Dual-task interference during gait is a common phenomenon in older adults and people with Parkinson's disease (PD). Dual-task performance is driven by cognitive processes involving executive function, attention and working memory which underpin resource capacity and allocation. The underlying processes that contribute to dual-task interference are poorly understood, and confounded by methodological differences. The aim of this study was to explore the nature of dual-task interference in PD with respect to age matched controls. We examined 121 people with early PD and 189 controls and controlled for baseline task demand on both tasks allowing between-group differences to be attributed to dual-task interference rather than differences in baseline performance. We also compared a wide range of gait characteristics to evaluate the pattern of interference. Participants walked for two minutes at preferred pace under single and dual-task (test of working memory capacity - digit span recall) conditions. In a sub-group task demand was increased (digit span +1) (n = 55 control, n = 44 PD) to assess the influence of resource capacity. Finally the association between dual-task interference with motor and cognitive characteristics were examined to evaluate resource capacity and allocation. PD and controls responded similarly to the dual-task for all gait characteristics except for step width and step width variability and this was the same when task demand increased (dual+1). Control participants took wider steps (p = .006) and step width variability increased significantly for controls (p = .001) but not PD. Interference was specific to the gait characteristic rather than a global pattern of impairment. Digit span error rates were not significantly different between groups during dual-task performance. There were no significant correlations with dual task interference and global cognition, motor deficit, and executive function for either group. Effects of dual-tasks on gait performance are two-fold and specific to the gait characteristic. They reflect an age related reduction in gait performance (especially forward progression) in PD and controls possibly due to reduced resource capacity; and secondly, show postural stability during walking in early PD is disproportionately affected highlighting a PD specific dual-task co-ordination deficit. Further work is required to identify the cognitive, executive and motor correlates of dual-task interference from which inferences about underlying cognitive processes can be made. These findings inform an understanding of dual-task impairment in early PD and suggest that management should target postural control under dual-task conditions from the early stages.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Health behaviours including diet, smoking, alcohol consumption, and physical activity, predict health risks at the population level. We explored health behaviours, barriers to healthy eating and self-rated health among individuals of retirement age.
Study design Eighty-two men and 124 women participated in an observational, cross-sectional online survey.
Main outcome measures A 14-item Mediterranean diet score (MDPS), perceived barriers to healthy eating (PBHE), self-reported smoking, physical activity habits, and current and prior perceived health status (PHS) were assessed. A health behaviours score (HBS) including smoking, physical activity, body mass index (BMI) and MDPS was created to evaluate associations with PHS. Two-step cluster analysis identified natural groups based on PBHE. Analysis of variance was used to evaluate between group comparisons.
PBHE number was associated with BMI (r= 0.28, P < 0.001), age (r= -0.19; P = 0.006), and MDPS (r= -0.31; P < 0.001). PHBE cluster analysis produced three clusters. Cluster-1 members (busy lifestyle) were significantly younger (57 years), more overweight (28 kg/m2), scored lower on MDPS (4.7) and reported more PBHE (7). Cluster-3 members (no characteristic PBHE) were leaner (25 kg/m2), reported the lowest number of PBHE (2), and scored higher on HBS (2.7) and MDPS (6.2). Those in PHS categories, bad/fair, good, and very good, reported mean HBS of 2.0, 2.4 and 3.0, respectively (P < 0.001). Compared with the previous year, no significant associations between PHS and HBS were observed.
PBHE clusters were associated with BMI, MDPS and PHS and could be a useful tool to tailor interventions for those of peri-retirement age.
[Show abstract][Hide abstract] ABSTRACT: Driving is an important aspect of daily living and for many older people provides autonomy and psycho-social benefits. Cognitive impairment has been found to impact driving skills at the level of dementia, however, uncertainty remains around the impact of a diagnosis of the pre-dementia condition mild cognitive impairment. Current official guidelines are unclear, and assessment of fitness to drive can be problematical. This editorial examines current official guidance available to the clinician and problems with existing assessment as well as the current position of research specifically into MCI and driving, and considers future direction for research in this field.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current treatments for these disorders are focussed on the management of the symptoms, rather than the correction of biochemical defects caused by the mutation. This review focuses on the molecular effects of the mutations, the symptoms they cause and current work focusing on the development of targeted treatments for mitochondrial DNA disease.
[Show abstract][Hide abstract] ABSTRACT: Visual sampling techniques are used to investigate the complex role of vision during real-world activities in Parkinson's disease. Earlier research is limited to static simple tasks or measurement of eye movements alone, but more recent investigations involve more real-world activities. The approach to the objective measurement of eye movements varies with respect to instrumentation, testing protocols, and mediating factors that may influence visual sampling.
The aim of this review was to examine previous work measuring visual sampling during real-world activities in Parkinson's disease to inform the development of robust protocols. Within this review a real-world activity was considered to be a goal-orientated motor task involving more than one body segment such as reaching or walking.
Medline, Embase, PsychInfo, Scopus, Web of Knowledge, PubMed and the Cochrane library databases were searched. Two independent reviewers and an adjudicator screened articles that described quantitative visual sampling in people with Parkinson's disease and healthy controls.
Twenty full-text articles were screened and 15 met inclusion/exclusion criteria. A wide range of instruments and outcome measures were reported which were generally used in a task-dependent manner. Instrument reliability and validity was insufficiently reported in all studies. Few studies considered mediators of visual sampling such as visual or cognitive deficits.
Future research is required to accurately characterise visual impairments in Parkinson's disease and during real-world activities. Composite use of instruments may be required to achieve reliability and validity of visual sampling outcomes which need to be standardised. Recommendations also include assessment of cognition and basic visual function.
[Show abstract][Hide abstract] ABSTRACT: Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.
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