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    ABSTRACT: In 1825, the actuary Benjamin Gompertz read a paper, 'On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies', to the Royal Society in which he showed that over much of the adult human lifespan, age-specific mortality rates increased in an exponential manner. Gompertz's work played an important role in shaping the emerging statistical science that underpins the pricing of life insurance and annuities. Latterly, as the subject of ageing itself became the focus of scientific study, the Gompertz model provided a powerful stimulus to examine the patterns of death across the life course not only in humans but also in a wide range of other organisms. The idea that the Gompertz model might constitute a fundamental 'law of mortality' has given way to the recognition that other patterns exist, not only across the species range but also in advanced old age. Nevertheless, Gompertz's way of representing the function expressive of the pattern of much of adult mortality retains considerable relevance for studying the factors that influence the intrinsic biology of ageing. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.
    Philosophical Transactions of The Royal Society B Biological Sciences 04/2015; 370(1666). DOI:10.1098/rstb.2014.0379
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    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. Results 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. Conclusions PBHE clusters were associated with BMI, MDPS and PHS and could be a useful tool to tailor interventions for those of peri-retirement age.
    Maturitas 11/2014; 79(3). DOI:10.1016/j.maturitas.2014.07.003
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    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). DOI:10.1111/nan.12073
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    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.
    Experimental Cell Research 07/2014; 325(1). DOI:10.1016/j.yexcr.2014.03.012
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    ABSTRACT: Perfusion single photon emission computed tomography (SPECT) and 18F fluorodeoxyglucose positron emission tomography (FDG-PET) both have clinical utility for the differential diagnosis of dementia. Although PET is often viewed by some as more accurate and therefore preferential, the extent to which published evidence supports this is not clear. The aim of this review was to address the question by reviewing studies of SPECT and PET imaging in dementia diagnosis, with a particular focus on all published head-to-head studies. A MEDLINE search was carried out using the following keywords: "PET" and "SPECT" and "dementia" or "Mild Cognitive Impairment," together with "alzheimers" or "DLB" or "lewy body" or "frontotemporal" or "FTD" or "Picks." Articles were included up to February 2013, limited to human studies and in English language. Published studies of SPECT accuracy show that it is a useful tool for differential diagnosis, with sensitivities of 65-85% for diagnosing Alzheimer's disease (AD) and specificities (for other neurodegenerative dementias) of 72-87%. PET studies generally report higher accuracy, with sensitivities of 75-99% for AD and specificities of 71-93%. However, there have been few direct head-to-head comparisons, with some indicating SPECT and PET to be equally useful in dementia diagnosis and others favouring PET. Many of these studies are limited with respect to numbers and methodically with poorly matched control groups. Overall, although studies suggest superiority of PET over SPECT, the evidence base for this is actually quite limited. We suggest that further direct comparative studies, including health economic and patient preference evaluations, are needed to help direct future service provision. Copyright © 2013 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 06/2014; 29(6). DOI:10.1002/gps.4036
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    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.
    Maturitas 06/2014; 78(2). DOI:10.1016/j.maturitas.2014.03.004
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    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.
    04/2014; 66(4):979-89. DOI:10.1002/art.38297
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    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.
    Neuroscience 02/2014; 265. DOI:10.1016/j.neuroscience.2014.01.041
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    ABSTRACT: Background Delirium is common and is associated with an increased risk of dementia. However, it is not clear whether delirium confers increased risk of any particular type of dementia. We performed a retrospective study of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) to ascertain whether a suspected episode of preceding delirium was more common prior to diagnosis in either type of dementia. Methods The study was carried out in a tertiary referral unit for the diagnosis of dementia. Clinic letters from the first presentation to the unit of 85 cases with DLB and 95 cases of AD were reviewed for documentation of any previous episodes of suspected delirium. ResultsIn this study, 25% of DLB cases had at least one reported episode of suspected delirium as compared to 7% of AD cases (p=0.001). For the DLB cases who had a prior suspected delirium, 23% had more than one episode compared with 14% of the AD group. The median time between most recent suspected episode of delirium and diagnosis of dementia in both groups was less than a year ConclusionsA greater proportion of those presenting and diagnosed with DLB had a documentation of a suspected delirium than those diagnosed with AD. Delirium may lead to a higher risk of DLB as opposed to other forms of dementia, or delirium may, at least in some cases, represent the early stages of DLB. These data suggest that a diagnosis of DLB should be specifically considered in those presenting with a delirium. Copyright (c) 2013 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 02/2014; 29(2). DOI:10.1002/gps.3986
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    ABSTRACT: Nonmotor symptoms (NMS) are common in patients with established Parkinson's disease (PD) and have a major impact upon quality of life. We investigated the significance of NMS in relation to health-related quality of life (HRQoL) in patients with newly diagnosed PD. Patients and healthy controls were recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study. Prevalence of NMS was determined with the Non-Motor Symptom Questionnaire. HRQoL was recorded with the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). Further assessments included measures of motor disability, depression, sleep, and cognition. One hundred and fifty-eight patients with newly diagnosed PD and 99 controls participated in this cross-sectional study. Patients reported greater numbers of NMS than controls (mean 8.3 ± 4.3 versus 2.8 ± 2.5 symptoms; P < 0.001). Patients reported lowest HRQoL in the domains assessing bodily discomfort, mobility, and activities of daily living. Motor and nonmotor symptoms impacted negatively upon HRQoL scores. Patients with the postural instability and gait difficulty motor subtype reported worse HRQoL, compared with those with tremor-dominant disease. Depression (P < 0.001), incomplete bowel emptying (P < 0.001), anxiety (P < 0.001), impaired concentration (P < 0.001), memory complaints (P < 0.001), and insomnia (P = 0.001) had the greatest negative impact upon HRQoL. NMS are common in patients with early PD and represent a significant cause of poorer health-related quality of life. Cognitive, neuropsychiatric, and sleep disturbances are particularly associated with reduced well-being. Screening and management of these symptoms should be prioritized at the time of diagnosis. © 2013 International Parkinson and Movement Disorder Society.
    Movement Disorders 02/2014; 29(2). DOI:10.1002/mds.25664
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