Insights into the pathological basis of dementia from population-based neuropathology studies

The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case–control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes

Buckle up safely: a cluster randomised trial to evaluate the effectiveness of a pre-school based program to increase appropriate use of child restraints

BACKGROUND: Road traffic crashes for car occupants are a leading cause of death and serious injury in children from high and middle income countries globally. Correct use of appropriate child restraints can significantly reduce death and serious injury but there is a need for well powered trials to examine effectiveness of programs to increase optimal child restraint practices. The aim of this trial is to examine the effectiveness of a comprehensive intervention to increase the use of appropriate child restraints, and decrease incorrect use of child restraints in pre-school aged children traveling in cars. METHODS AND DESIGN: A cluster randomised controlled trial will be conducted, involving 28 pre-school or childcare centres in low income areas of Sydney, Australia, over one calendar year. The intervention is an educational program involving an in-service for centre staff, distribution of educational materials to parents, a parent workshop demonstrating restraint use, subsidised restraints for parents in need, and vouchers for a free restraint checking service. Blinded assessors will observe restraint use at all centres at the end of the calendar year. Data will be analysed on an intention-to-treat basis; the primary analysis will compare the proportion of each of the two outcome measures (use of appropriate restraints, and incorrect use of restraints) at each centre between intervention and control groups. Detailed process evaluation will be conducted, including examination of implementation and utilisation of various elements of the program by both centres and families. DISCUSSION: This assessor blinded cluster randomised trial is powered to provide credible evidence about the efficacy of an education and distribution program in a pre-school setting to increase appropriate use, and decrease incorrect use of child restraints. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000612213

The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood-Brain Barrier Dysfunction

Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68 + microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68 + microglia were isolated from white matter groups (n = 4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort using immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material in the CFAS cohort and identified significantly differentially expressed genes (DEGs). Functional grouping and pathway analysis were assessed using the Database for Annotation Visualization and Integrated Discovery (DAVID) software, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCLs compared to non-lesional control white matter identified 181 significant DEGs (93 upregulated and 88 downregulated). Functional clustering analysis in DAVID revealed dysregu-lation of haptoglobin-haemoglobin binding (Enrichment score 2.5, p = 0.017), confirmed using CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCLs. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p < 0.001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in ageing white matter pathology, highlighting a neuroprotective adaptation in DSCLs microglia and a potentially lesion-promoting phenotype in NAWM microglia

Simple guide to starting a research group

Conducting cutting-edge research and scholarship becomes more complicated with each passing year; forming a collaborative research group offers a way to navigate this increasing complexity. Yet many individuals whose work might benefit from the formation of a collaborative team may feel overwhelmed by the prospect of attempting to build and maintain a research group. We propose this simple guide for starting and maintaining such an enterprise

The Effectiveness and Perceptions of Three Moderate Intensity Walking Cadence Aids and their Effects on Affective States: a Mixed Methods Study

Substantial health benefits can be derived from walking at a moderate intensity cadence. To help regulate this cadence three distinct aids exist 1) self-perception; 2) cadence prescription; 3) auditory cues. This study aimed to compare the effectiveness and explore perceptions of these aids to promote moderate intensity walking and effects on affective states, thereby addressing an important research gap. Individualised moderate relative intensity waking cadence was determined for participants (n = 23, Mage = 26.35, SD = 10.11). A convergent mixed-methods design was employed. A within-persons repeated measures design was used to explore the effectiveness of three aids (general guidelines, cadence prescription, and music) on promoting moderate intensity physical activity and positive affective states. Perceptions of these aids were elicited through qualitative interviews with thematic content analysis. Main effects for condition on relative physical activity intensity (η 2 = .72) and positive affect (η 2 = .25) were observed. Music evoked significantly higher relative physical activity intensity than other conditions (p values < .01), and higher positive affect compared to the general guidelines condition (p = .038). A significantly greater proportion of participants achieved moderate relative intensity physical activity during the music compared to general guidelines condition (p = .03). Congruently, qualitative findings suggested that participants predominantly perceived music as most effective for promoting a moderate intensity cadence and positive affect. However, individual variability existed in ability to utilise this aid. Implications of the findings for practitioners seeking to promote a moderate intensity cadence and positive affect during walking are discussed

NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain.

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer's disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response

Neutrophil-derived microvesicle induced dysfunction of brain microvascular endothelial cells in vitro

The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic levels of neutrophils have been detected in patients with altered BBB function, but the role of neutrophils in BMEC dysfunction is unknown. Neutrophils are key players of the immune response and, when activated, produce neutrophil-derived microvesicles (NMV). NMV have been shown to impact the integrity of endothelial cells throughout the body and we hypothesize that NMV released from circulating neutrophils interact with BMEC and induce endothelial cell dysfunction. Therefore, the current study investigated the interaction of NMV with human BMEC and determined whether they altered gene expression and function in vitro. Using flow cytometry and confocal imaging, NMV were shown to be internalized by the human cerebral microvascular endothelial cell line hCMEC/D3 via a variety of energy-dependent mechanisms, including endocytosis and macropinocytosis. The internalization of NMV significantly altered the transcriptomic profile of hCMEC/D3, specifically inducing the dysregulation of genes associated with TJ, ubiquitin-mediated proteolysis and vesicular transport. Functional studies confirmed NMV significantly increased permeability and decreased the transendothelial electrical resistance (TEER) of a confluent monolayer of hCMEC/D3. These findings indicate that NMV interact with and affect gene expression of BMEC as well as impacting their integrity. We conclude that NMV may play an important role in modulating the permeability of BBB during an infection

Reduced rates of primary joint replacement for osteoarthritis in Italian and Greek migrants to Australia: the Melbourne Collaborative Cohort Study

Introduction Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals. Methods Eligible participants (n = 39,023) aged 27 to 75 years, born in Italy, Greece, Australia and the United Kingdom, were recruited for the Melbourne Collaborative Cohort Study between 1990 and 1994. Primary hip and knee replacement for osteoarthritis between 2001 and 2005 was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Results Participants born in Italy and Greece had a lower rate of primary joint replacement compared with those born in Australia (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.26 to 0.39, P < 0.001), independent of age, gender, body mass index, education level, and physical functioning. This lower rate was observed for joint replacements performed in private hospitals (HR 0.17, 95% CI 0.13 to 0.23), but not for joint replacements performed in public hospitals (HR 0.96, 95% CI 0.72 to 1.29). Conclusions People born in Italy and Greece had a lower rate of primary joint replacement for osteoarthritis in this cohort study compared with Australian-born people, which could not simply be explained by factors such as education level, physical functioning, and weight. Although differential access to health care found in the population may explain the different rates of joint replacement, it may be that social factors and preferences regarding treatment or different rates of progression to end-stage osteoarthritis in this population are important to ethnic disparity.Yuanyuan Wang, Julie A Simpson, Anita E Wluka, Donna M Urquhart, Dallas R English, Graham G Giles, Stephen Graves and Flavia M Cicuttin

Relationship between body adiposity measures and risk of primary knee and hip replacement for osteoarthritis: a prospective cohort study

Introduction: Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. It is unknown whether the adipose mass and the distribution of adipose mass are associated with the risk of primary knee and hip replacement for osteoarthritis. The aim of the present investigation was to examine this in a cohort study. Methods: A total of 39,023 healthy volunteers from Melbourne, Australia were recruited for a prospective cohort study during 1990 to 1994. Their body mass index, waist circumference, and waist-to-hip ratio were obtained from direct anthropometric measurements. The fat mass and percentage fat were estimated from bioelectrical impedance analysis. Primary knee and hip replacements for osteoarthritis between 1 January 2001 and 31 December 2005 were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for primary joint replacement associated with each adiposity measure. Results: Comparing the fourth quartile with the first, there was a threefold to fourfold increased risk of primary joint replacement associated with body weight (HR = 3.44, 95% confidence interval (CI) = 2.83 to 4.18), body mass index (HR = 3.44, 95% CI = 2.80 to 4.22), fat mass (HR = 3.51, 95% CI = 2.87 to 4.30), and percentage fat (HR = 2.99, 95% CI = 2.46 to 3.63). The waist circumference (HR = 2.77, 95% CI = 2.26 to 3.39) and waist-to-hip ratio (HR = 1.46, 95% CI = 1.21 to 1.76) were less strongly associated with the risk. Except for the waist-to-hip ratio, which was not significantly associated with hip replacement risk, all adiposity measures were associated with the risk of both knee and hip joint replacement, and were significantly stronger risk factors for knee. Conclusions: Risk of primary knee and hip joint replacement for osteoarthritis relates to both adipose mass and central adiposity. This relationship suggests both biomechanical and metabolic mechanisms associated with adiposity contribute to the risk of joint replacement, with stronger evidence at the knee rather than the hip. © 2009 Wang et al.; licensee BioMed Central Ltd.Yuanyuan Wang, Julie Anne Simpson, Anita E Wluka, Andrew J Teichtahl, Dallas R English, Graham G Giles, Stephen Graves and Flavia M Cicuttin

Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer’s disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and –II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2O2-modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs= 0.312, p= 0.006) and the astrocyte response to oxidative DNA damage in vivo (rs= 0.238, p= 0.04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p=0.01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p=0.007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment