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ABSTRACT: Cultivation of an active cognitive lifestyle, including diverse and challenging educational, occupational and cognitively-loaded leisure activities may be protective against development of dementia but the mechanisms underlying this link are not clear. We used the Lifetime Experiences Questionnaire (LEQ) to assess the structural brain correlates of cognitive lifestyle in the Sydney Memory and Aging Study, a large population-based cohort of originally 1037 non-demented elderly aged over 70years of age. After excluding those without structural Magnetic Resonance Image data or Mild Cognitive Impairment at their most recent assessment, 151 cognitively intact subjects were studied. Whole-brain voxel based morphometric analysis found that higher total Lifetime Experiences Questionnaire scores are linked with increased grey matter volume in the medial temporal lobe, especially in the hippocampus. Through a series of more specific analyses, we found that supervisory and managerial experience in midlife was the dominant contributor to this effect. Furthermore, in those with longitudinal neuroimaging data (N=91), we measured hippocampal structural changes over a 2-3year period by gold-standard manual tracing. The rate of hippocampal atrophy in late-life in those with high level supervisory experience in midlife was five-times slower than those with no midlife supervisory experience (p<0.001). Individual differences in intracranial volume, age, gender, physical activity, depressive symptoms, or apolipoprotein ε4 genetic status could not explain these findings, nor could specific lifestyle patterns in late life. For the first time, we reveal that managerial and supervisory experience during our working life is connected to hippocampal integrity after retirement, some 20-30years later. Our results stimulate several questions about the nature of work-related effects on longterm behaviour, structural neuroplasticity and neuroprotection, and may help explain differences in dementia-risk based on cognitive lifestyle.
NeuroImage 08/2012; 63(3):1542-51. · 5.89 Impact Factor
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ABSTRACT: Effective non-pharmacological cognitive interventions to prevent Alzheimer's dementia or slow its progression are an urgent international priority. The aim of this review was to evaluate cognitive training trials in individuals with mild cognitive impairment (MCI), and evaluate the efficacy of training in memory strategies or cognitive exercises to determine if cognitive training could benefit individuals at risk of developing dementia.
A systematic review of eligible trials was undertaken, followed by effect size analysis. Cognitive training was differentiated from other cognitive interventions not meeting generally accepted definitions, and included both cognitive exercises and memory strategies.
Ten studies enrolling a total of 305 subjects met criteria for cognitive training in MCI. Only five of the studies were randomized controlled trials. Meta-analysis was not considered appropriate due to the heterogeneity of interventions. Moderate effects on memory outcomes were identified in seven trials. Cognitive exercises (relative effect sizes ranged from .10 to 1.21) may lead to greater benefits than memory strategies (.88 to -1.18) on memory.
Previous conclusions of a lack of efficacy for cognitive training in MCI may have been influenced by not clearly defining the intervention. Our systematic review found that cognitive exercises can produce moderate-to-large beneficial effects on memory-related outcomes. However, the number of high quality RCTs remains low, and so further trials must be a priority. Several suggestions for the better design of cognitive training trials are provided.
BMC Geriatrics 09/2011; 11:55. · 2.34 Impact Factor
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ABSTRACT: Plasma amyloid-β (Aβ) levels have been proposed as biomarkers of Alzheimer's disease (AD), but studies have produced inconsistent results. We present a meta-analytic review of cross-sectional studies that examined plasma Aβ levels in AD and cognitively normal subjects, and longitudinal studies that used baseline plasma Aβ levels to predict conversion from normal cognition to AD. Medline and EMBASE databases were searched to generate an initial list of relevant studies, and selected authors approached for additional data. Twelve cross- sectional studies (n = 1483) and seven longitudinal (n = 3920) met the inclusion criteria for meta-analysis. Random effects model was used to calculate the weighted mean difference (WMD) by Review Manager Version 4.2. In longitudinal studies, cognitively normal individuals who converted to AD had higher baseline Aβ1-40 and Aβ1-42 levels (WMD: 10.29, z = 3.80, p = 0.0001 and WMD: 8.01, z = 2.76, p = 0.006, respectively), and non-significantly increased Aβ1-42/Aβ1-40 ratio (WMD: 0.03, z = 1.65, p = 0.10). In cross sectional studies, compared to cognitively normal individuals, AD patients had marginally but non-significantly lower Aβ1-42 levels (WMD:-2.84, z = 1.73, p = 0.08), but Aβ1-40 levels were not significantly different (WMD: 3.43, z = 0.40, p = 0.69). Our systematic review suggests a model of differential longitudinal changes in plasma Aβ levels in cognitively stable individuals versus those who go on to develop AD dementia. Baseline Aβ1-40 and Aβ1-42 levels in cognitively normal elderly individuals might be predictors of higher rates of progression to AD, and should be further explored as potential biomarkers.
Journal of Alzheimer's disease: JAD 06/2011; 26(2):365-75. · 3.74 Impact Factor
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ABSTRACT: Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in individuals at risk of dementia has the potential to advance this objective. In a prior study, we evaluated the utility of a novel functional magnetic resonance imaging paradigm that incorporated a graded working memory (WM) task to detect changes associated with mild cognitive impairment (MCI). We observed greater deactivation of posteromedial cortex (PMC) under conditions of increased WM load in MCI compared with control subjects. Our objective here is to test whether this paradigm can predict ensuing functional decline.
Thirty individuals with MCI who underwent baseline functional magnetic resonance image scanning were followed clinically for 2 years. Multiple linear regression analyses were used to determine whether deactivation in PMC under increased load at baseline independently predicted decline in instrumental activities of daily living (IADL).
Greater deactivation in PMC to increased load predicted greater decline in IADL after controlling for baseline clinical severity, MCI subtype, apolipoprotein ε4 carrier status, gray matter, PMC and hippocampal volumes, and task performance.
Increased deactivation observed at baseline was a harbinger of subsequent functional decline as measured by IADL in a cohort with MCI. This graded WM challenge may operate like a memory stress test by producing a threshold effect beyond which abnormal deactivation is elicited in MCI subjects who are at greatest risk of functional decline.
Biological psychiatry 05/2011; 70(2):123-30. · 8.93 Impact Factor
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ABSTRACT: An active cognitive lifestyle has been linked to dementia incidence and survival, but the separate and combined effects of its subcomponents are not clear. Data were derived from the Medical Research Council Cognitive Function and Ageing Study, a population-based study of 13,004 individuals in England and Wales first interviewed in 1991-1992 and followed over a 10-year period for dementia incidence and 12 years for mortality. A Cognitive Lifestyle Score (CLS), defined as a composite of cognitive activity including education, occupational complexity, and social engagement, was available for 12,600 individuals in 3 stages of life. A higher CLS was protective of dementia (odds ratio = 0.6, 95% confidence interval: 0.4, 0.9). Sensitivity analyses found this main effect to be reliable and replicable even when considering just 2 components of the score, either education and occupation or education and late-life social engagement. No single CLS factor was associated with dementia incidence on its own. Survival differences did not reach statistical significance. Our data suggest that more years of education, as well as further stimulatory experiences in either midlife or late life. are necessary for a protective link with dementia incidence. There was little evidence of an effect of cognitive lifestyle on survival after dementia diagnosis.
American journal of epidemiology 03/2011; 173(9):1004-12. · 5.59 Impact Factor
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ABSTRACT: The capacity of visual working memory (WM) is substantially limited and only a fraction of what we see is maintained as a temporary trace. The process of binding visual features has been proposed as an adaptive means of minimising information demands on WM. However the neural mechanisms underlying this process, and its modulation by task and load effects, are not well understood.
To investigate the neural correlates of feature binding and its modulation by WM load during the sequential phases of encoding, maintenance and retrieval.
18 young healthy participants performed a visuospatial WM task with independent factors of load and feature conjunction (object identity and position) in an event-related functional MRI study. During stimulus encoding, load-invariant conjunction-related activity was observed in left prefrontal cortex and left hippocampus. During maintenance, greater activity for task demands of feature conjunction versus single features, and for increased load was observed in left-sided regions of the superior occipital cortex, precuneus and superior frontal cortex. Where these effects were expressed in overlapping cortical regions, their combined effect was additive. During retrieval, however, an interaction of load and feature conjunction was observed. This modulation of feature conjunction activity under increased load was expressed through greater deactivation in medial structures identified as part of the default mode network.
The relationship between memory load and feature binding qualitatively differed through each phase of the WM task. Of particular interest was the interaction of these factors observed within regions of the default mode network during retrieval which we interpret as suggesting that at low loads, binding processes may be 'automatic' but at higher loads it becomes a resource-intensive process leading to disengagement of activity in this network. These findings provide new insights into how feature binding operates within the capacity-limited WM system.
PLoS ONE 01/2011; 6(8):e23960. · 4.09 Impact Factor
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Nicola J Gates, Michael Valenzuela,
Perminder S Sachdev,
Nalin A Singh,
Bernhard T Baune,
Henry Brodaty,
Chao Suo,
Nidhi Jain,
Guy C Wilson,
Yi Wang,
Michael K Baker,
Dominique Williamson,
Nasim Foroughi,
Maria A Fiatarone Singh
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ABSTRACT: The extent to which mental and physical exercise may slow cognitive decline in adults with early signs of cognitive impairment is unknown. This article provides the rationale and methodology of the first trial to investigate the isolated and combined effects of cognitive training (CT) and progressive resistance training (PRT) on general cognitive function and functional independence in older adults with early cognitive impairment: Study of Mental and Regular Training (SMART). Our secondary aim is to quantify the differential adaptations to these interventions in terms of brain morphology and function, cardiovascular and metabolic function, exercise capacity, psychological state and body composition, to identify the potential mechanisms of benefit and broader health status effects.
SMART is a double-blind randomized, double sham-controlled trial. One hundred and thirty-two community-dwelling volunteers will be recruited. Primary inclusion criteria are: at risk for cognitive decline as defined by neuropsychology assessment, low physical activity levels, stable disease, and age over 55 years. The two active interventions are computerized CT and whole body, high intensity PRT. The two sham interventions are educational videos and seated calisthenics. Participants are randomized into 1 of 4 supervised training groups (2 d/wk×6 mo) in a fully factorial design. Primary outcomes measured at baseline, 6, and 18 months are the Alzheimer's Disease Assessment Scale (ADAS-Cog), neuropsychological test scores, and Bayer Informant Instrumental Activities of Daily Living (B-IADLs). Secondary outcomes are psychological well-being, quality of life, cardiovascular and musculoskeletal function, body composition, insulin resistance, systemic inflammation and anabolic/neurotrophic hormones, and brain morphology and function via Magnetic Resonance Imaging (MRI) and Spectroscopy (fMRS).
SMART will provide a novel evaluation of the immediate and long term benefits of CT, PRT, and combined CT and PRT on global cognitive function and brain morphology, as well as potential underlying mechanisms of adaptation in older adults at risk of further cognitive decline.
Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000489392.
BMC Geriatrics 01/2011; 11:19. · 2.34 Impact Factor
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ABSTRACT: Converging lines of research indicate that complex mental activity is associated with reduced dementia risk. Thus, intense interest exists in whether different forms of cognitive exercise can help protect against cognitive decline and dementia. However, there is considerable confusion in terminology that is hindering progress in the field. We therefore introduce a concrete definition of cognitive training (CT) and make this the focus of our article. Clinical research that has evaluated CT in normal aging, mild cognitive impairment, and dementia is then critically reviewed. Despite many methodological shortcomings, the overall findings indicate that multidomain CT has the potential to improve cognitive function in healthy older adults and slow decline in affected individuals. Finally, practical issues, including the strengths and weaknesses of commercial products, are explored, and recommendations for further research and clinical implementation are made.
Current Psychiatry Reports 02/2010; 12(1):20-7. · 2.71 Impact Factor
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ABSTRACT: Domestic dogs exhibit an extraordinary degree of morphological diversity. Such breed-to-breed variability applies equally to the canine skull, however little is known about whether this translates to systematic differences in cerebral organization. By looking at the paramedian sagittal magnetic resonance image slice of canine brains across a range of animals with different skull shapes (N = 13), we found that the relative reduction in skull length compared to width (measured by Cephalic Index) was significantly correlated to a progressive ventral pitching of the primary longitudinal brain axis (r = 0.83), as well as with a ventral shift in the position of the olfactory lobe (r = 0.81). Furthermore, these findings were independent of estimated brain size or body weight. Since brachycephaly has arisen from generations of highly selective breeding, this study suggests that the remarkable diversity in domesticated dogs' body shape and size appears to also have led to human-induced adaptations in the organization of the canine brain.
PLoS ONE 01/2010; 5(7):e11946. · 4.09 Impact Factor
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The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 04/2009; 17(3):175-8. · 3.35 Impact Factor
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ABSTRACT: Epidemiological and preclinical studies suggest that mental activity levels may alter dementia risk. Clinical trials are now beginning to address the key issues of persistence of effect over extended follow-up and transfer of effect to nontrained domains. The aim of this report was to therefore systematically review results from clinical trials, which have examined the effect of cognitive exercise on longitudinal cognitive performance in healthy elderly individuals.
MEDLINE, PubMed, and key references were used to generate an initial list of relevant studies (N = 54). These were reviewed to identify randomized controlled trials, which tested the effect of a discrete cognitive exercise training regime on longitudinal (>3 months) posttraining neuropsychological performance in healthy older adults. Seven RCTs met entry criteria. Prechange and postchange scores were integrated using a random effects weighted mean difference (WMD) meta-analytic approach (Review Manager Version 4.2).
A strong effect size was observed for cognitive exercise interventions compared with wait-and-see control conditions (WMD = 1.07, CI: 0.32-1.83, z = 2.78, N = 7, p = 0.006, N = 3,194). RCTs with follow-up greater than 2 years did not appear to produce lower effect size estimates than those with less extended follow-up. Quality of reporting of trials was in general low.
Cognitive exercise training in healthy older individuals produces strong and persistent protective effects on longitudinal neuropsychological performance. Transfer of these effects to dementia-relevant domains such as general cognition and daily functioning has also been reported in some studies. Importantly, cognitive exercise has yet to be shown to prevent incident dementia in an appropriately designed trial and this is now an international priority.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 03/2009; 17(3):179-87. · 3.35 Impact Factor
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ABSTRACT: The concepts of brain and cognitive reserve capture several elements of common wisdom - that we all differ in the neural resources we are endowed at birth, that experience and especially complex mental activities then modify how these neural resources are organized and cultivated, and that after any form of brain injury there is significant individual variation in the degree to which clinical deficits may manifest. Transforming these insights into a formal and refutable working definition, however, has been more challenging. Depending on the scale of analysis, brain and cognitive reserve have been defined from neurocentric, neuropsychological, computational, and behavioral perspectives. In our research, we have focused on the behavioral definition, whereby an individual's lifetime exposure to complex mental activities is used for prediction of longitudinal cognitive and neurological change. This approach also benefits from a wealth of epidemiological studies linking heightened complex mental activity with reduced dementia risk. Research in the field of cognitive training is also beginning to indicate that incident cognitive decline can be attenuated, with recent clinical trials addressing the major challenges of transfer of gain and durability of effect. High quality randomized clinical trials are therefore the most urgent priority in this area so that the promise of brain and cognitive reserve can be harnessed for the purpose of the primary prevention of dementia.
Indian Journal of Psychiatry 01/2009; 51 Suppl 1:S16-21.
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ABSTRACT: Background. Brain reserve is a property of the central nervous system related to complex mental activity which may mediate the course and clinical expression of brain injury. Since there is no instrument that comprehensively assesses complex mental activity through the lifespan, we developed and tested the Lifetime of Experiences Questionnaire (LEQ) in a prospective study of healthy ageing.
Psychological Medicine 06/2007; 37(07):1015 - 1025. · 6.16 Impact Factor
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ABSTRACT: Objective: To conduct a comprehensive literature review of the area of neural stem cells and neuropsychiatry.Methods: ‘Neural stem cells’ (NSCs) and ‘neurogenesis’ were used as keywords in Medline (1966 – November 2006) to identify relevant papers in the areas of Alzheimer’s disease (AD), depression, schizophrenia and Parkinson’s disease (PD). This list was supplemented with papers from reference lists of seminal reviews.Results: The concept of a ‘stem cell’ continues to evolve and is currently defined by operational criteria related to symmetrical renewal, multipotency and functional viability. In vivo adult mammalian neurogenesis occurs in discrete niches in the subventricular and subgranular zones – however, functional precursor cells can be generated in vitro from a wide variety of biological sources. Both artificial and physiological microenvironment is therefore critical to the characteristics and behaviour of neural precursors, and it is not straightforward how results from the laboratory can be extrapolated to the living organism. Transplant strategies in PD have shown that it is possible for primitive neural tissue to engraft into neuropathic brain areas, become biologically functional and lead to amelioration of clinical signs and symptoms. However, with long-term follow-up, significant problems related to intractable side-effects and potential neoplastic growth have been reported. These are therefore the potentials and pitfalls for NSC technology in neuropsychiatry. In AD, the physiology of amyloid precursor protein may directly interact with NSCs, and a role in memory function has been speculated. The role of endogenous neurogenesis has also been implicated in the etiology of depression. The significance of NSCs and neurogenesis for schizophrenia is still emerging.Conclusions: There are a number of technical and conceptual challenges ahead before the promise of NSCs can be harnessed for the understanding and treatment of neuropsychiatric disorders. Further research into fundamental NSC biology and how this interacts with the neuropsychiatric disease processes is required.
Acta Neuropsychiatrica 02/2007; 19(1):11 - 26. · 0.58 Impact Factor
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ABSTRACT: This paper briefly describes neuroimaging using magnetic resonance spectroscopy (MRS) and provides a systematic review of its application to psychiatric disorders.
A literature review (Index Medicus/Medline) was carried out, as well as a review of other relevant papers and data known to the authors.
Magnetic resonance spectroscopy is a complex and sophisticated neuroimaging technique that allows reliable and reproducible quantification of brain neurochemistry provided its limitations are respected. In some branches of medicine it is already used clinically, for instance, to diagnose tumours and in psychiatry its applications are gradually extending beyond research. Neurochemical changes have been found in a variety of brain regions in dementia, schizophrenia and affective disorders and promising discoveries have also been made in anxiety disorders.
Magnetic resonance spectroscopy is a non-invasive investigative technique that has provided useful insights into the biochemical basis of many neuropsychiatric disorders. It allows direct measurement, in vivo, of medication levels within the brain and has made it possible to track the neurochemical changes that occur as a consequence of disease and ageing or in response to treatment. It is an extremely useful advance in neuroimaging technology and one that will undoubtedly have many clinical uses in the near future.
Australian and New Zealand Journal of Psychiatry 03/2002; 36(1):31-43. · 2.93 Impact Factor
