ORCID Profile
0000-0001-7162-6607
Current Organisations
World Health Organization
,
University of New South Wales
,
University of Sydney
,
Skin2Neuron Pty Ltd
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2011
Publisher: Springer Science and Business Media LLC
Date: 06-2016
Publisher: Wiley
Date: 12-2015
DOI: 10.1111/JGS.3_13825
Publisher: Cambridge University Press (CUP)
Date: 20-11-2007
DOI: 10.1017/S003329170600938X
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. Method. The LEQ assesses educational, occupational and cognitive lifestyle activities at different stages through life. Test–retest, item analysis and Item Response Theory (IRT) were used to determine reliability. Dimensionality was evaluated using factor analysis. Validity was established through IRT analysis of test performance, correlation with an extant contemporaneous instrument (Cognitive Activities Scale CAS) and prediction of global cognitive change over 18 months controlling for age, baseline cognition and hypertension. Results. In a s le of healthy older in iduals ( n =79) the LEQ was found to be consistent, coherent and discriminate between in iduals with high and low mental activity levels. Factor analysis revealed a dominant factor which loaded heavily on education, occupation and leisure activity. Total LEQ was significantly correlated with the CAS. Furthermore, in iduals with higher LEQ scores showed less cognitive decline over 18 months, independent of covariates ( r =0·37, p =0·003). Conclusions. The LEQ is a reliable and valid instrument for assessing complex lifespan mental activity which is protective against cognitive decline. The LEQ is therefore proposed as a useful tool for estimating brain reserve in older in iduals and further development is anticipated.
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.NEURES.2006.07.003
Abstract: Motor disturbances in major depressive disorder (MDD) are increasingly recognized and may differentiate melancholic, from non-melancholic depression. Motor impairments in melancholic depression have been likened to Parkinson's disease and proposed to have a frontostriatal basis. This study investigated self-pacing and reprogramming skills, thought to rely on frontostriatal functioning, in groups of healthy in iduals (n=15), non-melancholic depression patients (n=10) and melancholic depression patients (n=9) using ocular motor tasks. Self-paced saccades were requested to be performed at a rhythm of 1 Hz between two continuously illuminated targets, before and after external cueing. Saccade reprogramming, for direction and litude, was explored using a saccadic "oddball" task. Results indicated no group differences for accuracy, intersaccadic intervals (during the self-paced task), latency or peak velocity. However, the melancholic group showed greater intrasubject variability of latencies than the control group, lower peak saccade velocities compared to the non-melancholic group, and reduced accuracy of the primary saccade when compared to the control and the non-melancholic groups. These findings provide further support for distinct motor impairments associated with melancholia that may reflect frontostriatal abnormalities.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.BRAINRESREV.2007.07.007
Abstract: There is strong evidence to suggest that high levels of complex mental activity can improve clinical outcome from brain injury. What are the neurobiological mechanisms underlying this observation? This paper proposes that complex mental activity induces a spectrum of biological changes on brain structure and function which can be best understood in a multiscalar spatiotemporal framework. Short-term molecular changes may include induction of BDNF, NGF and endopeptidase genes and elevation of the high-energy phosphocreatine-creatine resting state equilibrium. Animal models have implicated these processes in the reduction and even reversal of neurodegenerative changes secondary to mental work. These mechanisms can therefore be described as neuroprotective. Medium-term cellular changes are erse and include neurogenesis, synaptogenesis, angiogenesis and formation of more complex dendritic branching patterns. Importantly, these effects parallel behavioral improvement, and thus a neurogenerative class of mechanisms is implicated. Finally, in the post-lesion context, computation principles such as efficiency, small world connectivity and functional adaptation are identified as important, with supportive clinical evidence from neuroimaging studies. Thus, dynamic compensatory cortical network mechanisms may also be relevant, yet take some time to evolve. This paper will explore the neurobiological and clinical implications of this framework, in particular in the context of age-related brain disease.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2011
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.NEUROIMAGE.2012.08.015
Abstract: Cultivation of an active cognitive lifestyle, including erse 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 70 years 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 hippoc us. 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 hippoc al structural changes over a 2-3 year period by gold-standard manual tracing. The rate of hippoc al 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). In idual 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 hippoc al integrity after retirement, some 20-30 years 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.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 15-11-2017
Publisher: Elsevier BV
Date: 2012
Publisher: Elsevier BV
Date: 11-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2003
Publisher: Springer Science and Business Media LLC
Date: 20-12-2013
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.TVJL.2009.11.007
Abstract: Canine cognitive dysfunction (CCD) is a neurobehavioural syndrome affecting aged dogs. Using a large cross-sectional epidemiological study of older dogs, this study aimed to estimate the prevalence of CCD amongst community based dogs (mean age 11.67years range 8-19.75) and to determine the rate of veterinary diagnosis amongst affected dogs. An 84-item questionnaire was used to obtain information across six behavioural domains. Of the eligible survey responses obtained (n=957) a randomly selected one-half (n=497) was used for this study. Using a provisional diagnosis based on 27 significant behavioural items, the prevalence rate of CCD was estimated to be 14.2%. This was in contrast with only 1.9% diagnosed with CCD by a veterinarian. There was an exponential increase in prevalence of CCD with age (R2=0.9435), but prevalence did not differ by breed size or between longevity groups. The prevalence rate of CCD reported here is consistent with previous findings, and further supports the contention that the majority of these dogs do not receive a formal diagnosis.
Publisher: Elsevier BV
Date: 03-2009
Publisher: Public Library of Science (PLoS)
Date: 18-11-2014
Publisher: SAGE Publications
Date: 12-2001
DOI: 10.1046/J.1440-1614.2001.00969.X
Abstract: Objective: This paper examines the current literature pertaining to brain ageing. The objective of this review is to provide an overview of the effects of ageing on brain structure and function and to examine possible mediators of these changes. Methods: A MEDLINE search was conducted for each area of interest. A selective review was undertaken of relevant articles. Results: Although fundamental changes in fluid intellectual abilities occur with age, global cognitive decline is not a hallmark of the ageing process. Decline in fluid intellectual ability is paralleled by regionally specific age related changes apparent from both structural and functional neuroimaging studies. The histopathological mediators of these changes do not appear to be reduction in neuronal number, which, with the exception of selected hippoc al regions, remain relatively stable across age. At the molecular level, several mechanisms of age related change have been postulated. Such theoretical models await refinement and may eventually provide a basis for therapy designed to reduce effects of the ageing process. The role of possible protective factors such as ‘brain reserve’, neuroprotective agents and hormonal factors in modifying in idual vulnerability to the ageing process has been the focus of a limited number of studies. Conclusion: Our understanding of the functional and structural changes associated with both healthy and pathological ageing is rapidly gaining in sophistication and complexity. An awareness of the fundamental biological substrates underpinning the ageing process will allow improved insights into vulnerability to neuropsychiatric disease associated with advancing age.
Publisher: Informa UK Limited
Date: 10-2012
Publisher: Cambridge University Press (CUP)
Date: 06-10-2006
DOI: 10.1017/S0033291705006264
Abstract: Background. Behavioural brain reserve is a property of the central nervous system related to sustained and complex mental activity which can lead to differential expression of brain injury. Behavioural brain reserve has been assessed using autobiographical data such as education levels, occupational complexity and mentally stimulating lifestyle pursuits. So far there have been several epidemiological reports but no systematic review to put conflicting results into context. Our aim was to quantitatively review evidence for the effect of brain reserve on incident dementia. Method. Cohort studies of the effects of education, occupation, premorbid IQ and mental activities on dementia risk were of interest. Abstracts were identified in MEDLINE (1966–September 2004), CURRENT CONTENTS (to September, 2004), PsychINFO (1984–September 2004), Cochrane Library Databases and reference lists from relevant articles. Twenty-two studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Studies were combined through a quantitative random-effects meta-analysis. Results. Higher brain reserve was associated with a lowered risk for incident dementia (summary odds ratio, 0·54 95% confidence interval, 0·49–0·59). This effect was found over a median of 7·1 years follow-up and resulted from integrating data across more than 29000 in iduals. Notably, increased complex mental activity in late life was associated with lower dementia rates independent of other predictors a dose–response relationship was also evident between extent of complex mental activities in late life and dementia risk. Conclusions. This study demonstrates robust evidence that complex patterns of mental activity in the early, mid- and late-life stages is associated with a significant reduction in dementia incidence. Randomized control trials based on brain-reserve principles are now required.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Oxford University Press (OUP)
Date: 04-03-2011
DOI: 10.1093/AJE/KWQ476
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 in iduals 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 in iduals 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.
Publisher: Informa UK Limited
Date: 19-05-2016
DOI: 10.1080/13825585.2015.1048773
Abstract: Social and general cognitive abilities decline in late life. Those with high cognitive reserve display better general cognitive performance in old age however, it is unknown whether this is also the case for social cognition. A total of 115 healthy older adults, aged 60-85 years (m = 44, f = 71) were assessed using The Awareness of Social Inference Test (TASIT-R social cognition), the Lifetime of Experiences Questionnaire (LEQ cognitive reserve), and the Wechsler Abbreviated Scale of Intelligence (WASI-II general cognitive ability). The LEQ did not predict performance on any TASIT-R subtest: Emotion Evaluation Test (β = -.097, p = .325), Social Inference - Minimal (β = -.004, p = .972), or Social Inference - Enriched (β = -.016, p = .878). Sensitivity analyses using two alternative cognitive reserve measures, years of education and the National Adult Reading Test, supported these effects. Cognitive reserve was strongly related to WASI-II performance. Unlike general cognitive ability, social cognition appears unaffected by cognitive reserve. Findings contribute to the emerging understanding that cognitive reserve differentially affects in idual cognitive domains, which has implications for the theoretical understanding of cognitive reserve and its brain correlates. Cognitive measures unbiased by cognitive reserve may serve as best indicators of brain health, free of compensatory mechanisms.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Elsevier BV
Date: 03-2006
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.BIOPSYCH.2011.03.006
Abstract: Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in in iduals 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 in iduals 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 hippoc al 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.
Publisher: Cambridge University Press (CUP)
Date: 02-05-2006
DOI: 10.1017/S0033291706007744
Abstract: Background. A previous companion paper to this report (Valenzuela & Sachdev, Psychological Medicine 2006, 36 , 441–454) suggests a link between behavioural brain reserve and incident dementia however, the issues of covariate control and ascertainment bias were not directly addressed. Our aim was to quantitatively review an independent set of longitudinal studies of cognitive change in order to clarify these factors. Method. Cohort studies of the effects of education, occupation, and mental activities on cognitive decline were of interest. Abstracts were identified in MEDLINE (1966–September 2004), CURRENT CONTENTS (to September 2004), PsychINFO (1984–September 2004), Cochrane Library Databases and reference lists from relevant articles. Eighteen studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Cognitive decline studies were integrated using a non-parametric method after converting outcome data onto a common effect size metric. Results. Higher behavioural brain reserve was related to decreased longitudinal cognitive decline after control for covariates in source studies (ϕ=1·70, p ·001). This effect was robust to correction for both multiple predictors and multiple outcome measures and was the result of integrating data derived from more than 47000 in iduals. Conclusions. This study affirms that the link between behavioural brain reserve and incident dementia is most likely due to fundamentally different cognitive trajectories rather than confound factors.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NLM.2014.01.013
Abstract: Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and in idual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation.
Publisher: Public Library of Science (PLoS)
Date: 28-03-2013
Publisher: American Psychiatric Association Publishing
Date: 04-2017
DOI: 10.1176/APPI.AJP.2016.16030360
Abstract: Previous meta-analyses indicate that computerized cognitive training (CCT) is a safe and efficacious intervention for cognition in older adults. However, efficacy varies across populations and cognitive domains, and little is known about the efficacy of CCT in people with mild cognitive impairment or dementia. The authors searched Medline, Embase, PsychINFO, CINAHL, and CENTRAL through July 1, 2016, for randomized controlled trials of CCT in older adults with mild cognitive impairment or dementia. Overall cognition, in idual cognitive domains, psychosocial function, and activities of daily living were pooled separately for mild cognitive impairment and dementia trials. The overall effect on cognition in mild cognitive impairment across 17 trials was moderate (Hedges' g=0.35, 95% CI=0.20-0.51). There was no evidence of publication bias or difference between active- and passive-controlled trials. Small to moderate effects were found for global cognition, attention, working memory, learning, and memory, with the exception of nonverbal memory, and for psychosocial functioning, including depressive symptoms. In dementia, statistically significant effects were found on overall cognition (k=11, g=0.26, 95% CI=0.01-0.52) and visuospatial skills, but these were driven by three trials of virtual reality or Nintendo Wii. CCT is efficacious on global cognition, select cognitive domains, and psychosocial functioning in people with mild cognitive impairment. This intervention therefore warrants longer-term and larger-scale trials to examine effects on conversion to dementia. Conversely, evidence for efficacy in people with dementia is weak and limited to trials of immersive technologies.
Publisher: Mary Ann Liebert Inc
Date: 12-2008
Abstract: Recent work indicates that neural progenitors can be isolated from the skin of rodents and humans. The persistence of these cells in accessible adult tissue raises the possibility of their exploitation for research and therapeutic purposes. This study reports on the derivation, culture, and characterization of homogenous canine skin-derived neuroprecursor cells (SKiNPs) from mature animals. Canine tissue was used because naturalistic brain diseases in community-dwelling dogs are emerging as ecologically sound models for a range of neurological conditions. Adult SKiNPs were initially isolated as neurospheres and then cultured for 10-15 passages in an adherent monolayer assay. Serumfree expansion conditions contained B-27, 20 ng/mL EGF, and 40 ng/mL bFGF. Gene expressions by PCR indicated expression of nestin, CD133, NCAM, and FGF2R, but not GFAP. Highly uniform expression of nestin (76 +/- 8.3%), NCAM (84 +/- 3.3%), betaIII-tubulin (96 +/- 4.3%), and CD133 (68 +/- 13.5%) was also observed. Directed differentiation of SKiNPs in the presence of serum induced betaIIItubulin, NSE, NCAM, and MAP2 in >90% of differentiated cells by immunophenotype analysis. Our culture system rapidly induces canine skin cells into neural precursors, maintains nestin expression in more than 75% of proliferating cells, and generates an almost universal neuronal-like phenotype after 7 days of in vitro differentiation. Their biological characteristics are suggestive of transiently lifying fate-restricted neuroprecursors rather than true neural stem cells. This system may be an effective alternative for autologous neurorestorative cell replacement in canine models for further translational research.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 22-03-2016
DOI: 10.1038/MP.2016.19
Publisher: Springer Science and Business Media LLC
Date: 12-03-2013
DOI: 10.1038/MP.2013.26
Publisher: Springer Science and Business Media LLC
Date: 24-04-2012
DOI: 10.1038/TP.2012.28
Publisher: Cambridge University Press (CUP)
Date: 02-2007
DOI: 10.1111/J.1601-5215.2007.00176.X
Abstract: To conduct a comprehensive literature review of the area of neural stem cells and neuropsychiatry. ‘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. 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. 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.
Publisher: Wiley
Date: 12-2015
DOI: 10.1111/JGS.13825
Publisher: Springer Science and Business Media LLC
Date: 31-05-2011
DOI: 10.1038/MP.2011.62
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.BIOPSYCH.2011.07.036
Abstract: An active cognitive lifestyle is linked to diminished dementia risk, but the underlying mechanisms are poorly understood. Potential mechanisms include disease modification, neuroprotection, and compensation. Prospective, population-based brain series provide the rare opportunity to test the plausibility of these mechanisms in humans. Participants came from the United Kingdom Medical Research Council Cognitive Function and Ageing Study, comprising 13,004 in iduals aged over 65 years and followed for 14 years. In study 1, a Cognitive Lifestyle Score (CLS) was computed on all Cognitive Function and Ageing Study subjects to define low, middle, and high groups. By August 2004, 329 in iduals with CLS data had come to autopsy and underwent Consortium to Establish a Registry of Alzheimer's Disease assessment. Study 2 involved more detailed quantitative histology in the hippoc us and Brodmann area 9 in 72 clinically matched in iduals with high and low CLS. CLS groups did not differ on several Alzheimer disease neuropathologic measures however, high CLS men had less cerebrovascular disease after accounting for vascular risk factors, and women had greater brain weight. No group differences were evident in hippoc al neuronal density. In Brodmann area 9, cognitively active in iduals had significantly greater neuronal density, as well as correlated increases in cortical thickness. An active cognitive lifestyle was associated with protection from cerebrovascular disease in men, but there was no evidence for Alzheimer disease modification or hippoc al neuroprotection. Men and women both exhibited neurotrophic changes in the prefrontal lobe linked to cognitive lifestyle, consistent with a compensatory process. Lifespan complex cognitive activity may therefore protect against dementia through multiple biological pathways.
Publisher: JMIR Publications Inc.
Date: 2019
Abstract: ementia is the leading cause of disability worldwide, and interventions aimed at reducing the prevalence and burden of the disease are urgently needed. Maintain Your Brain (MYB) is a randomized controlled trial of a multimodal digital health intervention targeting modifiable dementia risk factors to combat cognitive decline and potentially prevent dementia. In addition to behavioral modules targeting mood, nutrition, and physical exercise, a new Brain Training System (BTS) will deliver computerized cognitive training (CCT) throughout the trial to provide systematic, challenging, and personally adaptive cognitive activity. his paper aimed to describe the design and development of BTS. TS has been designed with a central focus on the end user. Raw training content is provided by our partner NeuroNation and delivered in several innovative ways. A baseline cognitive profile directs selection and sequencing of exercises within and between sessions and is updated during the 10-week 30-session module. Online trainers are available to provide supervision at different levels of engagement, including face-to-face share-screen coaching, a key implementation resource that is triaged by a “red flag” system for automatic tracking of user adherence and engagement, or through user-initiated help requests. In idualized and comparative feedback is provided to aid motivation and, for the first time, establish a social support network for the user based on their real-world circle of friends and family. he MYB pilot was performed from November 2017 to March 2018. We are currently analyzing data from this pilot trial (n=100), which will make up a separate research paper. The main trial was launched in June 2018. Process and implementation data from the first training module (September to November 2018) are expected to be reported in 2019 and final trial outcomes are anticipated in 2022. he BTS implemented in MYB is focused on maximizing adherence and engagement with CCT over the short and long term in the setting of a fully digital trial, which, if successful, could be delivered economically at scale. ustralian New Zealand Clinical Trials Registry ACTRN12618000851268 www.anzctr.org.au /Trial/Registration/TrialReview.aspx?id=370631& isReview=true
Publisher: Springer Science and Business Media LLC
Date: 06-2016
Publisher: Public Library of Science (PLoS)
Date: 24-08-2011
Publisher: Public Library of Science (PLoS)
Date: 12-12-2012
Publisher: MyJove Corporation
Date: 29-11-2016
DOI: 10.3791/54953
Publisher: Wiley
Date: 14-05-2022
DOI: 10.5694/MJA2.51521
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.NEULET.2015.03.017
Abstract: During evolution a unique anterior-posterior flexure posited the canine dentate gyrus in two distinct dorsal and ventral positions. We therefore sought to explore neurogenesis and neurogenic cell-related difference along the canine hippoc al dorsal-ventral axis. Post mortem histological analysis revealed 49.1% greater doublecortin (DCX)-positive cells and a 158.5% greater percentage of double labeled DCX-positive/neuronal nuclei (NeuN) positive cells in the dorsal subgranular zone compared to the ventral. We then show neural precursor cells isolated from fresh hippoc al tissue are capable of proliferating long term, and after differentiation, express neuronal and glial markers. Dorsal hippoc al isolates produced a 120.0% higher frequency of sphere-forming neural precursor cells compared to ventral hippoc al tissue. Histological DCX and neurosphere assay results were highly correlated. Overall, we provide the first evidence that the dorsal canine hippoc us has a markedly higher rate of adult neurogenesis than the ventral hippoc us, possibly related to a greater frequency of contributory neural precursor cells.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000322112
Abstract: i Aim: /i To investigate dynamic changes in functional brain activity in mild cognitive impairment (MCI) in response to a graded working memory (WM) challenge with increasing memory load. i Methods: /i In an event-related functional magnetic resonance imaging (fMRI) study, 35 MCI and 22 cognitively normal subjects performed a visuospatial associative WM task with 3 load levels. Potential performance differences were controlled for by in idually calibrating the number of items presented at each load. i Results: /i An interaction between group and WM load was observed during stimulus encoding. At lower loads, greater activity in the right anterior cingulate and right precuneus was observed in MCI subjects. As the load increased to higher levels, reduced activation in these regions and greater deactivation in the posterior cingulate-medial precuneus were observed in MCI compared to control subjects. Stronger expression of load-related patterns of activation and deactivation in MCI subjects was associated with greater clinical severity and a more abnormal pattern of performance variability. i Conclusion: /i Patterns of overactivation, underactivation and deactivation during successful encoding in MCI subjects were dependent on WM load. This type of graded cognitive challenge may operate like a ‘memory stress test’ in MCI and may be a useful biomarker of disease at the predementia stage.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JAMDA.2014.09.010
Abstract: Mild cognitive impairment (MCI) increases dementia risk with no pharmacologic treatment available. The Study of Mental and Resistance Training was a randomized, double-blind, double-sham controlled trial of adults with MCI. Participants were randomized to 2 supervised interventions: active or sham physical training (high intensity progressive resistance training vs seated calisthenics) plus active or sham cognitive training (computerized, multidomain cognitive training vs watching videos/quizzes), 2-3 days/week for 6 months with 18-month follow-up. Primary outcomes were global cognitive function (Alzheimer's Disease Assessment Scale-cognitive subscale ADAS-Cog) and functional independence (Bayer Activities of Daily Living). Secondary outcomes included executive function, memory, and speed/attention tests, and cognitive domain scores. One hundred adults with MCI [70.1 (6.7) years 68% women] were enrolled and analyzed. Resistance training significantly improved the primary outcome ADAS-Cog [relative effect size (95% confidence interval) -0.33 (-0.73, 0.06) P < .05] at 6 months and executive function (Wechsler Adult Intelligence Scale Matrices P = .016) across 18 months. Normal ADAS-Cog scores occurred in 48% (24/49) after resistance training vs 27% (14/51) without resistance training [P < .03 odds ratio (95% confidence interval) 3.50 (1.18, 10.48)]. Cognitive training only attenuated decline in Memory Domain at 6 months (P < .02). Resistance training 18-month benefit was 74% higher (P = .02) for Executive Domain compared with combined training [z-score change = 0.42 (0.22, 0.63) resistance training vs 0.11 (-0.60, 0.28) combined] and 48% higher (P < .04) for Global Domain [z-score change = .0.45 (0.29, 0.61) resistance training vs 0.23 (0.10, 0.36) combined]. Resistance training significantly improved global cognitive function, with maintenance of executive and global benefits over 18 months.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JAGP.2013.02.018
Abstract: Investigations of exercise and cognition have primarily focused on healthy or demented older adults, and results have been equivocal in in iduals with mild cognitive impairment (MCI). Our aim was to evaluate efficacy of exercise on cognition in older adults with MCI. We conducted a meta-analysis of random controlled trials (RCTs) of exercise effects on cognitive outcomes in adults with MCI. Searches were conducted in Medline, EMBASE, CINAHL, PEDro, SPORTSDICUS, PsychInfo, and PubMed. Adults aged over 65 years with MCI or Mini-Mental State Exam mean score 24-28 inclusive. Study quality was assessed using the PEDro scale data on participant and intervention characteristics and outcomes were extracted, followed by meta-analysis. Fourteen RCTs (1,695 participants age 65-95 years) met inclusion criteria. Quality was modest and under-powering for small effects prevalent. Overall, 42% of effect sizes (ESs) were potentially clinically relevant (ES >0.20) with only 8% of cognitive outcomes statistically significant. Meta-analysis revealed negligible but significant effects of exercise on verbal fluency (ES: 0.17 [0.04, 0.30]). No significant benefit was found for additional executive measures, memory, or information processing. Overall results were inconsistent with benefits varying across exercise types and cognitive domains. There is very limited evidence that exercise improves cognitive function in in iduals with MCI, although published research is of moderate quality and inconclusive due to low statistical power. Questions remain regarding the magnitude, generalization, persistence, and mechanisms of benefits. Large-scale, high-quality RCTs are required to determine if exercise improves cognition or reduces dementia incidence in those with MCI.
Publisher: Frontiers Media SA
Date: 09-03-2015
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BRAINRESBULL.2005.01.015
Abstract: Ageing is associated with cognitive decline, with some studies indicating that this decline can be mostly accounted for by slowing of information processing speed. Whilst it is likely that this is associated with age-related changes in fronto-subcortical neuronal circuits, such changes are not visible on routine neuroimaging. We examined the integrity of this brain region using proton magnetic resonance spectroscopy (1H MRS) and hypothesised that functional changes measured by 1H MRS would be associated with cognitive performance. Fifty-nine healthy elderly subjects (age 58-85 years) underwent single-voxel 1H MRS in frontal white matter and occipito-parietal gray matter, and a comprehensive neuropsychological battery. The results showed a significant correlation between frontal white matter NAA/H2O and a composite measure of neuropsychological performance representing speed of information processing, attentional function and visual memory, controlling for age and sex. This research highlights the importance of the relationship between regional brain changes and cognitive function in the ageing brain, and suggests that MRS may be a sensitive marker of subclinical change in cognition.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.NEUROBIOLAGING.2004.07.008
Abstract: The pathophysiological basis of cognitive impairment in patients with cerebrovascular disease (CVD) is not well understood, particularly in relation to the role of non-infarction ischemic change and associated Alzheimer-type pathology. We used single voxel 1H MRS to determine the differences in brain neurometabolites in non-infarcted frontal white matter and occipito-parietal gray matter of 48 stroke patients with or without cognitive impairment and 60 elderly controls. The results showed that there were no significant neurometabolite differences between the stroke cohort and healthy elderly controls, but there was a difference in NAA/H2O between the stroke patients that had cognitive impairment (vascular dementia (VaD) and vascular cognitive impairment (VCI)) compared with those patients with no impairment. This was significant in the occipito-parietal gray matter, but not in the frontal white matter, although the results were in the same direction for the latter. This suggests that cognitive impairment in stroke patients may be related to cortical neuronal dysfunction rather than purely subcortical change. Moreover, cortical regions not obviously infarcted may have dysfunctional neurons, the pathophysiological basis for which needs further study.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.TVJL.2010.05.014
Abstract: Canine cognitive dysfunction (CCD) is an age-related neurobehavioural syndrome which, although common, is severely under-diagnosed in community-based dogs. Using data from a large cross-sectional survey of older dogs (n=957), this study aimed to develop a clinical scale for assessing CCD. Data-driven analytical techniques were used to distil 27 significant behavioural items (previously identified as relevant to CCD) into an assessment tool with maximal cognito-behavioural breadth whilst maintaining clinical utility. The resulting CCD rating scale (CCDR) comprised 13 behavioural items, of which three were sensitive to the severity of the disease stage. When tested on an independent survey s le, the CCDR had an overall 98.9% diagnostic accuracy with a 77.8% positive predictive value and a 99.3% negative predictive value. Test-re-test reliability of the CCDR over 2months was also high (r=0.73, P<0.0001). In conjunction with veterinary assessment, the CCDR could be a valuable tool in research and clinical settings for both the assessment and longitudinal tracking of cognitive change.
Publisher: Public Library of Science (PLoS)
Date: 26-07-2010
Publisher: Informa UK Limited
Date: 28-02-2023
Publisher: Elsevier BV
Date: 03-2009
Publisher: Public Library of Science (PLoS)
Date: 09-07-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-10-2015
Publisher: Public Library of Science (PLoS)
Date: 16-12-2013
Publisher: Springer Science and Business Media LLC
Date: 08-01-2010
DOI: 10.1007/S11920-009-0085-Y
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 in iduals. Finally, practical issues, including the strengths and weaknesses of commercial products, are explored, and recommendations for further research and clinical implementation are made.
Publisher: SAGE Publications
Date: 02-2002
DOI: 10.1046/J.1440-1614.2002.00992.X
Abstract: Objective: This paper briefly describes neuroimaging using magnetic resonance spectroscopy (MRS) and provides a systematic review of its application to psychiatric disorders. Method: A literature review ( Index Medicus/ Medline) was carried out, as well as a review of other relevant papers and data known to the authors. Results: 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. Conclusions: 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.
Publisher: Wiley
Date: 24-10-2017
DOI: 10.1111/JGS.14542
Abstract: To determine whether improvements in aerobic capacity (VO Randomized, double-blind, double-sham, controlled trial. University research facility. Community-dwelling older adults (aged ≥55) with mild cognitive impairment (MCI) (N = 100). PRT and cognitive training (CT), 2 to 3 days per week for 6 months. Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) global, executive, and memory domains peak strength (1 repetition maximum) and VO PRT increased upper (standardized mean difference (SMD) = 0.69, 95% confidence interval = 0.47, 0.91), lower (SMD = 0.94, 95% CI = 0.69-1.20) and whole-body (SMD = 0.84, 95% CI = 0.62-1.05) strength and percentage change in VO High-intensity PRT results in significant improvements in cognitive function, muscle strength, and aerobic capacity in older adults with MCI. Strength gains, but not aerobic capacity changes, mediate the cognitive benefits of PRT. Future investigations are warranted to determine the physiological mechanisms linking strength gains and cognitive benefits.
Publisher: European Delirium Association
Date: 21-02-2023
DOI: 10.56392/001C.67976
Abstract: Cognitive impairments, including delirium, are common after coronary artery bypass grafting (CABG). Improving cognition pre- and post-operatively using computerised cognitive training (CCT) may be an effective approach to improve cognitive outcomes in CABG patients. Investigate the effect of remotely supervised CCT on cognitive outcomes, including delirium, in older adults undergoing CABG surgery. Thirty-six participants, were analysed in a single-blinded randomised controlled trial (CCT Intervention: n = 18, Control: n = 18). CCT was completed by the intervention group pre-operatively (every other day, 45–60-minute sessions until surgery) and post-operatively, beginning 1-month post-CABG (3 x 45–60-minute sessions/week for 12-weeks), while the control group maintained usual care plus weekly phone calls. Cognitive assessments were conducted pre- and post-operatively at multiple follow-ups (discharge, 4-months and 6-months). Post-operative delirium incidence was assessed daily until discharge. Cognitive change data were calculated at each follow-up for each cognitive test (Addenbrooke’s Cognitive Examination III and CANTAB z-scored). Adherence to the CCT intervention (completion of three pre-operative or 66% of post-operative sessions) was achieved in 68% of pre-CABG and 59% of post-CABG participants. There were no statistically significant effects of CCT on any cognitive outcome, including delirium incidence. Adherence to the CCT program was comparatively higher than previous feasibility studies, possibly due to the level of supervision and support provided (blend of face-to-face and home-based training, with support phone calls). Implementing CCT interventions both pre- and post-operatively is feasible in those undergoing CABG. No statistically significant benefits from the CCT interventions were identified for delirium or cognitive function post-CABG, likely due to the s le size available (study recruitment greatly impacted by COVID-19). It also may be the case that multimodal intervention would be more effective.
Publisher: Elsevier BV
Date: 10-2015
Publisher: Cambridge University Press (CUP)
Date: 12-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2008
Publisher: Informa UK Limited
Date: 05-2014
DOI: 10.2147/CIA.S58866
Publisher: JMIR Publications Inc.
Date: 27-02-2019
DOI: 10.2196/13135
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.RADONC.2014.01.012
Abstract: ANZMTG 01.07 WBRTMel is a phase 3 randomized trial to address the role of whole brain radiation therapy (WBRT) after local treatment of 1-3 melanoma brain metastases. Modern radiation therapy technologies can now conformally spare the hippoc us during WBRT and therefore potentially reduce the risk of neurocognitive deficit. The aims of this study were to report the prevalence of melanoma metastases within the hippoc al sparing region and to identify variables that correlate with the presence of metastases within the hippoc al sparing region. The pre-local treatment MRI scans of 77 eligible WBRTMel patients were used to contour the in idual metastasis and the hippoc us. The volume, location and closest distance of each metastasis to the hippoc us were recorded. Binary logistic regression was performed to assess the influence of factors on the location of a metastasis within 5mm of the hippoc us. The median age was 61 and 66% were male. The distribution of the 115 metastases was frontal (50, 43.5%), parietal (23, 20.0%), temporal (13, 11.2%), occipital (18, 15.7%), cerebellum (10, 8.6%) and pineal gland (1, 1.0%). The median aggregate volume of the metastasis was 3516mm(3). None of the metastases were within the hippoc us. Four patients (5.2%) had metastases within 5mm of the hippoc us. The median distance from metastasis to the nearest hippoc us was 37.2mm. Only the total volume of metastases was a significant predictor for the risk of a metastasis within the hippoc al sparing region (OR 1.071, 95% CI: 1.003-1.144, p=0.040). This study confirmed a low incidence of melanoma metastasis in the hippoc al sparing region at diagnosis. Given the lack of randomized data on the safety and benefit of hippoc al sparing WBRT, the current WBRTMel trial provides the opportunity to explore the feasibility of this technique.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-08-2006
Publisher: S. Karger AG
Date: 2003
DOI: 10.1159/000068481
Abstract: i Background: /i Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. i Methods: /i We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B sub /sub , creatinine and plasma fibrinogen levels were obtained. i Results: /i tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B sub /sub and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T sub /sub -weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-to-brain ratios as measures of brain atrophy. i Conclusion: /i This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment.
Publisher: Cambridge University Press (CUP)
Date: 05-10-2005
DOI: 10.1017/S0033291705006173
Abstract: Background. The frequency and clinical, neuropsychological and neuroimaging correlates of apathy in patients who have had a stroke are inadequately defined. Method. A total of 167 consecutive patients admitted to the stroke units of two university hospitals after an ischaemic stroke and 109 controls received extensive medical, psychiatric and neuropsychological assessments a subset received a magnetic resonance imaging (MRI) scan. The groups were matched for sex and age. Patients were assessed 3–6 months after their stroke. The s le for this study comprised 135 patients and 92 controls who completed the Apathy Evaluation Scale (AES). Results. Apathy was present in 26·7% of stroke patients compared to 5·4% of controls. Apathetic stroke patients were older, more functionally dependent and had lower Mini-Mental State Examination (MMSE) scores than those without apathy. Apathy was not associated with risk factors for cerebrovascular disease or stroke severity. There was a weak but significant correlation between apathy and self-reported depression but not with clinician-rated depression. Neuropsychologically, after correction for age, premorbid intelligence (IQ) and depression, apathy was associated with reduced attention and speed of information processing. On neuroimaging there were trends for associations of apathy with the extent of hyperintensities in the right hemisphere and right fronto-subcortical circuit, but not with total stroke volume or number of strokes. Conclusions. Apathy is common following a cerebrovascular event. Presence of apathy may be related to older age and right fronto-subcortical pathway pathology, rather than stroke severity. It is associated with functional impairment and cognitive deficits.
Publisher: Elsevier BV
Date: 2014
Publisher: S. Karger AG
Date: 2006
DOI: 10.1159/000091434
Abstract: i Background: /i Dementia following stroke is common but its determinants are still incompletely understood. i Methods: /i In the Sydney Stroke Study, we performed detailed neuropsychological and medical-psychiatric assessments on 169 patients aged 50–85 years, 3–6 months after a stroke, and 103 controls with a majority of both groups undergoing MRI brain scans. Stroke subjects were diagnosed as having vascular mild cognitive impairment (VaMCI) or vascular dementia (VaD) or no cognitive impairment by consensus. Demographic, functional, cerebrovascular risk factors and neuroimaging parameters were examined as determinants of dementia using planned logistic regression. i Results: /i 21.3% of subjects were diagnosed with VaD, with one case in those aged 50–59 years, 24% in those aged 60–69 years and 23% in those 70–79 years. There was no difference by sex. The prevalence of VaMCI was 36.7%. VaD subjects had lower premorbid intellectual functioning and had 0.9 years less education than controls. The VaD and VaMCI groups did not differ from the no cognitive impairment group on any specific cerebrovascular risk factor, however overall those with impairment had a greater number of risk factors. They did not differ consistently on depression severity, homocysteine levels and neuroimaging parameters (atrophy, infarct volume and number of infarcts) except for an excess of white matter lesions on MRI and greater number of infarcts in the VaD and VaMCI groups. On a series of logistic regression analyses, stroke volume and premorbid function were significant determinants of cognitive impairment in stroke patients. i Conclusion: /i Post-stroke dementia and MCI are common, especially in older in iduals. Cerebrovascular risk factors are not independent risk factors for VaD, but stroke volume is a significant determinant of dementia. Premorbid functioning is a determinant of post- stroke impairment.
Publisher: Frontiers Media SA
Date: 27-10-2016
Publisher: Wiley
Date: 11-02-2015
DOI: 10.1002/HIPO.22395
Abstract: Functional compensation in late life is poorly understood but may be vital to understanding long-term cognitive trajectories. To study this we first established an empirically derived threshold to distinguish hippoc al atrophy in those with Mild Cognitive Impairment (MCI n = 34) from those with proficient cognition (PRO n = 22), using data from a population-based cohort. Next, to identify compensatory networks we compared cortical activity patterns during a graded spatial working memory (SWM) task in only cognitively proficient in iduals, either with (PROATR ) or without hippoc al atrophy (PRONIL ). Multivariate Partial Least Squares analyses revealed that these groups engaged spatially distinct SWM-related networks. In those with hippoc al atrophy and under conditions of basic-SWM demand, expression of a posterior compensatory network (PCN) comprised calcarine and posterior parietal cortex strongly correlated with superior SWM performance (r = -0.96). In these in iduals, basic level SWM response times were faster and no less accurate than in those with no hippoc al atrophy. Cognitively proficient older in iduals with hippoc al atrophy may, therefore, uniquely engage posterior brain areas when performing simple spatial working memory tasks.
Publisher: Elsevier BV
Date: 12-2000
Publisher: Springer Science and Business Media LLC
Date: 17-06-2022
DOI: 10.1186/S13287-022-02933-W
Abstract: Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippoc us using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses these were compared to a brain bank ( N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model ( N = 16) was used to more closely evaluate intrahippoc al engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippoc al slice preparation. Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippoc us specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippoc ally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippoc us, neuronal differentiation in situ , and physiologically-correct integration into pyramidal layer circuits. With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippoc us.
No related grants have been discovered for Michael Valenzuela.