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Villemagne V.L.,Austin Health | Villemagne V.L.,University of Melbourne | Burnham S.,CSIRO | Bourgeat P.,CSIRO | And 12 more authors.
The Lancet Neurology | Year: 2013

Background: Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. Methods: In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B (11C-PiB) PET scan. We included participants with three or more 11C-PiB PET follow-up assessments. Aβ burden was expressed as 11C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. Findings: 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of 11C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of 11C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1). Interpretation: Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. Funding: Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. © 2013 Elsevier Ltd.

Cromer J.R.,University of Connecticut | Cromer J.A.,The Picower Institute for Learning and Memory | Cromer J.A.,Massachusetts Institute of Technology | Maruff P.,CogState Ltd | And 2 more authors.
Experimental and Clinical Psychopharmacology | Year: 2010

Several psychological constructs (e.g., subjective perception of intoxication, visuomotor speed) display acute tolerance to alcohol, that is, show improvement at declining blood alcohol concentrations (BACs) relative to equivalent rising BACs. However, methodological challenges emerge when attempting to make such comparisons across limbs of the BAC curve, which have proven a barrier to advancing research on acute tolerance. To date, no studies have made multiple comparisons across the entire BAC trajectory. This study employs experimental procedures that overcome some of these difficulties, offering a clearer picture of recovery of impairment for subjective perception of intoxication and cognitive performance and the relationship between them. Twenty participants were assessed at multiple time points over 2 days. Continuous subjective perception of intoxication ratings and cognitive data derived from a computerized measure were paired with a novel analytic paradigm, which allowed comparisons at identified BACs. Results showed acute tolerance for individuals' subjective perception of intoxication and for performance on cognitive tasks measuring visuomotor speed and learning efficiency (recovery from impairment). In contrast, performance on measures of executive function and short-term memory showed no significant difference between limbs at exact concentrations (no recovery from impairment). Therefore, despite participants feeling less intoxicated over time, many cognitive functions remained impaired. The implication for these findings in terms of drunken driving behavior are substantial, suggesting that people may be likely to drive once they subjectively perceive that they have recovered from the acute intoxicating effects of alcohol, despite the persistence of " higher order" cognitive impairments. © 2010 American Psychological Association.

Dingwall K.M.,Charles Darwin University | Maruff P.,University of Melbourne | Maruff P.,CogState Ltd | Fredrickson A.,CogState Ltd | Cairney S.,Charles Darwin University
Drug and Alcohol Dependence | Year: 2011

Background: Cognitive impairment reflecting CNS disruption in chronic solvent abusers can resolve within two years of abstinence. However, the specific time course for recovery has yet to be determined empirically. This study monitored cognition among solvent (i.e., gasoline) abusers throughout 8 weeks of residential treatment. It also investigated the extent to which solvent-related cognitive impairments persisted following discharge. Methods: Non-drug using healthy controls (n= 33) and solvent abusers (n= 29) who had inhaled gasoline, regularly or episodically, for an average of 4.3 years (SD = 2.7) were assessed. Using linear mixed model analyses, solvent abusers were compared to healthy controls throughout treatment at baseline, two weeks, four weeks and six weeks, on visual motor, attention, learning, memory, and executive function tasks. Ten users who maintained abstinence were reassessed an average of 12 months later (SD = 2.8) and were compared to healthy controls (n= 12) retested at the same time interval using ANCOVA while controlling for age and baseline performance. Results: At baseline, solvent abusers showed cognitive deficits on visual motor, learning and memory, paired associate learning, and executive functions. Paired associate learning performance improved within 6 weeks of abstinence, however, impairments in visual motor speed, learning and memory, and executive function persisted throughout and in some cases beyond treatment. Conclusions: Cognitive deficits exist for solvent abusers upon treatment entry. Some impairments resolve within weeks of abstinence, while memory and executive function improves gradually over months to years of abstinence, and might never fully recover. © 2011 Elsevier Ireland Ltd.

Dingwall K.M.,Charles Darwin University | Maruff P.,University of Melbourne | Maruff P.,CogState Ltd | Cairney S.,Charles Darwin University
Addiction | Year: 2011

Aims The cognitive impairment and recovery associated with chronic alcohol abuse and subsequent abstinence is well understood. However, the recovery profile following heavy episodic or 'binge' use, which is common among some Australian Aboriginal users, has not been investigated thoroughly and no empirical studies have examined chronic use in this population. The aim of this study was to identify and compare cognitive impairment and recovery associated with chronic and episodic alcohol use among Aboriginal Australians. Design Longitudinal case-control design. Setting Residential alcohol treatment programmes in northern Australia. Participants Forty chronic alcohol users, 24 episodic users and 41 healthy controls [mean age=34.24; standard deviation (SD)=9.73]. Measurements Cognitive assessments of visual motor, attention, memory, learning and executive functions at baseline (start of treatment), then 4 weeks and 8 weeks later. Reassessment of 31% of participants an average of 11 months later (SD=4.4) comparing those who remained abstinent (n=5), those who relapsed (n=11) and healthy controls (n=19). Findings At baseline, chronic and episodic alcohol users showed impaired visual motor, learning, memory and executive functions. With the exception of visual motor impairment, all deficits had improved to normal levels within 4 weeks. Visual motor deficits had normalized within 11 months. Performances did not differ at any time between chronic and episodic alcohol groups. Conclusions In Aboriginal Australians, episodic drinking is associated with similar patterns of impairment and recovery as chronic alcohol use. Most cognitive deficits appear to recover within the first month of abstinence, while persisting visual motor problems recover within 1 year. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Pietrzak R.H.,Yale University | Pietrzak R.H.,CogState Ltd. | Snyder P.J.,Brown University | Snyder P.J.,Yale University | And 2 more authors.
Schizophrenia Research | Year: 2010

Background: Amelioration of cognitive impairment is an important treatment goal for a broad range of neuropsychiatric disorders, including schizophrenia. One critical issue in clinical trial design is the extent to which repeated exposure to cognitive tests (i.e., practice effects) may lead to improvement in performance on the cognitive tests in the absence of any true treatment effect. The current study examined the extent to which practice effects on a measure of executive function may influence the sensitivity of that task to detecting the cognitive-enhancing effects of a single acute dose of d-amphetamine in individuals with chronic schizophrenia. Methods: Twenty-four men with chronic schizophrenia were randomized to receive a constant or random/matched alternate form version of a hidden maze learning measure of executive function (Groton Maze Learning Test; GMLT) on four separate occasions in one month. They also completed a measure of psychomotor speed. Using a double-blind, placebo-controlled, parallel groups design, cognitive function following administration of a single dose of d-amphetamine (20 mg p.o) or placebo was then assessed. Results: The group who received the constant-pathway version of the GMLT showed a large practice effect (d = 2.05) over four practice sessions. Consequently, they did not evidence any improvement on the GMLT following d-amphetamine administration. In contrast, the group who received the random/matched alternate version of the GMLT showed a statistically significant and large effect size (d = .84) improvement on this measure. Both groups showed d-amphetamine-related improvement on a measure of psychomotor speed. Conclusions: Results of this study suggest that practice effects associated with repeated exposure to a cognitive test could obscure the sensitivity of the test to detecting true treatment-related cognitive improvement. © 2010.

Vogel A.P.,University of Melbourne | Vogel A.P.,Murdoch Childrens Research Institute | Fletcher J.,University of Melbourne | Snyder P.J.,Brown University | And 2 more authors.
Journal of Voice | Year: 2011

Assessment of the voice for supporting classifications of central nervous system (CNS) impairment requires a different practical, methodological, and statistical framework compared with assessment of the voice to guide decisions about change in the CNS. In experimental terms, an understanding of the stability and sensitivity to change of an assessment protocol is required to guide decisions about CNS change. Five experiments (N = 70) were conducted using a set of commonly used stimuli (eg, sustained vowel, reading, extemporaneous speech) and easily acquired measures (eg, f0-f4, percent pause). Stability of these measures was examined through their repeated application in healthy adults over brief and intermediate retest intervals (ie, 30 seconds, 2 hours, and 1 week). Those measures found to be stable were then challenged using an experimental model that reliably changes voice acoustic properties (ie, the Lombard effect). Finally, adults with an established CNS-related motor speech disorder (dysarthria) were compared with healthy controls. Of the 61 acoustic variables studied, 36 showed good stability over all three stability experiments (eg, number of pauses, total speech time, speech rate, f0-f4). Of the measures with good stability, a number of frequency measures showed a change in response to increased vocal effort resulting from the Lombard effect challenge. Furthermore, several timing measures significantly separated the control and motor speech impairment groups. Measures with high levels of stability within healthy adults, and those that show sensitivity to change and impairment may prove effective for monitoring changes in CNS functioning. © 2011 The Voice Foundation.

Thomas E.,University of Melbourne | Snyder P.J.,Brown University | Pietrzak R.H.,Yale University | Maruff P.,University of Melbourne | Maruff P.,CogState Ltd.
Neuropsychology Review | Year: 2014

Hidden pathway maze learning tasks (HPMLTs) have been used in neuropsychological research and practice for more than 80 years. These tasks require the use of visual and auditory task feedback signals to learn the order and direction of a pathway, typically within a grid of stepping-stones, or alleys. Hidden pathway maze learning tasks are purported to assess both visuospatial learning and executive processes. The original motivation for the HPMLT paradigm for humans was to reduce a complex tactual planning task to one in which decisions could be directly measured by discrete actions at choice points guided by visual cues. Hidden maze learning paradigms were used extensively throughout the 20th century, initially to study exploratory, anticipatory, and goal-related behavior within the context of memory research, and later as an experimental tool in neuropsychology. Computerization of HPMLTs have allowed for the measurement of different move categories according to the rule structure and ipso facto, clinically meaningful differences in memory and monitoring functions during spatial search and learning. Hidden pathway maze learning tests have been used to understand the cognitive effects of ageing, neurological disorders, and psychopharmacological challenges. We provide a review of historical antecedents relevant to contemporary applications of HPMLTs in neuropsychology. It is suggested that contemporary applications of HPMLTs could be advanced by analysis of component operations necessary for efficient performance that can inform theoretical interpretations of this class of tests in clinically meaningful terms. © 2014, Springer Science+Business Media New York.

Pietrzak R.H.,Yale University | Pietrzak R.H.,CogState Ltd. | Snyder P.J.,Brown University | Snyder P.J.,Yale University | And 2 more authors.
Human Psychopharmacology | Year: 2010

There is general agreement that pharmacologic improvement of cognition in chronic schizophrenia is a worthwhile therapeutic goal. Accordingly, there has been careful consideration about how neuropsychological methods can be used to detect improvement in cognition in people with schizophrenia. However, little data are available on the nature and magnitude of cognitive improvement that can occur with adjunctive therapeutic interventions. This double-blind, placebo-controlled crossover study examined the nature and magnitude of cognitive enhancement associated with a single-dose administration of d-amphetamine in 32 adult men with schizophrenia using a set of tasks developed specifically for detecting treatment-related change in cognitive function. Relative to placebo, acute d-amphetamine administration was associated with clinically meaningful improvement on measures of executive function and visual attention and vigilance, and with modest improvements on a measure of speed of processing. These results suggest that a brief computerized cognitive test battery designed for repeat administration, in combination with a statistical approach that emphasizes individual-level change, provides a sensitive approach to detecting the effect of cognitive-enhancing medications in people with chronic schizophrenia. Copyright © 2010 John Wiley & Sons, Ltd.

Harvey P.D.,University of Miami | Siu C.O.,Data Power DP Inc. | Hsu J.,Sunovion Pharmaceuticals | Cucchiaro J.,Sunovion Pharmaceuticals | And 2 more authors.
European Neuropsychopharmacology | Year: 2013

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80. mg/day and 160. mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N=267), lurasidone 160. mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80. mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40-160. mg) group compared to the quetiapine XR (200-800. mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls. © 2013 Elsevier B.V. and ECNP.

Vogel A.P.,University of Melbourne | Maruff P.,University of Melbourne | Maruff P.,CogState Ltd
Logopedics Phoniatrics Vocology | Year: 2014

Assessment for the purpose of monitoring change over time requires a different practical and statistical approach to that of assessment for diagnosing impairment. Sophisticated methods exist for identifying strengths and weaknesses in a patient's voice/speech profile, yet our understanding of the impact of repeated assessment is limited. Monitoring change necessitates that stimuli are stable in the absence of any true change in functioning, while remaining sensitive to influences that are considered to alter functioning (degeneration, therapy). The current paper discusses the issues relating to stimuli selection, identifying error within the sample and appropriate statistical models for identifying intra-individual change in the context of clinical and experimental speech or voice examinations. © 2014 Informa UK, Ltd.

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