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Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer's disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied., Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples., Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes., Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79-0.88), and CDR > 0.5 (AUCs ∼ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite., Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.

Introduction: The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β-amyloid burden (CN Aβ+)., Methods: Fifty-eight CN Aβ+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed., Results: In CN Aβ+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume., Discussion: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aβ+, more sensitive measures may be required to detect early subtle cognitive change., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD., Methods: CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid β1-42 (Aβ1-42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods., Results: POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Aβ1-42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes., Conclusions: Low CSF Aβ1-42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD.

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ(-) or Aβ(+). Relative to Aβ(-)ɛ4(-), Aβ(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ(-)ɛ4(-) and Aβ(-)ɛ4(+) groups. Among Aβ(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ(-) and Aβ(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

Background: Information provided by an informant about a patient with cognitive change is an essential component of clinical history taking. How an informant's report relates to the patient's phenomenological experience of memory loss is yet to be understood. The aim was to examine patterns of relationships between self and informant reports from a phenomenological perspective., Methods: Forty-three healthy non-memory complainers (HC-NMC), 37 healthy subjective memory complainers (HC-SMC) and 43 individuals with mild cognitive impairment (MCI) were administered a semi-structured interview, which measured their concerns of frequency of memory lapses and impact on mood. Informants responded to questionnaires., Results: Self-reported concerns of increasing frequency and impacted mood related to informant concerns in HC-SMCs. MCI with lower informant concern showed a similar pattern to HC-SMCs on complaints of increasing frequency. In those with higher informant concern, self-reports markedly separated from informant concern. The MCI group with greater informant concern performed comparatively poor on verbal and non-verbal memory measures., Conclusions: Our results suggest that the association between self-reported and informant memory concerns is moderated by MCI severity. Self and informant reports of increasing memory lapse frequency aligned in HC-SMC and MCIs with low informant concern, suggesting a similar dyadic experience of memory change. In MCIs with greater informant concern, the pattern changed exposing a changing insight with advancing memory impairment. These individuals are potentially reflecting a 'forgetting that they forget' phenomenon in elements of their concern., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes.

Background: This study investigated the prevalence of cognitive impairment in elderly noncardiac surgery patients and any association between preoperative cognitive impairment and postoperative cognitive dysfunction (POCD). Additionally, the incidence of cognitive decline at 12 months after surgery was identified., Methods: Three hundred patients for hip joint replacement and 51 nonsurgical controls aged 60 yr or older were studied in a prospective observational clinical trial. All study participants and controls completed a battery of eight neuropsychological tests before surgery and at 7 days, 3 months, and 12 months afterwards. Preoperative cognitive status was assessed using preexisting cognitive impairment (PreCI) defined as a decline of at least 2 SD on two or more of seven neuropsychological tests compared to population norms. POCD and cognitive decline were assessed using the reliable change index utilizing the results of the control group., Results: PreCI was classified in 96 of 300 (32%) patients (95% CI, 23 to 43%). After surgery, 49 of 286 (17%) patients (95% CI, 13 to 22%) and 27 of 284 (10%) patients (95% CI, 6 to 13%) demonstrated POCD at 7 days and 3 months, respectively, while 7 of 271 (3%) patients (95% CI, 1 to 4%) demonstrated cognitive decline at 12 months. Patients with PreCI had a significantly increased incidence of POCD at 7 days and 3 months and cognitive decline at 12 months., Conclusions: Patients with PreCI have an increased incidence of POCD and cognitive decline. PreCI is a good predictor of subsequent POCD and cognitive decline. The incidence of cognitive decline after 12 months in this group of patients is low.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: High β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression., Methods: Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later., Results: Compared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups., Conclusions: In healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD., (Copyright © 2014. Published by Elsevier Inc.)

Background: To determine the prevalence of neurocognitive impairment (NCI) in UK HIV-positive and HIV-negative men who have sex with men (MSM)., Methods: HIV-positive and HIV-negative participants were recruited to a cross-sectional study from 2 London clinics and completed computer-assisted neuropsychological tests and questionnaires of depression, anxiety, and activities of daily living. Published definitions of HIV-associated neurocognitive disorders (HAND) and global deficit scores were used. Age- and education-adjusted neuropsychological test scores were directly compared with reference population data., Results: A total of 248 HIV-positive and 45 HIV-negative MSM participated. In the HIV-positive group, median time since diagnosis was 9.4 years, median CD4 count was 550 cells per cubic millimeter, and 88% were on antiretroviral therapy. Prevalence of HAND was 21.0% in HIV-positive MSM (13.7% asymptomatic neurocognitive impairment, 6.5% mild neurocognitive disorder, and 0.8% HIV-associated dementia). Using a global deficit score threshold of 0.5, the prevalence of NCI was 31.5% (when averaged over 5 neuropsychological domains) and 40.3% (over 10 neuropsychological test scores). These results were not significantly different from the HIV-negative study sample. No consistent pattern of impairment was seen in HIV-positive patients relative to general male population data (n = 380)., Conclusions: We found a prevalence of HAND and degree of impairment on neuropsychological testing of HIV-positive MSM that could represent a normal population distribution. These findings suggest that NCI may be overestimated in HIV-positive MSM, and that the attribution of NCI to HIV infection implied by the term HAND requires revision.

Concussion-related cognitive impairments are typically evaluated with repeated neuropsychological assessments where post-injury performances are compared with pre-injury baseline data (baseline method). Many cases of concussions, however, are evaluated in the absence of baseline data by comparing post-injury performances with normative data (normative method). This study aimed to compare the sensitivity and specificity of these two methods using the CogSport/Axon test battery. Normative data and reliable change indices were computed from a non-injured athlete sample (n = 235). Test-retest data from non-injured (n = 260) and recently concussed (n = 29) athlete samples were then used to compare the two methods. The baseline method was found to be more sensitive than the normative method, and both methods had high specificity and overall correct classification rates. This suggests that while the normative method identifies most cases of recent concussions, the baseline method remains a more precise approach to assessing concussion-related cognitive impairments., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test.", Methods: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection., Results: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass., Conclusions: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer's disease (AD) when coupled to neuroimaging and neuropsychological parameters., Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months., Results: Comparisons of plasma Aβ levels between the transition and non-transitional groups showed Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01)., Conclusion: We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine the relationship between BDNF Val66Met and beta-amyloid (Aβ) on cognitive decline, hippocampal atrophy, and Aβ accumulation over 36 months in 165 healthy adults enrolled in the Australian Imaging, Biomarkers and Lifestyle study. In healthy adults with high Aβ, Met carriers showed significant and moderate-to-large declines in episodic memory, executive function, and language, and greater hippocampal atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippocampal volume in healthy adults with low Aβ. BDNF Val66Met did not relate to the amount of Aβ or to the rate of Aβ accumulation in either group. High Aβ levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippocampal degeneration in individuals in the preclinical stage of AD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Rationale: Use of cross-species neuropsychological paradigms such as visual-spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities., Objectives: This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, "process-based" computerized measure of visual-spatial PAL., Results: In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual-spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual-spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil., Conclusions: Acute scopolamine challenge can produce large and robust deficits in visual-spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual-spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

Aims: In a previous study, neurological and cognitive deficits reflecting central nervous system (CNS) disruption from chronic inhalant abuse showed substantial recovery after 2 years' abstinence. Functional recovery was progressive, with recovery rates dependent on the degree of impairment prior to abstinence, and severity and duration of initial abuse. Persistent deficits occurred in those with previous 'lead encephalopathy' from leaded petrol abuse. The current study examined recovery in the same cohort 15 years after baseline., Design: Prospective cohort design., Setting: Two remote Aboriginal communities in Arnhem Land, Australia., Participants: Using baseline group classifications, 27 healthy controls, 60 ex-chronic inhalant abusers and an additional 17 with previous lead encephalopathy were assessed., Measurements: Standard neurological, ocular-motor and cognitive functions and blood lead levels., Findings: Chronic (non-encephalopathic) inhalant abusers showed elevated blood lead levels and abnormal scores on most tasks at baseline. At 2 years' abstinence, blood lead was reduced but remained elevated and most scores had normalized. By 15 years, blood lead and all performance scores were equivalent to healthy controls for this group (P > 0.05). The encephalopathic group was more severely impaired on all scores at baseline and showed little improvement, if any, across all tests after both 2 and 15 years' abstinence. Blood lead for this group declined, and was not significantly different to controls after 15 years., Conclusions: Some inhalant abusers experience severe and persistent neurological deficits, suggesting irrecoverable damage attributable to lead encephalopathy. In the absence of this encephalopathy long-term abstinence from inhalants may allow recovery of normal brain function., (© 2013 The Authors, Addiction © 2013 Society for the Study of Addiction.)

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

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 ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-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 (11)C-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 (11)C-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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We aimed to characterize the nature and magnitude of cognitive decline in a group of adults with amnestic mild cognitive impairment (aMCI) with high and low levels of amyloid-β (Aβ) in relation to healthy older adults with low Aβ levels. Healthy older adults and adults with aMCI enrolled in the Australian Imaging, Biomarker, and Lifestyle study, completed the CogState brief battery at baseline and 18 months, and underwent positron emission tomography neuroimaging for Aβ at baseline. In this study, we included adults with MCI who had been classified as having high and low levels of Aβ and healthy older adults who had been classified as having low levels of Aβ. Linear model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, adults with aMCI and high Aβ showed greater decline in working memory and in verbal and visual episodic memory at 18 months. Adults with aMCI and low Aβ also showed greater decline in working memory; however they did not evidence any decline in episodic memory at 18 months. The results of our study suggests that relative to healthy older adults and adults with aMCI with low Aβ, adults with aMCI and high levels of Aβ showed faster rates of decline on measures of episodic memory over 18 months, and this was approximately twice that observed previously for healthy older adults with high Aβ levels.

We aimed to characterize the nature and magnitude of cognitive decline in a group of healthy older adults with high and low levels of amyloid-β (Aβ) and who were APOE ε4 carriers and non-carriers. Healthy older adults underwent positron emission tomography neuroimaging for Aβ, APOE genotyping, and cognitive and clinical assessment as part of their baseline assessment in the Australian Imaging, Biomarker, and Lifestyle study. Cognitive function and clinical ratings were reassessed 18 months later. Linear mixed model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, healthy older adults with high Aβ showed greater decline in episodic memory and language at 18 months. No decline on any measure of executive function, attention, or clinical rating was observed for healthy older adults with high Aβ levels. Compared to non-carriers, APOE ε4 carriers showed a greater decline only on the task of visual memory at the 18 month assessment. Importantly though, no interaction between APOE ε4 and Aβ was observed on any measure of cognitive function. The results of this study suggest that high Aβ load was associated with greater decline in episodic memory and language, that the magnitude of this decline was moderate and equivalent across both domains, and that APOE ε4 carriage did not moderate the relationship between Aβ and decline in memory and language functions.

Objective: Although the APOE ε4 allele is associated with more rapid decline in memory in healthy older adults, the significance of elevated cerebral β-amyloid (Aβ) load for longitudinal changes in cognition is unclear., Methods: Healthy and cognitively normal older adults (n = 141; mean age 76 years) underwent PET neuroimaging for cerebral Aβ, APOE genotyping, and cognitive assessment as part of their baseline assessment in the Australian Imaging Biomarkers and Lifestyle study. Cognitive function was reassessed 18 months later., Results: Linear mixed-model analyses adjusted for baseline cognitive function indicated that, relative to individuals with low cerebral Aβ, individuals with high cerebral Aβ showed significantly greater decline in working memory and verbal and visual episodic memory at 18 months. Compared with noncarriers, APOE ε4 carriers showed a greater decline in visual memory at the 18-month assessment. No interaction between APOE ε4 and cerebral Aβ load was observed for any measure of cognitive function., Conclusions: In this prospective study of healthy older adults, high cerebral Aβ load was associated with greater decline in episodic and working memory over 18 months. The APOE ε4 genotype was also associated with a decline in visual memory, although the effect was less than that observed for cerebral Aβ load.

A recent single-site study (Fisher et al., 2009. Am J Psychiatry. 166 (7) 805-11) showed that repeated training with the Brain Fitness Program (BFP) improved performance on a battery of neuropsychological tasks. If replicated these data suggest an important non-pharmacological method for ameliorating cognitive impairment in schizophrenia. Our study evaluated the BFP training effects in an open-label, multi-site, multinational clinical trial. Fifty-five stable adult patients with schizophrenia on regular antipsychotic medication completed ≥ 32 BFP training sessions over 8-10 weeks. Training effects on cognitive performance and functional capacity outcome measures were measured using CogState® schizophrenia battery, UCSD Performance based Skills Assessment (UPSA-2) and Cognitive Assessment Interview (CAI). BFP training showed a large and significant treatment effect on a training exercise task (auditory processing speed), however this effect did not generalize to improved performance on independent CogState® assessment. There were no significant effects on UPSA-2 or CAI scores. Our study demonstrated the feasibility of implementing BFP training in a multi-site study. However, BFP training did not show significant treatment effects on cognitive performance or functional capacity outcome measures despite showing large and significant effects on a training exercise., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this study was to validate the CogState Brief Battery, which assesses psychomotor, attentional, working memory, and visual learning functions, in healthy older people and in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. In healthy older adults, weak relationships between demographic variables (e.g., education, depression) and cognitive performance were observed. In AD and MCI groups, the magnitude of impairment was greatest for tasks of working memory and memory, with a negative influence of apolipoprotein E ϵ4 status on learning but not working memory. These results suggest that the CogState Brief Battery can be used to screen for AD-related cognitive changes.

Background: Progressive intraindividual decline in memory and cognition is characteristic of dementia and may be useful in detecting very early Alzheimer's disease pathology., Methods: This study evaluated the slopes of cognitive performance over a 12-month period in 263 healthy, community-dwelling, adult volunteers aged ≥50 years. Participants completed a brief computerized battery of cognitive tests (CogState) at baseline and during 3-, 6-, 9-, and 12-month follow-up assessments. Linear mixed models were used to estimate age-adjusted mean slopes and 95% confidence intervals of change for each of the cognitive measures., Results: By defining age-adjusted mean slopes, and 95% confidence intervals for a measure of episodic memory, individuals with greater than expected decline (equal to or lower than the fifth percentile level of decline) were identified. From these, four individuals completed a full medical, neurologic, and neuropsychological evaluation, with none of them fulfilling criteria for mild cognitive impairment, but three (75%) having positive amyloid-positron emission tomographic scans., Conclusions: Intraindividual decline in cognitive performance can be detected in otherwise healthy, community-dwelling, older persons, and this may deserve further study as a potential indicator of early Alzheimer's disease pathology., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.)

Background: The prevalence of preexisting cognitive impairment (PreCI) is documented before cardiac surgery, but there is less information before noncardiac surgery. In addition, the prevalence of mild cognitive impairment, defined by different cognitive criteria and subjective complaints, and which may progress to Alzheimer disease, is unknown in these subjects. Because anesthesia and surgery have been implicated in Alzheimer disease pathology, we prospectively measured PreCI and mild cognitive impairment in subjects scheduled for total hip joint replacement surgery in an observational study., Methods: One hundred fifty-two subjects 60 y of age and older who were scheduled for total hip joint replacement surgery underwent assessment, including neuropsychologic testing, 1 week before surgery. Test results were compared with published norms. PreCI was defined as impairment in two or more of seven cognitive tests, for which impairment in an individual test was defined as ≥ 2 SD below norms for that test. Amnestic mild cognitive impairment (aMCI) was defined as impairment ≥1.5 SD below norms for results of the immediate and/or delayed Auditory Verbal Learning Test plus a subjective complaint., Results: Subjects performed worse compared with normative data on five of seven neuropsychologic tests. Thirty (20% [95% CI, 13-26%]) subjects were classified as having PreCI. Thirty-four (22% [95% CI, 16-29%]) were classified as having aMCI. Ten (7%) subjects were classified as having both PreCI and aMCI, representing 33% of the 30 subjects with PreCI., Conclusions: The prevalence of aMCI in subjects scheduled for total hip joint replacement surgery is similar to that in the general community. PreCI and aMCI tend to identify different subjects. Because aMCI is known to progress to Alzheimer disease, future studies that track cognition before and after anesthesia and surgery should document the presence or absence of aMCI so that the rate of conversion to Alzheimer disease after anesthesia and surgery can be compared with the rate in the nonsurgical population.

Background: Postoperative cognitive dysfunction (POCD) has been documented after cardiac and noncardiac surgery. The type of surgery and anesthetic has been assumed to be associated with the incidence but there are few prospective data comparing the incidence after different procedures. In this study, we sought to determine the association of the type of surgical procedure and anesthesia on the incidence of POCD after procedures involving light sedation, general anesthesia for noncardiac surgery, and general anesthesia for cardiac surgery involving cardiopulmonary bypass., Methods: Eight neuropsychological tests were administered at baseline and at 7 days and 3 months postoperatively to subjects from 3 procedure groups and a nonoperative control group. Reliable change index was used to calculate POCD. The study sample consisted of subjects involved in 3 separate trials investigating coronary angiography (CA) (percutaneous diagnostic procedure) under sedation, major noncardiac surgery (total hip joint replacement [THJR] surgery) under general anesthesia, and coronary artery bypass graft (CABG) surgery under general anesthesia., Results: Data were collected from 644 patients in the patient groups and 34 subjects in the control group. Neuropsychological results were available for POCD at day 7 for THJR surgery (n=162) and CABG surgery (n=281). The incidence of POCD at day 7 was 17% for THJR surgery and 43% for CABG surgery (adjusted odds ratio=0.2, 95% confidence interval [CI]: 0.1, 0.4; P<0.01). At 3 months, the incidence of POCD for all groups combined (n=636) was 17% (21% for CA under sedation, 16% for THJR surgery, and 16% for CABG surgery). The mean (95% CI) for the difference in proportions of POCD among groups was 0.00 (-0.07, 0.07) (P=0.91) for CABG versus THJR; -0.05 (-0.12, 0.03) (P=0.21) for CABG versus CA; and -0.05 (-0.13, 0.03) (P=0.24) for THJR versus CA. There were no significant differences among groups (adjusted odds ratio=1.21, 95% CI: 0.94, 1.55; P=0.13)., Conclusions: The incidence of POCD in old and elderly patients at day 7 was higher after CABG surgery than THJR surgery, but POCD at 3 months was independent of the nature or the type of procedure or anesthetic when comparing CA, THJR, and CABG surgery groups. Cardiovascular risk factors were not predictive of POCD after any procedure., (© 2011 International Anesthesia Research Society)

Background and Purpose: Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer's disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI., Methods: This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls., Results: Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen's d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen's d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen's d = .21)., Conclusions: These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and "on-line" maintenance of task rules.

Background/aims: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear., Methods: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD)., Results: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted., Conclusion: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults., (Copyright © 2011 S. Karger AG, Basel.)

Background: Chronic petrol inhalation can be associated with significant cognitive impairment. While rehabilitation programs can rely on such skills to educate clients and achieve treatment outcomes, cognitive function is rarely assessed on admission. This is particularly true for Indigenous populations where standard assessments are not appropriate. This paper describes a process for assessing cognition in Indigenous Australians. Two studies investigate firstly the demographic factors impacting on cognition for healthy Indigenous Australians and secondly the utility of the assessment process for detecting petrol sniffing related cognitive impairments., Methods: Study One assessed a naturalistic sample of healthy Indigenous Australians from the Northern Territory (N = 206; mean age = 28.03) on computerised tests of psychomotor speed, visual attention, memory, learning, spatial awareness and executive functions. Multiple regression analyses determined the unique contributions of six factors (age, education, gender, familiarity with computers, regular long term cannabis use and locality) to the variance in performance for this group. Study Two examined group differences in cognitive performance on the same tests between healthy Indigenous Australians (N = 96) and Indigenous petrol sniffers (N = 50; both age restricted to < 26 years) while controlling those factors found to impact on performance from Study One., Results: Age, computer familiarity, and education significantly contributed to the variance in performance measures. While controlling these factors, petrol abuse was associated with poorer performance on complex tasks of psychomotor, visual attention, memory, learning, spatial awareness and executive function., Conclusions: This assessment process is useful for detecting substance abuse related impairments in Indigenous Australians and when using this assessment process, age and computer familiarity in particular should be controlled for.

Background: Decreased cognitive function associated with coronary artery bypass graft surgery is common. These deficits may be similar to the cognitive dysfunction seen in the spectrum of mild cognitive impairment to Alzheimer's disease, which are believed to result from the accumulation of amyloid beta (Abeta) peptide in the brain. We measured cognition both before and after coronary artery bypass graft surgery and assayed Abeta levels to investigate whether the cognitive dysfunction of cardiac surgery was associated with Abeta levels., Methods: The plasma of 332 patients, who had undergone neuropsychological testing before and 3 and 12 months after coronary artery bypass graft surgery, was analyzed for Abeta(42) and Abeta(40). Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group, and postoperative cognitive dysfunction was defined as a decline in two or more tests compared with the group mean baseline score., Results: Preexisting cognitive impairment was present in 117 patients (35.2%), and postoperative cognitive dysfunction was present in 40 (12%) at 3 months and 41 (13%) at 12 months after surgery. Both plasma Abeta(42) and Abeta(40) levels assessed before the surgery were significantly lower in patients who later had postoperative cognitive dysfunction at 3 months., Conclusions: Decreased preoperative plasma levels of Abeta(42) and Abeta(40) in patients who exhibit postoperative cognitive dysfunction at 3 months suggest that postoperative cognitive dysfunction at this time may share a common mechanism with mild cognitive impairment and Alzheimer's disease. This process may be exacerbated by anesthesia.

This study examined the criterion and construct validity of a brief computerized cognitive test battery (CogState Schizophrenia Battery) compared to a conventional cognitive test battery recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus. The CogState and MATRICS batteries yielded comparable effect sizes in comparing patients with schizophrenia to healthy controls (Cohen's ds = -1.50 for both batteries). Moderate to large correlations were observed between CogState and MATRICS measures of processing speed, attention/vigilance, working memory, verbal and visual learning, reasoning/problem solving, and social cognition (rs = .56-.79). CogState and MATRICS composite scores also correlated strongly with scores on the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA; rs = .76 and .79, respectively) in patients with schizophrenia. Results of this study suggest that the CogState Schizophrenia Battery provides valid measurement of the cognitive domains nominated by the MATRICS consensus group as being important to consider in the context of pharmacological treatments for cognitive impairment in schizophrenia.

Objectives: To assess effects of a semi-acute administration of buspirone in comparison to a placebo on cognitive function and negative symptoms in patients with schizophrenia and schizoaffective disorder., Methods: In a 6-week, double-blind, placebo-controlled, independent groups study 18 subjects (14 males, four females) received in random order either placebo or buspirone (15-30 mg/day). A neuropsychological assessment using the Hopkins verbal learning test (HVLT) simple reaction time (SRT), choice reaction time (CRT), n-back spatial working memory task and the stroop colour and word test was performed at baseline and final visit. Symptom rating scales were administered at testing weeks 0, 2, 4 and 6., Results: Repeated measures ANOVA was used to examine changes in performance on tests over time. There were no statistically significant differences between placebo and buspirone treatments on either cognitive function measures or symptom ratings., Conclusion: Semi-acute adjunct treatment with buspirone may be too short to be clinically efficacious in patients with schizophrenia. Intrinsic activation of 5-HT(1A) receptors by atypical antipsychotics may hinder the ability of buspirone to further improve cognitive functions. Buspirone did not affect clinical outcomes for this chronically ill group of patients being treated with atypical antipsychotic drugs., (2009 John Wiley & Sons, Ltd.)

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants., Methods: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning., Results: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring., Conclusion: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

This study examined the validity of the four standard psychological paradigms that have been operationally defined within the CogState brief computerized cognitive assessment battery. Construct validity was determined in a large group of healthy adults. CogState measures of processing speed, attention, working memory, and learning showed strong correlations with conventional neuropsychological measures of these same constructs (r's = .49 to .83). Criterion validity was determined by examining patterns of performance on the CogState tasks in groups of individuals with mild head injury, schizophrenia, and AIDS dementia complex. Each of these groups was impaired on the CogState performance measures (Cohen's d's = -.60 to -1.80) and the magnitude and nature of this impairment was qualitatively and quantitatively similar in each group. Taken together, the results suggest that the cognitive paradigms operationally defined in the CogState brief battery have acceptable construct and criterion validity in a neuropsychological context.

Objective: This study examined between- and within-subject stability of cognitive performance in individuals with chronic schizophrenia., Methods: Thirty individuals with schizophrenia and 20 healthy controls matched by age, sex, education, and estimated IQ underwent repeated cognitive assessments at baseline and 30 days using computerized tests of psychomotor function, visual attention/information processing, non-verbal learning, and executive function., Results: Compared to healthy controls, individuals with schizophrenia scored lower on all cognitive measures and demonstrated greater variability in cognitive performance. Within-subject variability in cognitive performance in both the schizophrenia and healthy control groups remained stable at brief (i.e., hours) and intermediate (i.e., one month) assessments., Conclusions: These results demonstrate the stability of between- and within-subject variability in cognitive performance in schizophrenia, and suggest that variability in cognitive performance may reflect an inherent characteristic of the disorder, rather than differences in test-retest reliability/error of cognitive measures.

Objective: Neuropsychological studies have suggested that frontal-striatal dysfunction plays a role in obsessive-compulsive disorder (OCD), although findings have been inconsistent, possibly due to heterogeneity within the disorder and methodological issues. The purpose of the present study was therefore to compare the neuropsychological performance of different subtypes of OCD and matched non-clinical controls (NCs) on the Cambridge Automated Neuropsychological Test Battery (CANTAB)., Methods: Fifty-nine OCD patients and 59 non-clinical controls completed selected tests from CANTAB examining executive function, visual memory and attentional-set shifting. Depression, anxiety and OCD symptoms were also assessed., Results: From 59 OCD patients, four subtypes were identified: (i) washers; (ii) checkers; (iii) obsessionals; and (iv) mixed symptom profile. Comparisons between washers, checkers, obsessionals and NCs indicated few differences, although checkers were generally found to exhibit poorer performance on spatial working memory, while obsessionals performed poorly on the spatial recognition task. Both checkers and the mixed subgroups showed slowed initial movement on the Stockings of Cambridge planning task and poorer pattern recognition relative to NCs., Conclusion: Overall the results suggested greater impairments in performance on neuropsychological tasks in checkers relative to other subtypes, although the observed effects were small and the conclusions limited by the small subtype samples. Future research will need to account for factors that influence neuropsychological performance in OCD subtypes.

Objectives: Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD)., Design: Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day., Setting: Early phase I clinical trial., Participants: 15 healthy older adults; 14 older adults with mild Alzheimer's disease., Intervention: Single acute dose of 5mg donepezil., Measurements: Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring., Results: A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing)., Conclusion: The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

Beta-amyloid (Abeta) deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), Abeta burden can be quantified using (11)C PiB PET. Neuropathological studies have shown that the initial plaques are located in the temporal and orbitofrontal cortices, extending later to the cingulate, frontal and parietal cortices (Braak and Braak, 1997). Previous studies have shown an overlap in (11)C PiB PET retention between AD, mild cognitive impairment (MCI) patients and normal elderly control (NC) participants. It has also been shown that there is a relationship between Abeta deposition and memory impairment in MCI patients. In this paper we explored the variability seen in 15 AD, 15 MCI and 18 NC by modeling the voxel data from spatially and uptake normalized PiB images using principal component analysis. The first two principal components accounted for 80% of the variability seen in the data, providing a clear separation between AD and NC, and allowing subsequent classification. The MCI cases were distributed along an apparent axis between the AD and NC group, closely aligned with the first principal component axis. The NC cases that were PiB(+) formed a distinct cluster that was between, but separated from the AD and PiB(-) NC clusters. The PiB(+) MCI were found to cluster with the AD cases, and exhibited a similar deposition pattern. The primary principal component score was found to correlate with episodic memory scores and mini mental status examination and it was observed that by varying the first principal component, a change in amyloid deposition could be derived that is similar to the expected progression of amyloid deposition observed from post mortem studies.

Reasoning and problem solving in the spatial domain are important aspects of executive function that are reliably impaired in schizophrenia, and the Groton Maze Learning Test(c) (GMLT) provides a valid measure of spatial working memory. In the current study, 34 patients with first-episode schizophrenia and 20 matched controls were assessed for baseline spatial working memory abilities using this hidden maze learning test. Approximately one month after baseline assessment, allowing for symptoms to stabilize in response to treatment with therapeutic doses of atypical antipsychotic medications for individuals with schizophrenia, all participants were again assessed with the GMLT. Prior to pharmacologic intervention, patients with schizophrenia showed significant impairments in performance of all aspects of the GMLT, including measures of learning efficiency and error monitoring. One month of treatment was associated with a reliable improvement in these domains, although impairments in accuracy and error monitoring on this spatial working memory test persisted despite symptomatic improvement. These results indicate that impairments in spatial working memory are present at the earliest stages of the illness, and that such deficits in performance remain present, albeit ameliorated, after treatment with atypical antipsychotic medication.

This study examined the construct validity of the Groton Maze Learning Test (GMLT) in assessing processing speed, working memory, and aspects of executive function in healthy adults. Performance on GMLT outcome measures was compared to performance on tests of psychomotor speed, working memory, and learning from the CogState computerized cognitive test battery (CGS; http://www.cogstate.com/). The factor structure of the GMLT was evaluated using exploratory factor analysis. The stability of this factor structure was examined in a large sample of patients undergoing parathyroidectomy or thyroidectomy. Results of this study suggest that the GMLT measures of spatial learning efficiency and error monitoring correlate with CogState measures of attention, working memory, and learning. Exploratory factor analysis yielded a two-factor solution of error monitoring and learning efficiency, which was stable across repeated assessments.

This study used a novel hidden maze learning test to examine the nature and magnitude of impairment on separable aspects of executive function in 36 children with ADHD. A within-subject analysis of children with ADHD was also conducted to assess cognitive effects of open-label stimulant treatment. Compared to 31 age-matched controls, unmedicated children with ADHD were slower and made significantly more errors that were indicative of relative impairment in prepotent response inhibition and ability to "maintain set" while using simple rules to complete the task. Open-label administration of stimulant medication led to faster and more efficient performance, with children with ADHD making fewer perseverative and rule-break errors than when off medication. This instrument might be useful in monitoring treatment response in specific aspects of executive function and in assisting with dose-titration decisions.

Cognitive and memory complaints were assessed in 100 healthy older adults on two occasions over 2.5 years as part of a 6-year study assessing cognition, mood, and general health factors. Diminished memory for names and actions and lapses in concentration were common complaints, regardless of the individuals' actual cognitive status. No change in cognitive complaints occurred over time, even for individuals whose memory had declined over 6 years. Cognitive complaints correlated with anxiety, depression, and general mental health but not with objectively measured memory or cognition, education or age. Complaints did not differ with gender, apolipoprotein E epsilon4 genotype, cardiovascular risk factors, or intake of sedating medications. Thus, cognitive complaints could not differentiate memory-declining older adults from cognitively normal older adults and were more closely associated with mood and general mental health than actual cognitive status, age, or potential risk factors for Alzheimer's disease. Thus, the evaluation of cognitive complaints must be broad and must consider the correspondence of complaints not only to relevant measurable cognitive abilities but also to the affect of the individual.

Approximately 30% of healthy persons aged over 75 years show Abeta deposition at autopsy. It is postulated that this represents preclinical Alzheimer's disease (AD). We evaluated the relationship between Abeta burden as assessed by PiB PET and cognitive decline in a well-characterized, non-demented, elderly cohort. PiB PET studies and cognitive tests were performed on 34 elderly participants (age 73+/-6) from the longitudinal Melbourne Healthy Aging Study (MHAS). Subjects were classified as being cognitively 'stable' or 'declining' by an independent behavioural neurologist based on clinical assessment and serial word-list recall scores from the preceding 6-10 years. Decline was calculated from the slope of the word-list recall scores. Abeta burden was quantified using Standardized Uptake Value normalized to cerebellar cortex. Ten subjects were clinically classified as declining. At the time of the PET scans, three of the declining subjects had mild cognitive impairment, one had AD, and six were declining but remained within the normal range for age on cognitive tests. Declining subjects were much more likely to show cortical PiB binding than stable subjects (70% vs. 17%, respectively). Neocortical Abeta burden correlated with word-list recall slopes (r=-0.78) and memory function (r=-0.85) in the declining group. No correlations were observed in the stable group. Abeta burden correlated with incident memory impairment and the rate of memory decline in the non-demented ageing population. These observations suggest that neither memory decline nor Abeta deposition are part of normal ageing and likely represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis.

Objective: The aim of the study was to investigate the impact of treatment-related clearance of hepatitis C virus (HCV) on cognitive function., Methods: A prospective study was conducted in 19 HCV-monoinfected and 15 HIV/HCV-coinfected individuals undergoing pegylated interferon alpha-2a and ribavirin therapy between April 2003 and August 2005. Neuropsychological, mood, and health-related quality of life (HRQOL) effects were assessed using computer-based battery, Trail Making Tests, Depression Anxiety Stress Scales and the Short Form-36 health survey., Results: Pretreatment cognitive function, mood status, and HRQOL were similar between the HCV patient groups. Sustained virological response (SVR) rates were similar between HCV-monoinfected (68%) and HIV/HCV-coinfected (73%) groups. SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL improvement., Conclusions: Our findings provide evidence to support cognitive effects of HCV independent of mood status and HRQOL profiles.

Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.

Background: With chronic alcohol abuse, cognitive studies suggest that progressive cognitive decline may precede more serious and irreversible neurological syndromes. The early detection of cognitive impairment may therefore aid in the prevention of permanent brain damage. Despite the devastating consequences of alcohol abuse among Aboriginal Australians, the effects on brain function have never been studied in this population and a lack of appropriate assessment tools has prevented the development of such research., Aims: To determine the impact of long-term and heavy episodic alcohol use on cognitive function in Aboriginal people., Design: Cross-sectional comparing heavy episodic alcohol users with non-alcohol users., Setting: Two remote Aboriginal communities in north-east Arnhem Land, northern Australia., Subjects: The control group consisted of 24 non-drinkers (15 males, nine female) and the heavy episodic group consisted of 20 people (19 males, one female) who had been drinking alcohol in a heavy episodic style (median 14 drinks per occasion) for a mean of 8.9 years (SD = 5.0)., Measurements: Interview to obtain demographic information, substance abuse history and symptoms of mental health and wellbeing, together with a computerized cognitive assessment battery (CogState Ltd)., Findings: Compared with non-drinkers, heavy episodic drinkers showed reduced psychomotor speed (P = 0.04) and reduced accuracy when performing tasks of attention (P = 0.045), working memory (P = 0.04), implicit memory (P = 0.03) and associate learning and memory (P = 0.001)., Conclusions: Specific cognitive abnormalities that suggest frontostriatal abnormalities and have been observed in association with chronic alcoholism in other populations were observed among Aboriginal Australians who were heavy episodic alcoholic users.