Paul Maruff

IMAGING β-AMYLOID BURDEN IN AGING AND DEMENTIA

Objective: To compare brain β-amyloid (Aβ) burden measured with [11C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. Methods: Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Aβ burden was quantified using PIB distribution volume ratio. Results: Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an “AD-like” (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-ε4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. Conclusions: Pittsburgh Compound B PET findings match histopathologic reports of β-amyloid (Aβ) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Aβ deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Aβ may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Aβ may benefit this condition.

Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

BACKGROUND Similar to most chronic diseases, Alzheimers 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 Alzheimers Drug Discovery Foundation, and the Alzheimers Association.

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease

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 Alzheimers 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.

Intensity of dementia through latent variable modelling (I-DeLV) in the AIBL cohort

69% of Mild Cognitively Impaired and 96% of AD. Conclusions: The described models provide accurate estimations of NAB based on demographic corrected cognitive test scores. If NAB is a predictor for progression to AD and given such models can accurately predict NAB, it follows that this work may lead to an effective and economical screen for early detection of individuals at risk of developing AD, in-turn providing justification for further confirmatory tests (e.g. PET) or to identify suitable participants for intervention or therapeutic trials.

Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children.

BACKGROUND Executive function deficits have been reported repeatedly in children with Attention Deficit Hyperactivity Disorder (ADHD). Stimulant medication has been shown to be effective in improving cognitive performance on most executive function tasks, but neuropsychological tests of executive function in this population have yielded inconsistent results. Methodological limitations may explain these inconsistencies. This study aimed to measure executive function in medicated and non-medicated children with ADHD by using a computerized battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), which is sensitive to executive function deficits in older patients with frontostriatal neurological impairments. METHODS Executive function was assessed in 30 children with ADHD: 15 were stimulant medication naive and 15 were treated with stimulant medication. These two groups were compared to 15 age, sex and IQ matched controls. RESULTS The unmedicated children with ADHD displayed specific cognitive impairments on executive function tasks of spatial short-term memory, spatial working memory, set-shifting ability and planning ability. Impairments were also seen on spatial recognition memory and delayed matching to sample, while pattern recognition memory remained intact. The medicated children with ADHD were not impaired on any of the above executive function tasks except for deficits in spatial recognition memory. CONCLUSIONS ADHD is associated with deficits in executive function. Stimulant medication is associated with better executive function performance. Prospective follow-up studies are required to examine these effects.

The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals.

Performance on many cognitive and neuropsychological tests may be improved by prior exposure to testing stimuli and procedures. These beneficial practice effects can have a significant impact on test performance when conventional neuropsychological tests are administered at test-retest intervals of weeks, months or years. Many recent investigations have sought to determine changes in cognitive function over periods of minutes or hours (e.g., before and after anesthesia) using computerized tests. However, the effects of practice at such brief test-retest intervals has not been reported. The current study sought to determine the magnitude of practice effects in a group of 113 individuals assessed with an automated cognitive test battery on 4 occasions in 1 day. Practice effects were evident both between and within assessments, and also within individual tests. However, these effects occurred mostly between the 1st and 2nd administration of the test battery, with smaller, nonsignificant improvements observed between the 2nd, 3rd, and 4th administrations. On the basis of these results, methodological and statistical strategies that may aid in the differentiation of practice effects from drug-induced cognitive changes are proposed.

The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment.

Subjects in the preclinical stages of Alzheimers disease (AD) typically record neuropsychological performance between that of healthy older individuals and demented patients. More specifically, deficits on measures of verbal episodic memory are commonly reported in these patients, while other cognitive functions (e.g. language, praxis and executive function) seem to be spared. A similar neuropsychological profile is observed in elderly subjects with mild cognitive impairment (MCI), a disorder that is attracting increasing research interest. Evidence from lesion and functional imaging studies, as well as volumetric imaging in probable AD and MCI patients, suggests that the cognitive deficits observed in these disorders may be related to medial temporal lobe dysfunction. An issue currently under investigation is whether MCI represents the preclinical stages of AD or a distinct and static cognitive aetiology. In an attempt to address this issue, present investigations are adopting a convergent approach to the detection of preclinical AD, where multiple risk factors are considered when making a diagnosis.

Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: A combined study of two cohorts

The objective of this study was to assess the prevalence and pattern of neuropsychological impairment in cohorts of human immunodeficiency virus (HIV)-infected individuals across pre- and post-HAART (highly active antiretroviral therapy) eras. Two cohorts of HIV-infected individuals attending tertiary referral hospital outpatient clinics were studied. The cohorts represented two eras of antiretroviral medication: monotherapy (n = 51) and HAART (n = 90). Each was compared in nine neuropsychological domains in regard to the prevalence as well as pattern of neuropsychological impairment. Because the authors intended to characterize the prevalence and pattern of neuropsychological deficits in nondemented advanced HIV-infected individuals, patients with a current diagnosis of acquired immunodeficiency syndrome (AIDS) dementia complex were not included. The prevalence of impairment was not significantly different across pre-HAART and HAART eras using a standard criterion to define impairment: −2 SD in two neuropsychological measures (41.1%/38.8%). Prevalence of deficits was not significantly reduced in patients with undetectable plasma viral load. The pattern of neuropsychological impairment was different across pre-HAART and HAART eras, with an improvement in attention, verbal fluency, visuoconstruction deficits, but a deterioration in learning efficiency and complex attention. This change remained even in patients with an undetectable plasma viral load, although the severity was partially diminished. Neuropsychological deficits remain common in the HAART era, essentially uninfluenced by HAART. The finding that some neuropsychological functions are improving while other are deteriorating indicates that these deficits do not reflect “burnt out” damage but rather that there is an active intracerebral process occurring, the nature of which is still to be determined.

The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: A meta-analysis of the current literature

OBJECTIVE Several studies have identified that adjuvant chemotherapy for breast cancer is associated with cognitive impairment; however, the magnitude of this impairment is unclear. This study assessed the severity and nature of cognitive impairment associated with adjuvant chemotherapy by conducting a meta-analysis of the published literature to date. METHOD Six studies (five cross-sectional and one prospective) meeting the inclusion criteria provided a total of 208 breast cancer patients who had undergone adjuvant chemotherapy, 122 control participants and 122 effect sizes (Cohens d) falling into six cognitive domains. First, the mean of all the effect sizes within each cognitive domain was calculated (separately for cross-sectional and prospective studies); second, a mean effect size was calculated for all of the effect sizes in each cross-sectional study; and third, regression analyses were conducted to determine any relationships between effect size for each study and four different variables. RESULTS For the cross-sectional studies, each of the cognitive domains assessed (besides attention) showed small to moderate effect sizes (-0.18 to -0.51). The effect sizes for each study were small to moderate (-0.07 to -0.50) and regression analysis detected a significant negative logarithmic relationship (R2 = .63) between study effect size and the time since last receiving chemotherapy. For the prospective study, effect sizes ranged from small to large (0.11-1.09) and indicated improvements in cognitive function from the beginning of chemotherapy treatment to 3 weeks and even 1 year following treatment. CONCLUSION This meta-analysis suggests that cognitive impairment occurs reliably in women who have undergone adjuvant chemotherapy for breast cancer but that the magnitude of this impairment depends on the type of design that was used (i.e., cross-sectional or prospective). Thus, more prospective studies are required before definite conclusions about the effects of adjuvant chemotherapy on cognition can be made.

Validity of the CogState Brief Battery: Relationship to Standardized Tests and Sensitivity to Cognitive Impairment in Mild Traumatic Brain Injury, Schizophrenia, and AIDS Dementia Complex

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 (rs = .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 (Cohens ds = -.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.