Greg Savage

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.

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.

Predicting Alzheimer disease with β-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing

Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β‐amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E ε4 status in nondemented, older individuals.

Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults

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.

Factors affecting subjective memory complaints in the AIBL aging study: biomarkers, memory, affect, and age.

BACKGROUND The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimers type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. METHODS We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimers disease (AD) biomarkers (β-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. RESULTS SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. CONCLUSION SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aβ plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline.

Crossmodal congruency measures of lateral distance effects on the rubber hand illusion.

Body ownership for an artificial hand and the perceived position of ones own hand can be manipulated in the so-called rubber hand illusion. To induce this illusion, typically an artificial hand is placed next to the participants body and stroked in synchrony with the real hand, which is hidden from view. Our first aim was to test if the crossmodal congruency task could be used to obtain a measure for the strength of body ownership in the rubber hand illusion. In this speeded location discrimination task participants responded to tactile targets presented to their index or middle finger, while trying to ignore irrelevant visual distracters placed on the artificial hand either on the congruent finger or on the incongruent finger. The difference between performance on congruent and incongruent trials (crossmodal congruency effect, CCE) indicates the amount of multisensory interactions between tactile targets and visual distracters. In order to investigate if changes in body ownership influence the CCE, we manipulated ownership for an artificial hand by synchronous and asynchronous stroking before the crossmodal congruency task (blocked design) in Experiment 1 and during the crossmodal congruency task (interleaved trial-by-trial design) in Experiment 2. Modulations of the CCE by ownership for an artificial hand were apparent in the interleaved trial-by-trial design. These findings suggest that the CCE can be used as an objective measure for body ownership. Secondly, we tested the hypothesis that the lateral spatial distance between the real hand and artificial hand limits the rubber hand illusion. We found no lateral spatial limits for the rubber hand illusion created by synchronous stroking within reaching distances. In conclusion, the sense of ownership seems to be related to modulations of multisensory interactions possibly through peripersonal space mechanisms, and these modulations do not appear to be limited by an increase in distance between artificial hand and real hand.

Use of the CogState brief battery in the assessment of Alzheimer's disease related cognitive impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study

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 Alzheimers 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.

Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer's disease

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.

Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study

BACKGROUND Brain amyloid β (Aβ) deposition and neurodegeneration have been documented in about 50-60% of cognitively healthy elderly individuals (aged 60 years or older). The long-term cognitive consequences of the presence of Alzheimers disease pathology and neurodegeneration, and whether they have an independent or synergistic effect on cognition, are unclear. We aimed to characterise the long-term clinical and cognitive trajectories of healthy elderly individuals using a two-marker (Alzheimers disease pathology and neurodegeneration) imaging construct. METHODS Between Nov 3, 2006, and Nov 25, 2014, 573 cognitively healthy individuals in Melbourne and Perth, Australia, (mean age 73·1 years [SD 6·2]; 58% women) were enrolled in the Australian Imaging, Biomarker and Lifestyle (AIBL) study. Alzheimers disease pathology (A) was determined by measuring Aβ deposition by PET, and neurodegeneration (N) was established by measuring hippocampal volume using MRI. Individuals were categorised as A(-)N(-), A(+)N(-), A(+)N(+), or suspected non-Alzheimers disease pathophysiology (A(-)N(+), SNAP). Clinical progression, hippocampal volume, standard neuropsychological tests, and domain-specific and global cognitive composite scores were assessed over 6 years of follow-up. Linear mixed effect models and a Cox proportional hazards model of survival were used to evaluate, compare, and contrast the clinical, cognitive, and volumetric trajectories of patients in the four AN categories. FINDINGS 50 (9%) healthy individuals were classified as A(+)N(+), 87 (15%) as A(+)N(-), 310 (54%) as A(-)N(-), and 126 (22%) as SNAP. APOE ε4 was more frequent in participants in the A(+)N(+) (27; 54%) and A(+)N(-) (42; 48%) groups than in the A(-)N(-) (66; 21%) and SNAP groups (23; 18%). The A(+)N(-) and A(+)N(+) groups had significantly faster cognitive decline than the A(-)N(-) group (0·08 SD per year for AIBL-Preclinical AD Cognitive Composite [PACC]; p<0·0001; and 0·25; p<0·0001; respectively). The A (+)N(+) group also had faster hippocampal atrophy than the A(-)N(-) group (0·04 cm(3) per year; p=0·02). The SNAP group generally did not show significant decline over time compared with the A(-)N(-) group (0·03 SD per year [p=0·19] for AIBL-PACC and a 0·02 cm(3) per year increase [p=0·16] for hippocampal volume), although SNAP was sometimes associated with lower baseline cognitive scores (0·20 SD less than A(-)N(-) for AIBL-PACC). Within the follow-up, 24% (n=12) of individuals in the A(+)N(+) group and 16% (n=14) in the A(+)N(-) group progressed to amnestic mild cognitive impairment or Alzheimers disease, compared with 9% (n=11) in the SNAP group. INTERPRETATION Brain amyloidosis, a surrogate marker of Alzheimers disease pathology, is a risk factor for cognitive decline and for progression from preclinical stages to symptomatic stages of the disease, with neurodegeneration acting as a compounding factor. However, neurodegeneration alone does not confer a significantly different risk of cognitive decline from that in the group with neither brain amyloidosis or neurodegeneration. FUNDING CSIRO Flagship Collaboration Fund and the Science and Industry Endowment Fund (SIEF), National Health and Medical Research Council, the Dementia Collaborative Research Centres programme, McCusker Alzheimers Research Foundation, and Operational Infrastructure Support from the Government of Victoria.

Multimodal functional imaging of motor imagery using a novel paradigm

Neuroimaging studies have shown that the neural mechanisms of motor imagery (MI) overlap substantially with the mechanisms of motor execution (ME). Surprisingly, however, the role of several regions of the motor circuitry in MI remains controversial, a variability that may be due to differences in neuroimaging techniques, MI training, instruction types, or tasks used to evoke MI. The objectives of this study were twofold: (i) to design a novel task that reliably invokes MI, provides a reliable behavioral measure of MI performance, and is transferable across imaging modalities; and (ii) to measure the common and differential activations for MI and ME with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). We present a task in which it is difficult to give accurate responses without the use of either motor execution or motor imagery. The behavioral results demonstrate that participants performed similarly on the task when they imagined vs. executed movements and this performance did not change over time. The fMRI results show a spatial overlap of MI and ME in a number of motor and premotor areas, sensory cortices, cerebellum, inferior frontal gyrus, and ventrolateral thalamus. MI uniquely engaged bilateral occipital areas, left parahippocampus, and other temporal and frontal areas, whereas ME yielded unique activity in motor and sensory areas, cerebellum, precuneus, and putamen. The MEG results show a robust event-related beta band desynchronization in the proximity of primary motor and premotor cortices during both ME and MI. Together, these results further elucidate the neural circuitry of MI and show that our task robustly and reliably invokes motor imagery, and thus may prove useful for interrogating the functional status of the motor circuitry in patients with motor disorders.