Kerryn E. Pike

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 imaging results, from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimers Disease Neuroimaging Initiative (ADNI), performed (11)C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimers disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-epsilon4 carriers vs 21% in noncarriers) and increased with age, most strongly in epsilon4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in epsilon4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Abeta) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline.

Longitudinal Assessment of Aβ and Cognition in Aging and Alzheimer Disease

Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.

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.

Relationship between atrophy and β‐amyloid deposition in Alzheimer disease

Elucidating the role of aggregated β‐amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship.

Subtypes of progressive aphasia: application of the international consensus criteria and validation using β-amyloid imaging

Primary progressive aphasia comprises a heterogeneous group of neurodegenerative conditions with diverse clinical profiles and underlying pathological substrates. A major development has been the publication of the recent International Consensus Criteria for the three major variants namely: semantic, non-fluent/agrammatic and logopenic. The logopenic variant is assumed to represent an atypical presentation of Alzheimer pathology although evidence for this is, at present, limited. The semantic and non-fluent/agrammatic variants are largely associated with frontotemporal lobar degeneration with TDP-43 and tau pathology, respectively. The applicability of the International Consensus Criteria to an unselected clinical sample is unknown and no agreed clinical evaluation scale on which to derive the diagnosis exists. We assessed 47 consecutive cases of primary progressive aphasic seen over a 3-year period in a specialist centre, using a newly developed progressive aphasia language scale. A subgroup of 30 cases underwent (11)C-labelled Pittsburgh Compound B positron emission tomography imaging, a putative biomarker of Alzheimers disease that detects β-amyloid accumulation, and they were compared with an age-matched group (n = 10) with typical, predominately amnestic Alzheimers disease. The application of an algorithm based on four key speech and language variables (motor speech disorders, agrammatism, single-word comprehension and sentence repetition) classified 45 of 47 (96%) of patients and showed high concordance with the gold standard expert clinical diagnosis based on the International Consensus Criteria. The level of neocortical β-amyloid burden varied considerably across aphasic variants. Of 13 logopenic patients, 12 (92%) had positive β-amyloid uptake. In contrast, one of nine (11%) semantic variant and two of eight (25%) non-fluent/agrammatic cases were positive. The distribution of β-amyloid across cortical regions of interest was identical in cases with the logopenic variant to that of patients with typical Alzheimers disease although the total load was lower in the aphasic cases. Impairments of sentence repetition and sentence comprehension were positively correlated with neocortical burden of β-amyloid, whereas impaired single-word comprehension showed a negative correlation. The International Consensus Criteria can be applied to the majority of cases with primary progressive aphasic using a simple speech and language assessment scale based upon four key variables. β-amyloid imaging confirms the higher rate of Alzheimer pathology in the logopenic variant and, in turn, the low rates in the other two variants. The study offers insight into the biological basis of clinical manifestations of Alzheimers disease, which appear topographically independent of β-amyloid load.

β-Amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia

Objective: To investigate whether global and regional β-amyloid (Aβ) burden as measured with 11C Pittsburgh compound B (PIB) PET is associated with hippocampal atrophy characterized using MRI in healthy controls and patients with amnestic mild cognitive impairment (aMCI) or Alzheimer disease (AD). Methods: Ninety-two elderly healthy controls, 32 subjects with aMCI, and 35 patients with AD were imaged using 11C-PIB PET and MRI. Hippocampal volume was measured and PIB standardized uptake value ratio was extracted after partial volume correction within 41 regions of interest. Global, regional, and voxel-based correlations between PIB and hippocampal volume were computed for each group. Results: In healthy control participants with elevated neocortex PIB retention, significant correlation was found between PIB retention in the inferior temporal region and hippocampal volume using both region-based and voxel-based approaches. No correlation was found in any other group. Conclusions: The strong correlation between hippocampal atrophy and β-amyloid (Aβ) burden in the Pittsburgh compound B–positive healthy control group suggests that Aβ deposition in the inferior temporal neocortex is related to hippocampal synaptic and neuronal degeneration.

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.

Independent contribution of temporal β-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease

The relationship between β-amyloid deposition and memory deficits in early Alzheimers disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional β-amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimers disease, i.e. with β-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and β-amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical β-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for β-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal β-amyloid deposition provided independent contributions to memory deficits. In contrast to global β-amyloid deposition, temporal β-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical β-amyloid. In the pre-dementia stage of Alzheimers disease, subtle episodic memory impairment is related to β-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline.

The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias

Molecular neuroimaging based on annihilation radiation tomographic (ART) techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid (CSF), are proving valuable in the early and differential diagnosis of Alzheimer’s disease (AD). With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Aβ burden as assessed by molecular imaging matches histopathological reports of Aβ plaque distribution in aging and dementia and appears more accurate than FDG for the diagnosis of AD. Aβ imaging is also a very powerful tool in the differential diagnosis of AD from fronto-temporal dementia (FTD). Although Aβ burden as assessed by PET does not correlate with measures of cognitive decline in AD, it does correlate with memory impairment and rate of memory decline in mild cognitive impairment (MCI) and healthy older subjects. Approximately 30% of asymptomatic controls present cortical 11C-PiB retention. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis and to better elucidate the role of Aβ deposition in the course of Alzheimer’s disease.