Addressing population aging and Alzheimer's disease through the Australian Imaging Biomarkers and Lifestyle study: Collaboration with the Alzheimer's Disease Neuroimaging Initiative

The Australian Imaging Biomarkers and Lifestyle (AIBL) study is a longitudinal study of 1112 volunteers from healthy, mild cognitive impairment, and Alzheimer's disease (AD) populations who can be assessed and followed up for prospective research into aging and AD. AIBL aims to improve understanding of the pathogenesis, early clinical manifestation, and diagnosis of AD, and identify diet and lifestyle factors that influence the development of AD. For AIBL, the magnetic resonance imaging parameters of Alzheimer's Disease Neuroimaging Initiative (ADNI) were adopted and the Pittsuburgh compound B (¹¹C-PiB) positron emission tomography (PET) acquisition and neuropsychological tests were designed to permit comparison and pooling with ADNI data. Differences to ADNI include assessment every 18-months, imaging in 25% (magnetic resonance imaging, ¹¹C-PiB PET but no fluorodeoxyglucose PET), more comprehensive neuropsychological testing, and detailed collection of diet and lifestyle data. AIBL has completed the first 18-month follow-up and is making imaging and clinical data available through the ADNI website. Cross-sectional analysis of baseline data is revealing links between cognition, brain amyloid burden, structural brain changes, biomarkers, and lifestyle.     

Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease

IntroductionNeuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential.MethodsWe compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB-PET), ¹⁸F-fluorodeoxyglucose PET (FDG-PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed.ResultsPiB-PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG-PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB-PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non-Alzheimer's pathophysiology” represented 15% of the group.DiscussionPiB-PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG-PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non-Alzheimer's pathophysiology most commonly had primary age-related tauopathy.     

Autopsy consent,brain collection,and standardized neuropathologic assessment of ADNI participants: The essential role of the Neuropathology Core

BackgroundOur objectives are to facilitate autopsy consent, brain collection, and perform standardized neuropathologic assessments of all Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who come to autopsy at the 58 ADNI sites in the USA and Canada.MethodsBuilding on the expertise and resources of the existing Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, MO, a Neuropathology Core (NPC) to serve ADNI was established with one new highly motivated research coordinator. The ADNI-NPC coordinator provides training materials and protocols to assist clinicians at ADNI sites in obtaining voluntary consent for brain autopsy in ADNI participants. Secondly, the ADNI-NPC maintains a central laboratory to provide uniform neuropathologic assessments using the operational criteria for the classification of AD and other pathologies defined by the National Alzheimer Coordinating Center (NACC). Thirdly, the ADNI-NPC maintains a state-of-the-art brain bank of ADNI-derived brain tissue to promote biomarker and multi-disciplinary clinicopathologic studies.ResultsDuring the initial year of funding of the ADNI Neuropathology Core, there was notable improvement in the autopsy rate to 44.4%. In the most recent year of funding (September 1^st, 2008 to August 31^st 2009), our autopsy rate improved to 71.5%. Although the overall numbers to date are small, these data demonstrate that the Neuropathology Core has established the administrative organization with the participating sites to harvest brains from ADNI participants who come to autopsy.ConclusionsWithin two years of operation, the Neuropathology Core has: (1) implemented a protocol to solicit permission for brain autopsy in ADNI participants at all 58 sites who die and (2) to send appropriate brain tissue from the decedents to the Neuropathology Core for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI of the implementation of the NPC is very clear. Prior to the establishment of the NPC in September 2007, there were 6 deaths but no autopsies in ADNI participants. Subsequent to the establishment of the Core there have been 17 deaths of ADNI participants and 10 autopsies. Hence, the autopsy rate has gone from 0% to 59%. The third major accomplishment is the detection of co-existent pathologies with AD in the autopsied cases. It is possible that these co-morbidities may contribute to any variance in ADNI data.     

Quantification of blood flow-dependent component in estimates of beta-amyloid load obtained using quasi-steady-state standardized uptake value ratio

Longitudinal positron emission tomography (PET) imaging of beta-amyloid is used in basic research and in drug efficacy trials in Alzheimer''s disease (AD). However, the extent of amyloid accumulation after clinical onset is not fully known. Importantly, regional PET data are typically quantified using the standardized uptake value ratio (SUVR), which according to simulations is sensitive to changes in regional cerebral blood flow (rCBF). We aimed to better understand the potentials of longitudinal amyloid imaging by disentangling the influence of blood flow on SUVR using experimental data. [18F]AV-45 PET data from 101 subjects, ranging from cognitively normal to AD patients, in the Alzheimer''s Disease Neuroimaging Initiative were extracted. The relationship between global cortical distribution volume ratio, indicator of rCBF (R1), and SUVR was examined using multilinear regression. There was a significant effect of rCBF on SUVR. The effect increased by disease severity. Results suggest that changes in rCBF can produce apparent changes in SUVR in AD. Therefore, future longitudinal studies should measure amyloid changes in a way not sensitive to this effect, ideally using quantitative PET imaging. Furthermore, the results suggest no true accumulation beyond clinical onset and highlight the risks of longitudinal amyloid imaging in drug trials in AD.     

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer''s disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [¹⁸F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [¹⁸F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [¹⁸F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [¹⁸F]-T807 PET imaging revealed striatal and nigral [¹⁸F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [¹⁸F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [¹⁸F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [¹⁸F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [¹⁸F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [¹⁸F]-fluorodeoxyglucose, [¹⁸F]-Florbetapir and/or [¹⁸F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.     

The Alzheimer's Disease Neuroimaging Initiative: Progress report and future plans

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid β (Aβ) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of Aβ and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD.     

[18F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid β detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies

Molecular imaging techniques developed to ??visualize?? amyloid in vivo represent a major achievement in Alzheimer??s disease (AD) research. This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid ?? positron emission tomography (PET) imaging agent [¹⁸F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) and neuritic plaques and fibrillar amyloid ?? measured by pathologic staining of cortical region biopsy samples. Fifty-two patients with suspected normal pressure hydrocephalus underwent prospective (n?=?30) or retrospective (n?=?22) [¹⁸F]flutemetamol PET imaging for detection of cerebral cortical fibrillar amyloid ?? and cortical brain biopsy during intracranial pressure measurement or ventriculo-peritoneal shunting. [¹⁸F]Flutemetamol uptake was quantified using standardized uptake value ratio (SUVR) with cerebellar cortex as the reference region. Tissue fibrillar amyloid ?? was evaluated using immunohistochemical monoclonal antibody 4G8 and histochemical agents Thioflavin S and Bielschowsky silver stain, and an overall pathology result based on all available immunohistochemical and histochemical results. Biopsy site and contralateral [¹⁸F]flutemetamol SUVRs were significantly associated with neuritic plaque burden assessed with Bielschowsky silver stain (r _spearman??s?=?0.61, p?=?0.0001 for both), as was the composite SUVR with biopsy pathology (r _spearman??s?=?0.74, p?<?0.0001). SUVR and immunohistochemical results with 4G8 for detecting fibrillar amyloid ?? were similar. Blinded image evaluation showed strong agreement between readers (???=?0.86). Overall sensitivity and specificity by majority read were 93 and 100?%. Noninvasive in vivo [¹⁸F]flutemetamol PET imaging demonstrates strong concordance with histopathology for brain fibrillar amyloid ??, supporting its promise as a tool to assist physicians with earlier detection of the disease process and making diagnostic decisions about concomitant AD and other diseases associated with brain amyloidosis.     

Molecular imaging of dementia

Diagnosis and treatment strategies for dementia are based on the sensitive and specific detection of the incipient neuropathological characteristics, combined with emerging treatments that counteract molecular processes in its pathogenesis. Positron emission tomography (PET) is used for diverse clinical and basic studies on dementia with a wide range of radiotracers. Approaches to visualize amyloid deposition in human brains non‐invasively with PET depend on imaging agents reacting with amyloid fibrils. The most widely used tracer is [¹¹C]‐6‐OH‐BTA‐1, also known as Pittsburgh Compound‐B, which has a high affinity to amyloid β peptide (Aβ) aggregates. Some ¹⁸F‐labeled amyloid ligands with a longer radioactive half‐life have also been developed for broader clinical applications. In addition, there have been demonstrated advantages of tracers with high specific radioactivity in the sensitive detection of amyloid, which have indicated the significance of Aβ‐N3‐pyroglutamate as a new diagnostic and therapeutic target. Furthermore, beneficial outcomes of Aβ and tau immunization in humans and mouse models have highlighted crucial roles of immunocompetent glia in the protection of neurons against amyloid toxicities. The utility of PET with a radioligand for translocator protein as a biomarker for tau‐triggered toxicity, and as a complement to amyloid and tau imaging for diagnostic assessment of tauopathies with and without Aβ pathologies, has also been demonstrated. Meanwhile, brain cholinergic function can be estimated by measuring acetylcholinesterase activity in the brain with PET and radiolabeled acetylcholine analogues. It has been reported that patients with early Parkinson's disease exhibit a reduction in acetylcholinesterase activity in the cerebral cortex, and this decline is more profound in patients with Parkinson's disease with dementia and dementia with Lewy bodies than in patients with Parkinson's disease without dementia. The Alzheimer's Disease Neuroimaging Initiative was a multicentre research project conducted over 6 years that studied changes in cognition, brain structure, and biomarkers in healthy elderly controls and subjects with mild cognitive impairment and Alzheimer's disease. An international workgroup of the National Institute on Aging‐Alzheimer's Association has suggested that Alzheimer's disease would be optimally treated before significant cognitive impairment, defined as a ‘presymptomatic’ or ‘preclinical’ stage. Therefore, PET will be of technical importance for both clinical and basic research aimed at prodromal pathologies of Alzheimer's disease.     

Association of plasma and cortical amyloid beta is modulated by APOE ε4 status

BackgroundApolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([¹¹C]PiB PET) has not been assessed.MethodsNinety-six Alzheimer's Disease Neuroimaging Initiative participants with [¹¹C]PiB scans and plasma Aβ_1–40 and Aβ_1–42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [¹¹C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ_1–40, Aβ_1–42, and Aβ_1–40/Aβ_1–42 with [¹¹C]PiB uptake.ResultsIn APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ_1–40/Aβ_1–42 and [¹¹C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ_1–40/Aβ_1–42 improved the explained variance in [¹¹C]PiB binding compared with using APOE and plasma Aβ_1–40/Aβ_1–42 as separate terms.ConclusionsThe results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.     

The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [¹⁸F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.     

The effect of amyloid β on cognitive decline is modulated by neural integrity in cognitively normal elderly

ObjectiveAlzheimer's disease (AD) pathology of amyloid β (Aβ) accumulation and neurodegeneration may be relevant to preclinical cognitive decline. The objective of this study was to relate AD-sensitive biomarkers of Aβ and neurodegeneration and their interaction to longitudinal cognitive change in cognitively normal elderly.MethodsThirty-eight older people completed at least three consecutive neuropsychological examinations. Using positron emission tomography (PET), Aβ plaque burden was measured with [¹¹C]Pittsburgh compound B (PiB). PiB retention was dichotomized into a positive (n = 13) and negative (n = 25) PiB status. Neurodegenerative biomarkers were extracted within AD-vulnerable regions of interest (ROIs)—namely, the hippocampus and temporoparietal cortical areas. Within each ROI, metabolism was quantified with [¹⁸F] fluorodeoxyglucose (FDG) PET, and the gray matter structure was evaluated using volume (hippocampus) or thickness (cortical regions). ROI-specific functional and structural biomarkers were combined further into cross-modality neurodegenerative composite measures. Using hierarchical regression models, PiB and the neurodegenerative biomarkers were related to cognitive trajectories.ResultsPiB positivity was associated with memory and nonmemory worsening. The neurodegenerative biomarkers modified these relationships. Longitudinal cognitive decline was accelerated in those individuals who exhibited both PiB positivity and lower neurodegenerative biomarker scores, although the two measures appeared to be independent. PiB retention interacted predominantly with the cortical neurodegenerative composite for nonmemory change. Memory decline was best explained by the interaction between PiB and the hippocampal neurodegenerative composite, suggesting regional specificity of the neurodegenerative modulations.ConclusionsOur findings indicate that cognitive trajectories deteriorate at a faster rate in cognitively normal individuals expressing Aβ burden and neurodegeneration within specific AD-sensitive regions.     

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.     

Biological heterogeneity in ADNI amnestic mild cognitive impairment

BackgroundPrevious work examining normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) identified substantial biological heterogeneity. We hypothesized that ADNI mild cognitive impairment (MCI) subjects would also exhibit heterogeneity with possible clinical implications.MethodsADNI subjects diagnosed with amnestic MCI (n = 138) were clustered based on baseline magnetic resonance imaging, cerebrospinal fluid, and serum biomarkers. The clusters were compared with respect to longitudinal atrophy, cognitive trajectory, and time to conversion.ResultsFour clusters emerged with distinct biomarker patterns: The first cluster was biologically similar to normal controls and rarely converted to Alzheimer's disease (AD) during follow-up. The second cluster had characteristics of early Alzheimer's pathology. The third cluster showed the most severe atrophy but barely abnormal tau levels and a substantial proportion converted to clinical AD. The fourth cluster appeared to be pre-AD and nearly all converted to AD.ConclusionsSubjects with MCI who were clinically similar showed substantial heterogeneity in biomarkers.     

Data‐driven approaches for tau‐PET imaging biomarkers in Alzheimer's disease

Previous positron emission tomography (PET) studies have quantified filamentous tau pathology using regions‐of‐interest (ROIs) based on observations of the topographical distribution of neurofibrillary tangles in post‐mortem tissue. However, such approaches may not take full advantage of information contained in neuroimaging data. The present study employs an unsupervised data‐driven method to identify spatial patterns of tau‐PET distribution, and to compare these patterns to previously published “pathology‐driven” ROIs. Tau‐PET patterns were identified from a discovery sample comprised of 123 normal controls and patients with mild cognitive impairment or Alzheimer's disease (AD) dementia from the Swedish BioFINDER cohort, who underwent [¹⁸F]AV1451 PET scanning. Associations with cognition were tested in a separate sample of 90 individuals from ADNI. BioFINDER [¹⁸F]AV1451 images were entered into a robust voxelwise stable clustering algorithm, which resulted in five clusters. Mean [¹⁸F]AV1451 uptake in the data‐driven clusters, and in 35 previously published pathology‐driven ROIs, was extracted from ADNI [¹⁸F]AV1451 scans. We performed linear models comparing [¹⁸F]AV1451 signal across all 40 ROIs to tests of global cognition and episodic memory, adjusting for age, sex, and education. Two data‐driven ROIs consistently demonstrated the strongest or near‐strongest effect sizes across all cognitive tests. Inputting all regions plus demographics into a feature selection routine resulted in selection of two ROIs (one data‐driven, one pathology‐driven) and education, which together explained 28% of the variance of a global cognitive composite score. Our findings suggest that [¹⁸F]AV1451‐PET data naturally clusters into spatial patterns that are biologically meaningful and that may offer advantages as clinical tools.     

Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease

BackgroundIt is unknown which commonly used Alzheimer disease (AD) biomarker values—baseline or progression—best predict longitudinal cognitive decline.Methods526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values.ResultsAbout 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients.ConclusionsFor most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.     

Reference region automatic extraction in dynamic [11C]PIB

The positron emission tomography (PET) radiotracer [¹¹C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [¹¹C]PIB retention in familial Alzheimer''s disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [¹¹C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [¹¹C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [¹¹C]PIB studies.     

Unbiased comparison of sample size estimates from longitudinal structural measures in ADNI

Structural changes in neuroanatomical subregions can be measured using serial magnetic resonance imaging scans, and provide powerful biomarkers for detecting and monitoring Alzheimer's disease. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has made a large database of longitudinal scans available, with one of its primary goals being to explore the utility of structural change measures for assessing treatment effects in clinical trials of putative disease‐modifying therapies. Several ADNI‐funded research laboratories have calculated such measures from the ADNI database and made their results publicly available. Here, using sample size estimates, we present a comparative analysis of the overall results that come from the application of each laboratory's extensive processing stream to the ADNI database. Obtaining accurate measures of change requires correcting for potential bias due to the measurement methods themselves; and obtaining realistic sample size estimates for treatment response, based on longitudinal imaging measures from natural history studies such as ADNI, requires calibrating measured change in patient cohorts with respect to longitudinal anatomical changes inherent to normal aging. We present results showing that significant longitudinal change is present in healthy control subjects who test negative for amyloid‐β pathology. Therefore, sample size estimates as commonly reported from power calculations based on total structural change in patients, rather than change in patients relative to change in healthy controls, are likely to be unrealistically low for treatments targeting amyloid‐related pathology. Of all the measures publicly available in ADNI, thinning of the entorhinal cortex quantified with the Quarc methodology provides the most powerful change biomarker. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

[18F]THK-5351 PET Patterns in Patients With Alzheimer’s Disease and Negative Amyloid PET Findings

Background and PurposeAlzheimer’s disease (AD) does not always mean amyloid positivity. [¹⁸F]THK-5351 has been shown to be able to detect reactive astrogliosis as well as tau accompanied by neurodegenerative changes. We evaluated the [¹⁸F]THK-5351 retention patterns in positron-emission tomography (PET) and the clinical characteristics of patients clinically diagnosed with AD dementia who had negative amyloid PET findings.MethodsWe performed 3.0-T magnetic resonance imaging, [¹⁸F]THK-5351 PET, and amyloid PET in 164 patients with AD dementia. Amyloid PET was visually scored as positive or negative. [¹⁸F]THK-5351 PET were visually classified as having an intratemporal or extratemporal spread pattern.ResultsThe 164 patients included 23 (14.0%) who were amyloid-negative (age 74.9±8.3 years, mean±standard deviation; 9 males, 14 females). Amyloid-negative patients were older, had a higher prevalence of diabetes mellitus, and had better visuospatial and memory functions. The frequency of the apolipoprotein E ε4 allele was higher and the hippocampal volume was smaller in amyloid-positive patients. [¹⁸F]THK-5351 uptake patterns of the amyloid-negative patients were classified into intratemporal spread (n=10) and extratemporal spread (n=13). Neuropsychological test results did not differ significantly between these two groups. The standardized uptake value ratio of [¹⁸F]THK-5351 was higher in the extratemporal spread group (2.01±0.26 vs. 1.61±0.15, p=0.001). After 1 year, Mini Mental State Examination (MMSE) scores decreased significantly in the extratemporal spread group (-3.5±3.2, p=0.006) but not in the intratemporal spread group (-0.5±2.8, p=0.916). The diagnosis remained as AD (n=5, 50%) or changed to other diagnoses (n=5, 50%) in the intratemporal group, whereas it remained as AD (n=8, 61.5%) or changed to frontotemporal dementia (n=4, 30.8%) and other diagnoses (n=1, 7.7%) in the extratemporal spread group.ConclusionsApproximately 70% of the patients with amyloid-negative AD showed abnormal [¹⁸F]THK-5351 retention. MMSE scores deteriorated rapidly in the patients with an extratemporal spread pattern.     

In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings

Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1–42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([¹¹C]PIB). [¹¹C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimer's disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [¹¹C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients’ [¹¹C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [¹¹C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.