Medicine (Austin & Northern Health) - Research Publications
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ItemAβ Imaging: feasible, pertinent, and vital to progress in Alzheimer's disease(SPRINGER, 2012-02)
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ItemClinical Profile of PiB-Positive Corticobasal Syndrome(PUBLIC LIBRARY SCIENCE, 2013-04-05)BACKGROUND: Corticobasal syndrome (CBS) is a multifaceted neurodegenerative disorder characterized by a combination of motor and cognitive deficits. Several different pathological entities, including Alzheimer's pathology, have been described in association with CBS. The present study aimed to establish clinical, neuropsychological, and neuroimaging features that could be useful in the distinction of CBS due to AD pathology from other CBS cases in life based on [(11)C] Pittsburgh Compound B positron emission tomography (PiB-PET) status. METHODS: Patients with CBS were prospectively recruited from a specialized cognitive disorders clinic. All patients underwent detailed clinical and neuropsychological assessment, with structural imaging using voxel-based analysis of magnetic resonance imaging. Alzheimer's pathology was detected using PiB-PET imaging, and PiB-positive and PiB-negative groups were compared. RESULTS: Fourteen CBS patients meeting defined criteria were included (7 male, 7 female; mean age 66.1+/-6.9 years; median symptom duration was 35.5+/-22.6 months) and compared to 20 matched control subjects. Of the 14 patients, 4 were PiB-positive and 10 PiB-negative. There were no significant differences between PiB-positive and PiB-negative CBS patients in age, gender, education, symptom duration, or motor features. PiB-positive patients had greater visuospatial deficits, a higher rate of sentence repetition impairment, and more functional decline. Voxel-based morphometry analyses demonstrated extensive peri-insular and post-central atrophy in both groups, but PiB-positive patients had atrophy that extended to include the posterior part of the left superior temporal gyrus. CONCLUSIONS: Visuospatial function, aspects of language, and the pattern of cerebral atrophy may be useful in distinguishing patients with CBS due to underlying AD pathology.
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ItemImago Mundi, Imago AD, Imago ADNI(BMC, 2014)Since the launch in 2003 of the Alzheimer's Disease Neuroimaging Initiative (ADNI) in the USA, ever growing, similarly oriented consortia have been organized and assembled around the world. The various accomplishments of ADNI have contributed substantially to a better understanding of the underlying physiopathology of aging and Alzheimer's disease (AD). These accomplishments are basically predicated in the trinity of multimodality, standardization and sharing. This multimodality approach can now better identify those subjects with AD-specific traits that are more likely to present cognitive decline in the near future and that might represent the best candidates for smaller but more efficient therapeutic trials - trials that, through gained and shared knowledge, can be more focused on a specific target or a specific stage of the disease process. In summary, data generated from ADNI have helped elucidate some of the pathophysiological mechanisms underpinning aging and AD pathology, while contributing to the international effort in setting the groundwork for biomarker discovery and establishing standards for early diagnosis of AD.
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ItemAtrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials(PUBLIC LIBRARY SCIENCE, 2013-03-15)There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ~1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ~18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195-1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.
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ItemIn vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106(SPRINGER, 2013)BACKGROUND: The activation of microglia, in general, and the upregulation of the translocator protein (18 kDa) (TSPO) system, in particular, are key features of neuroinflammation, of which the in vivo visualization and quantitative assessment are still challenging due to the lack of appropriate molecular imaging biomarkers. Recent positron emission tomography (PET) studies using TSPO radioligands such as [11C]PK11195 and [11C]PBR28 have indicated the usefulness of these PET biomarkers in patients with neuroinflammatory diseases, including multiple sclerosis (MS). [18F]FEDAA1106 is a recently developed PET radioligand for the in vivo quantification of TSPO. In the present study, we aimed at investigating the diagnostic usefulness of [18F]FEDAA1106 in patients with MS. METHODS: Nine patients (three on the interferon beta therapy and six without immunomodulatory therapy; seven females/two males; age 34.2 ± 9.1 years old) with relapsing-remitting MS in acute relapse and with gadolinium (Gd)-enhancing lesion(s) in the magnetic resonance imaging (MRI) scans and five healthy controls (four females/one male, age 38.0 ± 9.7 years old) were investigated in this study. Genetic information about the TSPO binding could not be obtained because knowledge about the importance of genetic background for TSPO binding was not available at the time the study was performed. Dynamic PET measurements were performed using an ECAT EXACT HR system (CTI/Siemens, Knoxville, TN, USA) for a total of 150 min, with a 30-min break after the injection of 153.4 ± 10.2 MBq of [18F]FEDAA1106. Metabolite-corrected arterial plasma samples were used to calculate the input function. PET data were analyzed in the following ways: (1) region-of-interest analysis for cortical and subcortical regions was performed using a two-tissue compartment kinetic model in order to estimate binding potentials (BPND) and distribution volume (VT), (2) the feasibility of the estimation of BPND and VT was investigated for MS lesions, and (3) VT parametric images by a Logan plot and standard uptake value (SUV) images were visually compared with the corresponding MRI, focusing on MRI-identified MS lesions. RESULTS: There were no significant differences in the BPND or VT values between patients with MS and healthy controls. Robust BPND and VT values could not be obtained for most MS lesions due to noisy time-activity curves. Visual inspection of VT and SUV images in all nine patients did not reveal high uptake of the radioligand inside and beyond MRI-identified active MS lesions with the exception of one Gd-enhanced MS lesion in the whole patient population. CONCLUSIONS: In our study, [18F]FEDAA1106 as a PET radioligand could neither differentiate patients with MS from healthy controls nor detect active plaques in the brain of MS patients. Stratification with respect to genetics and binder status might help to uncover the differences between the groups, which could not be detected here. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01031199.
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ItemThe hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease(ROCKEFELLER UNIV PRESS, 2012-04-09)Parkinson's disease (PD) is a progressive, chronic disease characterized by dyskinesia, rigidity, instability, and tremors. The disease is defined by the presence of Lewy bodies, which primarily consist of aggregated α-synuclein protein, and is accompanied by the loss of monoaminergic neurons. Current therapeutic strategies only give symptomatic relief of motor impairment and do not address the underlying neurodegeneration. Hence, we have identified Cu(II)(atsm) as a potential therapeutic for PD. Drug administration to four different animal models of PD resulted in improved motor and cognition function, rescued nigral cell loss, and improved dopamine metabolism. In vitro, this compound is able to inhibit the effects of peroxynitrite-driven toxicity, including the formation of nitrated α-synuclein oligomers. Our results show that Cu(II)(atsm) is effective in reversing parkinsonian defects in animal models and has the potential to be a successful treatment of PD.
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ItemInfluence of BDNF Val66Met on the relationship between physical activity and brain volume(LIPPINCOTT WILLIAMS & WILKINS, 2014-10-07)OBJECTIVE: To investigate the association between habitual physical activity levels and brain temporal lobe volumes, and the interaction with the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism. METHODS: This study is a cross-sectional analysis of 114 cognitively healthy men and women aged 60 years and older. Brain volumes quantified by MRI were correlated with self-reported physical activity levels. The effect of the interaction between physical activity and the BDNF Val66Met polymorphism on brain structure volumes was assessed. Post hoc analyses were completed to evaluate the influence of the APOE ε4 allele on any found associations. RESULTS: The BDNF Val66Met polymorphism interacted with physical activity to be associated with hippocampal (β = -0.22, p = 0.02) and temporal lobe (β = -0.28, p = 0.003) volumes. In Val/Val homozygotes, higher levels of physical activity were associated with larger hippocampal and temporal lobe volumes, whereas in Met carriers, higher levels of physical activity were associated with smaller temporal lobe volume. CONCLUSION: The findings from this study support higher physical activity levels in the potential attenuation of age- and disease-related hippocampal and temporal lobe volume loss in Val/Val homozygotes.
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ItemAnti-Aβ antibody target engagement: a response to Siemers et al.(SPRINGER, 2014-10)
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ItemIn vivo evaluation of a novel tau imaging tracer for Alzheimer's disease(SPRINGER, 2014-05)PURPOSE: Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate (18)F-THK523 as a potential tau imaging tracer. METHODS: Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics. RESULTS: (18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical (18)F-THK523 retention did not correlate with Aβ distribution as assessed by (11)C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy. CONCLUSION: (18)F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.
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ItemDo current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target?(SPRINGER, 2014-06)Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.