Publications by authors named "Christopher C Rowe"

261 Publications

PET Imaging of brain muscarinic receptors with F-Fluorobenzyl-Dexetimide: A first in human study.

Psychiatry Res Neuroimaging 2021 10 8;316:111354. Epub 2021 Aug 8.

Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia.

M1 and M4 muscarinic receptor (mAChR) agonists are under development for the treatment of schizophrenia, Alzheimer's and Parkinson's disease. We performed first-in-human PET imaging of mAChR with F-Fluorobenzyl-Dexetimide (FDEX) in 10 healthy participants (29.4±4.3yrs). Four underwent dynamic brain scanning for 240 min, and then six underwent static brain scans at 120 and 160-min post injection of 250 MBq of FDEX. Gjedde-Patlak graphical analysis was applied to determine the influx constant (Ki). Regional tissue ratios (SUVR) were calculated using the cerebellar cortex as the reference region. No adverse events were observed. The tracer showed good brain entry (∼4.2% ID at 5 min) but irreversible distribution kinetics over four hours in regions of high mAChR. Binding was consistent with the distribution of mAChR receptors with striatum > cortex > hippocampus >> thalamus >>> cerebellum with low variance in regional binding between subjects. Ki was 0.42±0.04 in the putamen, 0.27±0.01 in frontal cortex, 0.25±0.02 in the hippocampus and 0.10±0.01 in the thalamus. SUVR at 120 and 240 min. were highly correlated with these Ki values with R of 0.91 and 0.99 respectively. FDEX yields high quality brain images with uptake in the known distribution of mAChR with remarkably little variance between normal subjects.
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http://dx.doi.org/10.1016/j.pscychresns.2021.111354DOI Listing
October 2021

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

J Alzheimers Dis Rep 2021 3;5(1):443-468. Epub 2021 Jun 3.

The Florey Institute, The University of Melbourne, Parkville, VIC, Australia.

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019).

Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation.

Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations.

Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression.

Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.
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http://dx.doi.org/10.3233/ADR-210005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293663PMC
June 2021

Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults.

J Alzheimers Dis 2021 ;81(3):1039-1052

Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.

Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable.

Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years.

Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study.

Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs.

Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.
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http://dx.doi.org/10.3233/JAD-201243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293653PMC
September 2021

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.

Lancet Neurol 2021 06 29;20(6):484-496. Epub 2021 Apr 29.

Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, La Jolla, CA, USA; Alzheimer Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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http://dx.doi.org/10.1016/S1474-4422(21)00066-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339877PMC
June 2021

Does cognitive decline occur decades after moderate to severe traumatic brain injury? A prospective controlled study.

Neuropsychol Rehabil 2021 Apr 15:1-20. Epub 2021 Apr 15.

Monash-Epworth Rehabilitation Research Centre, Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia.

This prospective controlled study examined long-term trajectories of neuropsychological performance in individuals with traumatic brain injury (TBI) compared to healthy controls, and the impact of IQ, age at injury, time since injury, and injury severity on change over time. Fifty-three individuals with moderate to severe TBI (60.37% male; = 59.77 yrs, SD= 14.03), and 26 controls (46.15% male; = 63.96 yrs, SD= 14.42) were studied prospectively ( = 12.72 yrs between assessments). Participants completed measures of premorbid IQ (Weschler Test of Adult Reading), processing speed (Digit Symbol Coding Test), working memory (Digit Span Backwards), memory (Rey Auditory Verbal Learning Test) and executive function (Trail Making Test Part B; Hayling Errors), at a mean of 10.62 yrs (Initial) and 23.91 yrs (Follow-Up) post injury. Individuals with TBI did not show a significantly greater decline in neuropsychological performance over time compared with demographically similar controls. There was no association between change over time with IQ, time since injury or injury severity. Being older at injury had a greater adverse impact on executive function at follow-up. In this small sample, a single moderate to severe TBI was not associated with ongoing cognitive decline up to three decades post injury. Changes in cognitive function were similar between the groups and likely reflect healthy aging.
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http://dx.doi.org/10.1080/09602011.2021.1914674DOI Listing
April 2021

Is Associated with Amyloid-β and ε4-Related Cognitive Decline in Cognitively Normal Adults.

J Alzheimers Dis Rep 2021 Feb 24;5(1):111-120. Epub 2021 Feb 24.

Collaborative Genomics and Translation Group, Center for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.

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Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease.

Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults.

Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.

Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E 4 and rs11023139 in individuals with high amyloid-β burden. 4/rs11023139-A carriers declined significantly faster than 4/rs11023139-G_G carriers in measures of global cognition ( = 0.011) and verbal episodic memory ( = 0.020).

Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in 4 cognitively normal older adults with a high neocortical amyloid-β burden.
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http://dx.doi.org/10.3233/ADR-200246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990462PMC
February 2021

Early detection of amyloid load using F-florbetaben PET.

Alzheimers Res Ther 2021 03 27;13(1):67. Epub 2021 Mar 27.

Fundació ACE Institut Català de Neurociències Aplicades, Research Center and Memory Unit - Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition.

Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology.

Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology.

Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention.

Trial Registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
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http://dx.doi.org/10.1186/s13195-021-00807-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005243PMC
March 2021

Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition.

Horm Behav 2021 May 11;131:104966. Epub 2021 Mar 11.

Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, Western Australia, Australia; Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia; Cooperative Research Centre for Mental Health, Carlton, Victoria, Australia; Department of Biomedical Sciences, Faculty of Medicine and Health Science, Macquarie University, Sydney, New South Wales, Australia. Electronic address:

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.
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http://dx.doi.org/10.1016/j.yhbeh.2021.104966DOI Listing
May 2021

Relationship between amyloid and tau levels and its impact on tau spreading.

Eur J Nucl Med Mol Imaging 2021 07 26;48(7):2225-2232. Epub 2021 Jan 26.

Department of Molecular Imaging & Therapy, Austin Health, LVL1 Harrold STOKES Block, 145 Studley Road, Heidelberg, Melbourne, Victoria, 3084, Australia.

Purpose: Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear.

Methods: Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined.

Results: The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL.

Conclusion: Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.
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http://dx.doi.org/10.1007/s00259-021-05191-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175299PMC
July 2021

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

Neurology 2021 03 25;96(12):e1632-e1645. Epub 2021 Jan 25.

From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK; Departments of Neurology (J.P.C., K.A.J.) and Radiology (K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (H.C.C., J.M.R.), Keck School of Medicine of USC, Los Angeles, CA; Department of Psychiatry and Human Behavior (S.C., A.K.W.L., S.S.), Memory and Aging Program, Butler Hospital, Brown University Alpert Medical School, Providence, RI; Center for Neuroimaging, Department of Radiology and Imaging Science (M.R.F., A.J.S.), Department of Pathology and Laboratory Medicine (B.G.), and Indiana Alzheimers Disease Research Center (A.J.S.), Indiana University School of Medicine, Indianapolis; Departments of Molecular Imaging and Neurology (M.F.), Royal Prince Alfred Hospital, University of Sydney, Australia; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; German Center for Neurodegenerative Diseases (DZNE) (C.L., J.L., I.Y.); Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy (C.L.), University of Tübingen; Department of Neurology (J.L., I.Y.), Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (J.L., I.Y.), Germany; Florey Institute and The University of Melbourne (C.L.M.), Australia; Department of Neurology (J.M.N.), Columbia University Irving Medical Center, New York, NY; Department of Radiology (K.K., C.R.J., G.M.P.), Mayo Clinic, Rochester, MN; Department of Molecular Imaging and Therapy (C.C.R., V.L.V.), Austin Health, University of Melbourne, Heidelberg, Australia; Clinical Research Center for Dementia (H.S.), Osaka City University; Department of Neurology (M.S.), Hirosaki University Graduate School of Medicine; and Department of Neurology (K.S.), The University of Tokyo, Japan.

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).

Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
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http://dx.doi.org/10.1212/WNL.0000000000011542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032370PMC
March 2021

Advances in Brain Amyloid Imaging.

Semin Nucl Med 2021 May 19;51(3):241-252. Epub 2021 Jan 19.

Department of Molecular Imaging & Therapy, Austin Health, Victoria, Australia; The Australian Dementia Network (ADNeT), Melbourne, Australia; The University of Melbourne, Victoria, Australia. Electronic address:

Amyloid-β (Aβ) PET imaging has now been available for over 15 years. The ability to detect Aβ in vivo has greatly improved the clinical and research landscape of Alzheimer's disease (AD) and other neurodegenerative conditions. Aβ imaging provides very reliable, accurate, and reproducible measurements of regional and global Aβ burden in the brain. It has proved invaluable in anti-Aβ therapy trials, and is now recognized as a powerful diagnostic tool. The appropriate use of Aβ PET, when combined with comprehensive clinical evaluation by a dementia-trained specialist, can improve the accuracy of a clinical diagnosis of AD and substantially alter management. It can assist in differentiating AD from other neurodegenerative conditions, often by its ability to rule out the presence of Aβ. When combined with tau imaging, further increase in specificity for the diagnosis of AD can be achieved. The integration of Aβ PET, in conjunction with biomarkers of tau, neurodegeneration and neuroinflammation, into large, longitudinal, observational cohort studies continues to increase our understanding of the development of AD. Its incorporation into clinical trials has been pivotal in defining the most effective anti-Aβ biological therapies and optimal dosing so that effective disease modifying therapy now appears imminent. Aβ deposition is a gradual and protracted process, permitting a wide treatment window for anti-Aβ therapies and Aβ PET has made trials in this preclinical AD period feasible. Continuing improvement in Aβ tracer target to background ratio is allowing trials in earlier AD that tailor drug dosage to Aβ level. The quest to standardize quantification and define universally applicable thresholds for all Aβ tracers has produced the Centiloid method. Centiloid values that correlate well with neuropathologic findings and prognosis have been identified. Rapid cloud-based automated individual scan analysis is now possible and does not require MRI. Challenges remain, particularly around cross camera standardized uptake value ratio variation that need to be addressed. This review will compare available Aβ radiotracers, discuss approaches to quantification, as well as the clinical and research applications of Aβ PET.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.12.005DOI Listing
May 2021

Case Report: F-MK6240 Tau Positron Emission Tomography Pattern Resembling Chronic Traumatic Encephalopathy in a Retired Australian Rules Football Player.

Front Neurol 2020 22;11:598980. Epub 2020 Dec 22.

Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, VIC, Australia.

It remains unclear if tau imaging may assist diagnosis of chronic traumatic encephalopathy (CTE). Flortaucipir PET has shown superior frontal with medial temporal tau binding consistent with the provisional neuropathological criteria for mid-stage CTE in group-level analyses of retired symptomatic NFL players and in one individual with pathologically confirmed CTE. F-MK6240 is a new PET ligand that has high affinity for tau. We present the case of a 63-year-old cognitively impaired, former Australian rules football player with distinct superior frontal and medial temporal F-MK6240 binding and show it to be significantly different to the pattern seen in prodromal Alzheimer's disease (AD). The participant was recruited for a study of amyloid-β and tau several decades after traumatic brain injury. He had multiple concussions during his football career but no cognitive complaints at retirement. A thalamic stroke in his mid 50s left stable mild cognitive deficits but family members reported further short-term memory, behavioral, and personality decline preceding the study. Imaging showed extensive small vessel disease on MRI, a moderate burden of amyloid-β plaques, and F-MK6240 binding in bilateral superior frontal and medial temporal cortices. Voxel-wise analysis demonstrated that the frontally predominant pattern of the participant was significantly different to the posterior temporo-parietal predominant pattern of prodromal AD. Although lacking neuropathological examination to distinguish CTE from a variant of AD, the clear demonstration of a CTE-like tau pattern in a single at-risk individual suggests further research on the potential of F-MK6240 PET for identifying CTE is warranted.
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http://dx.doi.org/10.3389/fneur.2020.598980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783156PMC
December 2020

In vivo microstructural heterogeneity of white matter lesions in healthy elderly and Alzheimer's disease participants using tissue compositional analysis of diffusion MRI data.

Neuroimage Clin 2020 26;28:102479. Epub 2020 Oct 26.

Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.

White matter hyperintensities (WMH) are regions of high signal intensity typically identified on fluid attenuated inversion recovery (FLAIR). Although commonly observed in elderly individuals, they are more prevalent in Alzheimer's disease (AD) patients. Given that WMH appear relatively homogeneous on FLAIR, they are commonly partitioned into location- or distance-based classes when investigating their relevance to disease. Since pathology indicates that such lesions are often heterogeneous, probing their microstructure in vivo may provide greater insight than relying on such arbitrary classification schemes. In this study, we investigated WMH in vivo using an advanced diffusion MRI method known as single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), which models white matter microstructure while accounting for grey matter and CSF compartments. Diffusion MRI data and FLAIR images were obtained from AD (n = 48) and healthy elderly control (n = 94) subjects. WMH were automatically segmented, and classified: (1) as either periventricular or deep; or (2) into three distance-based contours from the ventricles. The 3-tissue profile of WMH enabled their characterisation in terms of white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our SS3T-CSD findings revealed substantial heterogeneity in the 3-tissue profile of WMH, both within lesions and across the various classes. Moreover, this heterogeneity information indicated that the use of different commonly used WMH classification schemes can result in different disease-based conclusions. We conclude that future studies of WMH in AD would benefit from inclusion of microstructural information when characterising lesions, which we demonstrate can be performed in vivo using SS3T-CSD.
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http://dx.doi.org/10.1016/j.nicl.2020.102479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652769PMC
June 2021

What Is T+? A Gordian Knot of Tracers, Thresholds, and Topographies.

J Nucl Med 2021 05 31;62(5):614-619. Epub 2020 Dec 31.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.
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http://dx.doi.org/10.2967/jnumed.120.245423DOI Listing
May 2021

Non-negative matrix factorisation improves Centiloid robustness in longitudinal studies.

Neuroimage 2021 02 26;226:117593. Epub 2020 Nov 26.

Department of Molecular Imaging & Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.

Background: Centiloid was introduced to harmonise β-Amyloid (Aβ) PET quantification across different tracers, scanners and analysis techniques. Unfortunately, Centiloid still suffers from some quantification disparities in longitudinal analysis when normalising data from different tracers or scanners. In this work, we aim to reduce this variability using a different analysis technique applied to the existing calibration data.

Method: All PET images from the Centiloid calibration dataset, along with 3762 PET images from the AIBL study were analysed using the recommended SPM pipeline. The PET images were SUVR normalised using the whole cerebellum. All SUVR normalised PiB images from the calibration dataset were decomposed using non-negative matrix factorisation (NMF). The NMF coefficients related to the first component were strongly correlated with global SUVR and were subsequently used as a surrogate for Aβ retention. For each tracer of the calibration dataset, the components of the NMF were computed in a way such that the coefficients of the first component would match those of the corresponding PiB. Given the strong correlations between the SUVR and the NMF coefficients on the calibration dataset, all PET images from AIBL were subsequently decomposed using the computed NMF, and their coefficients transformed into Centiloids.

Results: Using the AIBL data, the correlation between the standard Centiloid and the novel NMF-based Centiloid was high in each tracer. The NMF-based Centiloids showed a reduction of outliers, and improved longitudinal consistency. Furthermore, it removed the effects of switching tracers from the longitudinal variance of the Centiloid measure, when assessed using a linear mixed effects model.

Conclusion: We here propose a novel image driven method to perform the Centiloid quantification. The methods is highly correlated with standard Centiloids while improving the longitudinal reliability when switching tracers. Implementation of this method across multiple studies may lend to more robust and comparable data for future research.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049633PMC
February 2021

Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals.

Neurology 2021 02 12;96(5):e662-e670. Epub 2020 Nov 12.

From Austin Health (L.M.v.d.K., T.T., V.D., R.S.M., S.B., F.L., S.S., V.L.V., C.C.R.); CSIRO (S.C.B., V.D.), Melbourne; CSIRO (P.B., J.F., O.S.), Brisbane; The Florey Institute of Neuroscience and Mental Health (Y.Y.L., C.F., J.R., P.M., C.L.M.), Melbourne; University of Melbourne (T.T., D.A., C.L.M., V.L.V., C.C.R.); Edith Cowan University (S.M.L., S.R.R.-S., R.N.M.), Perth, Australia; and Washington University (S.S.), St. Louis, MO.

Objective: To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals.

Methods: All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline.

Results: Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3-7.6; < 0.05), for high was 7.0 (95% CI 3.7-13.3; < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, = 0.05), while the high and very high declined substantially (high -0.08 SD/year, < 0.001; very high -0.35 SD/year, < 0.001).

Conclusion: The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.
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http://dx.doi.org/10.1212/WNL.0000000000011222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884996PMC
February 2021

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.

Nat Commun 2020 11 10;11(1):5698. Epub 2020 Nov 10.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.
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http://dx.doi.org/10.1038/s41467-020-19473-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655942PMC
November 2020

Mesial temporal tau is related to worse cognitive performance and greater neocortical tau load in amyloid-β-negative cognitively normal individuals.

Neurobiol Aging 2021 01 1;97:41-48. Epub 2020 Oct 1.

Department of Molecular Imaging & Therapy, Austin Health, Melbourne, Victoria, Australia.

We examined whether mesial temporal (Me) tau relates to cognitive performance in 47 amyloid-β (Aβ)-negative, cognitively normal older adults (>60 years old). Me-tau was measured using [F]flortaucipir-positron emission tomography standardized uptake value ratio. The effect of continuous and categorical (stratified at standardized uptake value ratio = 1.2 [21% Me-positive]) Me-tau on cognition (mini-mental state examination, pre-Alzheimer's cognitive composite, a memory composite, and a nonmemory composite score) was examined using general linear models, and associations between Me-tau and [F]flortaucipir signal in the neocortex were assessed using voxelwise regressions (continuous) and voxelwise contrasts (categorical). In addition, we assessed the effect of age and Aβ burden on Me-tau. Both continuous and categorical Me-tau was associated with worse cognitive performance across all tests and with higher lateral temporal and parietal [F]flortaucipir signal. Furthermore, we observed a marginal association between Me-tau and age, whereas there was no association with Aβ burden. Our findings indicate that Me-tau in Aβ-negative cognitively normal individuals, which is likely age-related (i.e., primary age-related tauopathy), might not be as benign as commonly thought.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.017DOI Listing
January 2021

Reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism.

Sci Rep 2020 10 23;10(1):17631. Epub 2020 Oct 23.

Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.

Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson's disease (PD) (n = 20) participants underwent F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson's Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.
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http://dx.doi.org/10.1038/s41598-020-74495-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584593PMC
October 2020

Severe Obstructive Sleep Apnea Is Associated with Higher Brain Amyloid Burden: A Preliminary PET Imaging Study.

J Alzheimers Dis 2020 ;78(2):611-617

Institute for Breathing and Sleep, Austin Health, Heidelberg, Australia.

Background: Obstructive sleep apnea (OSA) has been linked to an increase risk of dementia. Few studies have cross-sectionally examined whether clinically-confirmed OSA is associated with a higher brain amyloid burden.

Objective: The aim of this study was to compare brain amyloid burden in individuals with untreated OSA and healthy controls, and explore associations between amyloid burden and polysomnographic and subjective measures of sleep, demographics, and mood.

Methods: Thirty-four individuals with OSA (mean age 57.5±4.1 y; 19 males) and 12 controls (mean age 58.5±4.2 y; 6 males) underwent a clinical polysomnogram and a 11C-PiB positron emission tomography (PET) scan to quantify amyloid burden.

Results: Amyloid burden was elevated in the OSA group relative to controls, and was significantly higher in those with severe OSA relative to mild/moderate OSA. Correlation analyses indicated that higher amyloid burden was associated with a higher Non-REM apnea hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep, when controlling for age.

Conclusion: Severe OSA is associated with a modest elevation of brain amyloid, the significance of which should be further investigated to explore the implications for dementia risk.
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http://dx.doi.org/10.3233/JAD-200571DOI Listing
May 2021

Longitudinal exploration of cancer-related cognitive impairment in patients with newly diagnosed aggressive lymphoma: protocol for a feasibility study.

BMJ Open 2020 09 29;10(9):e038312. Epub 2020 Sep 29.

Cancer Nursing Research Group, Department of Nursing/Centre for Cancer Research, School of Health Sciences/University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.

Introduction: Cancer-related cognitive impairment (CRCI) is a distressing and disabling side-effect of cancer treatments affecting up to 75% of patients. For some patients, their cognitive impairment may be transient, but for a subgroup, these symptoms can be long-standing and have a major impact on the quality of life. This paper describes the protocol for a study: (1) to assess the feasibility of collecting longitudinal data on cognition via self-report, neuropsychological testing, peripheral markers of inflammation and neuroimaging and (2) to explore and describe patterns of cancer-related cognitive impairment over the course of treatment and recovery in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent.

Methods And Analysis: This is a prospective, longitudinal, feasibility study in which 30 newly diagnosed, treatment-naive patients with aggressive lymphoma will be recruited over a 12-month period. Patients will complete comprehensive assessments at three time points: baseline (time 1, pre-treatment) and two post-baseline follow-up assessments (time 2, mid-treatment and time 3, 6-8 weeks post-treatment completion). All patients will be assessed for self-reported cognitive difficulties and objective cognitive function using Stroop Colour and Word, Trail Making Test Part A and B, Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association and Digit Span. Blood cell-based inflammatory markers and neuroimaging including a positron emission tomography (PET) with F-labelled fluoro-2-deoxyglucose (F-FDG) and CT (F-FDG-PET/CT) and a MRI will explore potential inflammatory and neuroanatomical or functional mechanisms and biomarkers related to CRCI. The primary intent of analysis will be to assess the feasibility of collecting longitudinal data on cognition using subjective reports and objective tasks from patients during treatment and recovery for lymphoma. These data will inform the design of a larger-scale investigation into the patterns of cognitive change over the course of treatment and recovery, adding to an underexplored area of cancer survivorship research.

Ethics And Dissemination: Ethical approval has been granted by Austin Health Human Rights Ethics Committee (HREC) in Victoria Australia. Peer reviewed publications and conference presentations will report the findings of this novel study.

Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12619001649101).
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http://dx.doi.org/10.1136/bmjopen-2020-038312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526311PMC
September 2020

Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging.

J Alzheimers Dis 2020 ;78(1):321-334

The Australian e-Health Research Centre, CSIRO Health and Biosecurity, Brisbane, QLD, Australia.

Background: Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis.

Objective: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association.

Methods: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+.

Results: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age.

Conclusion: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.
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http://dx.doi.org/10.3233/JAD-200419DOI Listing
September 2021

Plasma Amyloid-β Biomarker Associated with Cognitive Decline in Preclinical Alzheimer's Disease.

J Alzheimers Dis 2020 ;77(3):1057-1065

Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

Background: Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear.

Objective: We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts.

Methods: Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry.

Results: Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures.

Conclusion: Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals.
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http://dx.doi.org/10.3233/JAD-200475DOI Listing
September 2021

The protocol of a clinical quality registry for dementia and mild cognitive impairment (MCI): the Australian dementia network (ADNeT) Registry.

BMC Geriatr 2020 09 7;20(1):330. Epub 2020 Sep 7.

School of Public Health and Preventive Medicine, Monash University, Level 3, 553 St Kilda Rd, Melbourne, Victoria, 3004, Australia.

Background: Dementia was identified as a priority area for the development of a Clinical Quality Registry (CQR) in Australia in 2016. The Australian Dementia Network (ADNeT) Registry is being established as part of the ADNeT initiative, with the primary objective of collecting data to monitor and enhance the quality of care and patient outcomes for people diagnosed with either dementia or Mild Cognitive Impairment (MCI). A secondary aim is to facilitate the recruitment of participants into dementia research and trials. This paper describes the Registry protocol.

Methods: The ADNeT Registry is a prospective CQR of patients newly diagnosed with either dementia or MCI. Eligible patients will be identified initially from memory clinics and individual medical specialists (e.g., geriatricians, psychiatrists and neurologists) involved in the diagnosis of dementia. Participants will be recruited using either an opt-out approach or waiver of consent based on three key determinants (capacity, person responsible, and communication of diagnosis). Data will be collected from four sources: participating sites, registry participants, carers, and linkage with administrative datasets. It is anticipated that the Registry will recruit approximately 10,000 participants by the end of 2023. The ADNeT registry will be developed and implemented to comply with the national operating principles for CQRs and governed by the ADNeT Registry Steering Committee.

Discussion: The ADNeT Registry will provide important data on current clinical practice in the diagnosis, treatment and care of people with dementia and MCI in Australia as well as long-term outcomes among these people. These data will help to identify variations in clinical practice and patient outcomes and reasons underlying these variations, which in turn, will inform the development of interventions to improve care and outcomes for people with dementia and MCI.
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http://dx.doi.org/10.1186/s12877-020-01741-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487842PMC
September 2020

Evaluation of GammaH2AX in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer's Disease in the AIBL Study of Ageing.

Life (Basel) 2020 Aug 6;10(8). Epub 2020 Aug 6.

CSIRO Health and Biosecurity, Molecular Diagnostic Solutions, Adelaide SA5005, Australia.

In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer's disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in -trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 ( = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD.
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http://dx.doi.org/10.3390/life10080141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459751PMC
August 2020

Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition.

Neurobiol Aging 2020 11 10;95:46-55. Epub 2020 Jun 10.

Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5-77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6-70.3); however, noncarriers reached the threshold later at age 78 (76.1-84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609543PMC
November 2020

Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance.

J Alzheimers Dis 2020 ;77(2):733-744

School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia.

Background: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL.

Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition.

Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests.

Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels.

Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.
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http://dx.doi.org/10.3233/JAD-200291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592676PMC
September 2021

Human biodistribution and internal dosimetry of 4-[ F]fluorobenzyl-dexetimide: a PET radiopharmaceutical for imaging muscarinic acetylcholine receptors in the brain and heart.

EJNMMI Res 2020 Jun 12;10(1):61. Epub 2020 Jun 12.

Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Australia.

Background: 4-[F] fluorobenzyl dexetimide (F-DEX) is the first non-subtype selective fluorine-18 labelled tracer for muscarinic receptors (mAChR) used in humans. A recent first-in-human study found high regional brain uptake with low variation in normal subjects. Disturbance of mAChR has been reported in Alzheimer's and Parkinson's disease, schizophrenia and depression and various cardiac diseases. The following work assesses the biodistribution, organ tracer kinetics and radiation dose associated with F-DEX.

Method: Dose calculations were based on activity uptake derived from multiple time point whole body PET CT imaging and the organ-specific dosimetric S-factors derived from the ICRP 133 standard man and woman mathematical phantoms. Effective doses were calculated using the latest ICRP tissue weighting factors.

Results: Serial images and time activity curves demonstrate high brain and left ventricular myocardial uptake (5% and 0.65% of injected activity, respectively) with greater retention in brain than myocardium. The mean effective dose was in concordance with other F labelled tracers at 19.70 ± 2.27 μSv/MBq. The largest absorbed doses were in the liver (52.91 ± 1.46 μGy/MBq) and heart wall (43.94 ± 12.88 μGy/MBq) for standard man and the liver (61.66 ± 13.61 μGy/MBq) and lungs (40.93 ± 3.11 μGy/MBq) for standard woman. The absorbed dose to all organs, most notably, the red bone marrow (20.03 ± 2.89 μGy/MBq) was sufficiently low to ensure no toxicity after numerous follow-up procedures.

Conclusions: The radiation dose associated with an administration of F-DEX is comparable to that of other F labelled tracers such as FDG (19.0 μSv/MBq) and lower than tracers used for SPECT imaging of muscarinic receptors (I-DEX 28.5 μSv/MBq). Clinical use would likely result in an effective dose less than 4 mSv for the ICRP 133 standard phantoms after dose optimisation allowing justification for numerous follow-up procedures. Recent results from first in-human studies and a comparatively low radiation dose make F-DEX an attractive option for future applications of imaging muscarinic receptors in the brain. Further investigation of the potential of F-DEX for imaging parasympathetic innervation of the heart may be warranted.
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http://dx.doi.org/10.1186/s13550-020-00641-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292855PMC
June 2020

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.

Neurobiol Dis 2020 08 6;142:104960. Epub 2020 Jun 6.

The Florey Institute, University of Melbourne, Parkville, VIC, Australia.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.nbd.2020.104960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363568PMC
August 2020

Relationships Between Plasma Lipids Species, Gender, Risk Factors, and Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(1):303-315

School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, WA, Australia.

Background: Lipid metabolism is altered in Alzheimer's disease (AD); however, the relationship between AD risk factors (age, APOEɛ4, and gender) and lipid metabolism is not well defined.

Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals.

Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species.

Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOEɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOEɛ4 may, in part, be mediated by changes in lipid metabolism.

Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.
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http://dx.doi.org/10.3233/JAD-191304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369125PMC
May 2021
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