Tau, ß-Amyloid, and Glucose Metabolism Following Service-Related Traumatic Brain Injury in Vietnam War Veterans: The Australian Imaging Biomarkers and Lifestyle Study of Aging-Veterans Study (AIBL-VETS).

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, ß-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent ß-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. ß-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in ß-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The ß-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases.

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aß). 18F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aß, but positive tau positron emission tomography (PET) findings. Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aß (18F-NAV4694) and tau (18F-MK6240) PET scans were included. Centiloid <25 defined negative Aß PET (Aß-). The presence of neocortical tau was defined quantitatively and visually. Results: Aß- PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2, and MAPT genes did not identify relevant functional mutations. Discussion: Discordant cases were infrequent (1.4% of all Aß- participants). In these cases, the Aß PET ligand may not be detecting the Aß that is present.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-ß positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

Mesial temporal tau in amyloid-ß-negative cognitively normal older persons.

BACKGROUND: Tau deposition in the mesial temporal lobe (MTL) in the absence of amyloid-ß (Aß-) occurs with aging. The tau PET tracer 18F-MK6240 has low non-specific background binding so is well suited to exploration of early-stage tau deposition. The aim of this study was to investigate the associations between MTL tau, age, hippocampal volume (HV), cognition, and neocortical tau in Aß- cognitively unimpaired (CU) individuals. METHODS: One hundred and ninety-nine Aß- participants (Centiloid < 25) who were CU underwent 18F-MK6240 PET at age 75 ± 5.2 years. Tau standardized uptake value ratio (SUVR) was estimated in mesial temporal (Me), temporoparietal (Te), and rest of the neocortex (R) regions and four Me sub-regions. Tau SUVR were analyzed as continuous variables and compared between high and low MTL SUVR groups. RESULTS: In this cohort with a stable clinical classification of CU for a mean of 5.3 years prior to and at the time of tau PET, MTL tau was visually observed in 9% of the participants and was limited to Braak stages I-II. MTL tau was correlated with age (r = 0.24, p < 0.001). Age contributed to the variance in cognitive scores but MTL tau did not. MTL tau was not greater with subjective memory complaint, nor was there a correlation between MTL tau and Aß Centiloid value, but high tau was associated with smaller HV. Participants with MTL tau had higher tau SUVR in the neocortex but this was driven by the cerebellar reference region and was not present when using white matter normalization. CONCLUSIONS: In an Aß- CU cohort, tau tracer binding in the mesial temporal lobe was age-related and associated with smaller hippocampi, but not with subjective or objective cognitive impairment.

The role of artificial photo backgrounds of shelter dogs on pet profile clicking and the perception of sociability.

With the increasing prevalence of technology, the internet is often the first step for potential pet owners searching for an adoptable dog. However, best practices for the online portrayal of shelter and foster dogs remain unclear. Different online photo backgrounds appearing on adoption websites for shelter dogs may impact adoption speed by influencing viewer interest. Online clicking behaviour on pet profiles and human-directed sociability, broadly defined, has been previously linked to increased adoption likelihood. Therefore, the objective of this study was to determine the relationship between photo backgrounds of shelter dogs and online clicking as well as perceived human-directed sociability. In a virtual experiment, 680 participants were asked to rank the sociability and friendliness of four different adoptable dogs on a scale from 0-10. The photo background of each dog was digitally altered and randomly assigned to four experimental background conditions: 1) outdoor, 2) home indoor, 3) in-kennel, and 4) plain coloured. As a proxy for adoption interest, a link to the dog's adoption profile was presented on each slide and the clicking behaviour of participants on this link was recorded. Mixed logistic regression and Poisson models revealed that background did not affect participants' link-clicking behaviour (chisq = 3.55, df = 3, p = .314) nor perceptions of sociability (statistic = 6.19, df = 3, p = .103). Across all backgrounds, only 4.74% of presented slides culminated in participant link-clicking. Sociability scores also did not predict link clicking. Assessment of participant-related factors and dog ID revealed that link-clicking and sociability scores of photographs were influenced by differences between dogs themselves and unaffected by participants' awareness of study hypotheses. We conclude that artificial background types did not affect participant responses. The results demonstrate the importance of empirical data in making marketing decisions in animal shelters. Understanding which aspects of online marketing materials impact viewer interest will provide guidance for both animal shelter personnel and foster families to improve the speed of adoption of the animals in their care.

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI.

To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-ß in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.

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.

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 Aß-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.

Acute haemorrhagic leukoencephalitis (Hurst disease) in severe COVID- 19 infection.

Coronavirus Disease 2019 (COVID-19) is well documented as a cause of respiratory tract infection. Increasingly, multi-systemic effects, including COVID-19-related neurologic features, are being reported. Here we report, what we believe to be, the first reported case of acute haemorrhagic leukoencephalitis (AHLE) with presence of oligoclonal bands in the cerebrospinal fluid. AHLE is a rare fulminant demyelinating disease, associated with severe COVID-19 infection.

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

OBJECTIVE: To determine the effect of ß-amyloid (Aß) 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 Aß PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aß positive; follow-up 5.3 ± 1.7 years). Aß 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: Aß 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 Aß, the hazard ratio for progression for moderate Aß was 3.2 (95% confidence interval [CI] 1.3-7.6; p < 0.05), for high was 7.0 (95% CI 3.7-13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p = 0.05), while the high and very high declined substantially (high -0.08 SD/year, p < 0.001; very high -0.35 SD/year, p < 0.001). CONCLUSION: The risk of MCI or dementia over 5 years in older CN is related to Aß 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.

Case Report: 18F-MK6240 Tau Positron Emission Tomography Pattern Resembling Chronic Traumatic Encephalopathy in a Retired Australian Rules Football Player.

Introduction: 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. 18F-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 18F-MK6240 binding and show it to be significantly different to the pattern seen in prodromal Alzheimer's disease (AD). Findings: The participant was recruited for a study of amyloid-ß 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-ß plaques, and 18F-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. Conclusion: 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 18F-MK6240 PET for identifying CTE is warranted.

Amyloid-ß, Tau, and 18F-Fluorodeoxyglucose Positron Emission Tomography in Posttraumatic Stress Disorder.

BACKGROUND: Epidemiological studies suggest a relationship between posttraumatic stress disorder (PTSD) and dementia. OBJECTIVE: This study assessed whether Alzheimer's disease (AD) imaging biomarkers were elevated in Vietnam veterans with PTSD. METHODS: The study compared cognition, amyloid-ß, tau, regional brain metabolism and volumes, and the effect of APOE in 83 veterans with and without PTSD defined by the Clinician-Administered PTSD Scale. RESULTS: The PTSD group had significantly lower education, predicted premorbid IQ, total intracranial volume, and Montreal Cognitive Assessment score compared with the controls. There was no difference between the two groups in the imaging or genetic biomarkers for AD. CONCLUSION: Our findings do not support an association between AD pathology and PTSD of up to 50 years duration. Measures to assess cognitive reserve, a factor that may delay the onset of dementia, were lower in the PTSD group compared with the controls and this may account for the previously observed higher incidence of dementia with PTSD.

Risk of Alzheimer's Disease in Obstructive Sleep Apnea Syndrome: Amyloid-ß and Tau Imaging.

BACKGROUND: An association between obstructive sleep apnea (OSA) and Alzheimer's disease has been suggested but little is known about amyloid-ß and tau deposition in this syndrome. OBJECTIVE: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. METHODS: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18F-florbetaben and 18F-AV1451, to quantify amyloid and tau burden. RESULTS: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p = 0.04). There were more apolipoprotein E ɛ4 allele (APOE ɛ4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18F-AV1451 uptake between the two groups. CONCLUSIONS: Obstructive sleep apnea is associated with Alzheimer's disease pathology, but this relationship is moderated by APOE ɛ4 and BMI.

Aß imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study.

BACKGROUND: We assessed the clinical utility of ß-amyloid (Aß) imaging with (18)F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to Alzheimer's disease (AD), comparing semiquantitative with visual scan assessment, and exploring the relationships among Aß, hippocampal volume (HV) and memory over time. METHODS: 45 MCI underwent FBB positron emission tomography, MRI and neuropsychological assessment at baseline and 2 years and clinical follow-up at 4 years. Positive FBB (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥ 1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) Z-score of <-1.5. RESULTS: At baseline, 24 (53%) MCI were FBB+. Majority reads agreed with SUVR classification (κ 0.96). In 2 years, 18 (75%) FBB+ progressed to AD compared with 2 (9.5%) FBB-, yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB- developed non-AD dementia. Predictive accuracies of HV (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By 4 years, 21 (87.5%) FBB+ had AD whereas 5 (24%) FBB- had non-AD dementia yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over 2 years, the association between EM and HV became stronger. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB-. CONCLUSIONS: (18)F-florbetaben Aß imaging facilitates accurate detection of prodromal AD. As neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy and not Aß, seems to drive memory decline. TRIAL REGISTRATION NUMBER: NCT01138111.

Predictors of subjective cognitive complaint in postacute older adult stroke patients.

OBJECTIVE: To investigate the impact of objective cognitive impairment, negative affect, and fatigue on cognitive complaint in a postacute (mean=6.64±1.32mo) sample of patients with ischemic stroke. DESIGN: Cross-sectional study. SETTING: Specialized stroke units at major metropolitan hospitals. PARTICIPANTS: Patients with first-ever ischemic stroke (N=25) aged between 50 and 85 years with relatively good neurologic recovery (National Institutes of Health Stroke Scale score ≤7) during the postacute period. Participants were excluded from the study if there was a documented history of psychiatric illness, neurologic disease, dementia, or a moderate or severe aphasia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Cognitive complaint as measured by the A-B Neuropsychological Assessment Schedule. RESULTS: Ninety percent of the patients reported some level of cognitive difficulty in everyday life. Fatigue, cognitive slowing, memory difficulties, and poor concentration were the most frequently reported complaints. More than half of all participants had significant impairment in at least 1 cognitive domain after their stroke. A standard multiple regression was performed to evaluate the relative impact of negative affect, fatigue, and objective cognitive functioning on subjective cognitive complaint. This model accounted for 61% of the variance in total subjective cognitive complaint (R=.78, F3,21=10.96, P<.001), with depression being the only variable to make a significant independent contribution to the prediction of subjective cognitive complaint. CONCLUSIONS: Cognitive complaints are reported by almost all patients after a stroke. Although 50% of the participants had objective evidence of a cognitive impairment, neither objective cognitive impairment nor fatigue predicted cognitive complaint independently of negative affect. Clinicians who receive reports of cognitive complaints in the postacute period after stroke should be alert to the possibility of psychological distress in their patient.

(18)F-florbetaben Aß imaging in mild cognitive impairment.

INTRODUCTION: (18)F-florbetaben and positron emission tomography were used to examine the relationships between ß-amyloid (Aß) deposition, cognition, hippocampal volume, and white matter hyperintensities in mild cognitive impairment (MCI). METHODS: Forty-five MCI participants were evaluated. A neocortical standardized uptake value ratio threshold ≥ 1.45 was used to discriminate high from low Aß burden. Correlations were adjusted for age, gender and years of education. RESULTS: High Aß burden was found in 53% of MCI. Regression analyses showed standardized uptake value ratio (r = -0.51, P = 0.0015) and hippocampal volume (r = 0.60, P = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with nonmemory cognition, and this correlation was particularly associated with Aß burden. CONCLUSION: Higher Aß deposition in MCI is associated with more severe memory impairment and is contributing to early amnestic symptoms independent of hippocampal atrophy.

Prediction of amyloid-ß pathology in amnestic mild cognitive impairment with neuropsychological tests.

Assessment of disease biomarkers, particularly the in vivo assessment of amyloid-ß (Aß) burden with positron emission tomography (PET), is gradually becoming central to the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD). However, the incorporation of biomarker evidence to the diagnostic process is currently restricted mainly to research settings. The identification of memory measures that are associated with Aß is of clinical relevance as this may enhance the confidence in making a diagnosis of MCI due to AD in clinical settings. Forty one persons with amnestic MCI underwent Aß imaging with (18)F-Florbetaben PET, magnetic resonance imaging, and a comprehensive neuropsychological assessment. All measures of episodic memory were significantly correlated with Aß burden, but regression analyses revealed a strong and selective association between story recall and Aß over and beyond the effects of age, education, global cognition, hippocampal volume, or other memory tests. Analyses of sensitivity and specificity of memory measures to detect high versus low Aß scans suggested that word-list recall performed better when high sensitivity was preferred, whereas story recall performed better when high specificity was preferred. In conclusion, a measure of story recall may increase the confidence in making a diagnosis of MCI due to AD in clinical settings.