Tau and amyloid biomarkers modify the degree to which cognitive reserve and brain reserve predict cognitive decline.

OBJECTIVE: Brain reserve, cognitive reserve, and education are thought to protect against late-life cognitive decline, but these variables have not been directly compared to one another in the same model, using future cognitive and functional decline as outcomes. We sought to determine whether the influence of these protective factors on executive function (EF) and daily function decline was dependent upon Alzheimer's disease (AD) pathology severity, as measured by the total tau to beta-amyloid (T-τ/Aß1-42) ratio in cerebrospinal fluid (CSF). METHOD: Participants were 1201 older adult volunteers in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Brain reserve was defined using a composite index of structural brain volumes (total brain matter, hippocampus, and white matter hyperintensity). Cognitive reserve was defined as the variance in episodic memory performance not explained by brain integrity and demographics. RESULTS: At higher levels of T-τ/Aß1-42, brain and cognitive reserve predicted slower decline in EF. Only brain reserve attenuated decline at lower levels of T-τ/Aß1-42. Education had no independent association with cognitive decline. CONCLUSIONS: These results point to a hierarchy of protection against aging- and disease-associated cognitive decline. When pathology is low, only structural brain integrity predicts rate of future EF decline. The ability of cognitive reserve to predict future EF decline becomes stronger as CSF biomarker evidence of AD increases. Although education is typically thought of as a proxy for cognitive reserve, it did not show any protective effects on cognition after accounting for brain integrity and the residual cognitive reserve index.

Residual reserve index modifies the effect of amyloid pathology on fluorodeoxyglucose metabolism: Implications for efficiency and capacity in cognitive reserve.

Background: The residual approach to measuring cognitive reserve (using the residual reserve index) aims to capture cognitive resilience conferred by cognitive reserve, but may be confounded by factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing interactions between the residual reserve index and amyloid, tau, and neurodegeneration ["AT(N)"] biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience). Methods: Participants (N = 332) were from the Alzheimer's Disease Neuroimaging Initiative. The residual reserve index represented the difference between observed and predicted memory performance (a positive residual reserve index suggests higher cognitive reserve). AT(N) biomarkers were: CSF ß-amyloid1-42/ß-amyloid1-40 (A), plasma phosphorylated tau-181 (T), and FDG metabolism in AD-specific regions ([N]). AT(N) biomarkers (measured at consecutive time points) were entered in a sequential mediation model testing the indirect effects from baseline amyloid to executive function intercept (third annual follow-up) and slope (baseline to seventh follow-up), via tau and/or FDG metabolism. The baseline residual reserve index was entered as a moderator of paths between AT(N) biomarkers (e.g., amyloid-tau), and paths between AT(N) biomarkers and executive function. Results: The residual reserve index interacted with amyloid pathology when predicting FDG metabolism: the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, executive function performance was comparable at different levels of the residual reserve index, but a higher residual reserve index was associated with lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism. Conclusion: The effect of the residual reserve index on executive function performance via FDG metabolism was consistent with cognitive resilience. This suggests the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency, and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of greater amyloid pathology. Implications for future research include the potential bidirectionality between neural efficiency and amyloid accumulation.

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.

Synthetic microbleeds generation for classifier training without ground truth.

BACKGROUND AND OBJECTIVE: Cerebral microbleeds (CMB) are important biomarkers of cerebrovascular diseases and cognitive dysfunctions. Susceptibility weighted imaging (SWI) is a common MRI sequence where CMB appear as small hypointense blobs. The prevalence of CMB in the population and in each scan is low, resulting in tedious and time-consuming visual assessment. Automated detection methods would be of value but are challenged by the CMB low prevalence, the presence of mimics such as blood vessels, and the difficulty to obtain sufficient ground truth for training and testing. In this paper, synthetic CMB (sCMB) generation using an analytical model is proposed for training and testing machine learning methods. The main aim is creating perfect synthetic ground truth as similar as reals, in high number, with a high diversity of shape, volume, intensity, and location to improve training of supervised methods. METHOD: sCMB were modelled with a random Gaussian shape and added to healthy brain locations. We compared training on our synthetic data to standard augmentation techniques. We performed a validation experiment using sCMB and report result for whole brain detection using a 10-fold cross validation design with an ensemble of 10 neural networks. RESULTS: Performance was close to state of the art (~9 false positives per scan), when random forest was trained on synthetic only and tested on real lesion. Other experiments showed that top detection performance could be achieved when training on synthetic CMB only. Our dataset is made available, including a version with 37,000 synthetic lesions, that could be used for benchmarking and training. CONCLUSION: Our proposed synthetic microbleeds model is a powerful data augmentation approach for CMB classification with and should be considered for training automated lesion detection system from MRI SWI.

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

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-ß 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.

SPON1 Is Associated with Amyloid-ß and APOE ε4-Related Cognitive Decline in Cognitively Normal Adults.

. 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 (APOE) ɛ4 and rs11023139 in individuals with high amyloid-ß burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020). CONCLUSION: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-ß burden.

A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

Generative Model of Brain Microbleeds for MRI Detection of Vascular Marker of Neurodegenerative Diseases.

Cerebral microbleeds (CMB) are increasingly present with aging and can reveal vascular pathologies associated with neurodegeneration. Deep learning-based classifiers can detect and quantify CMB from MRI, such as susceptibility imaging, but are challenging to train because of the limited availability of ground truth and many confounding imaging features, such as vessels or infarcts. In this study, we present a novel generative adversarial network (GAN) that has been trained to generate three-dimensional lesions, conditioned by volume and location. This allows one to investigate CMB characteristics and create large training datasets for deep learning-based detectors. We demonstrate the benefit of this approach by achieving state-of-the-art CMB detection of real CMB using a convolutional neural network classifier trained on synthetic CMB. Moreover, we showed that our proposed 3D lesion GAN model can be applied on unseen dataset, with different MRI parameters and diseases, to generate synthetic lesions with high diversity and without needing laboriously marked ground truth.

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.

Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging.

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-ß (Aß) 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 Aß deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aß and cerebrovascular disease (V) as Aß-V-, Aß-V+, Aß+V-, or Aß+V+. RESULTS: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aß load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aß positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aß 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 Aß and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aß and WMH burden, future longitudinal studies are required to further confirm this.

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

Neocortical Aß-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 Aß-amyloid deposition and the age at which Aß-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 Aß-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aß-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 Aß-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.

Restricted Effect of Cerebral Microbleeds on Regional Magnetic Susceptibility.

BACKGROUND: Cortical iron accumulation has been reported as a pathological feature of Alzheimer's disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. OBJECTIVE: To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. METHODS: 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. RESULTS: 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. CONCLUSION: The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex.

Personality factors and cerebral glucose metabolism in community-dwelling older adults.

Personality factors have been associated with Alzheimer's disease (AD) and dementia, but they have not been examined against markers of regional brain glucose metabolism (a primary measure of brain functioning) in older adults without clinically diagnosed cognitive impairment. The relationship between personality factors derived from the five-factor model and cerebral glucose metabolism determined using positron emission tomography (PET) with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET) was examined in a cohort of 237 non-demented, community-dwelling older adults aged 60-89 years (M ± SD = 73.76 ± 6.73). Higher neuroticism and lower scores on extraversion and conscientiousness were significantly associated with decreased glucose metabolism in brain regions typically affected by AD neuropathological processes, including the hippocampus and entorhinal cortex. Furthermore, while there were significant differences between apolipoprotein E (APOE) ε4 allele carriers and non-carriers on 18F-FDG-PET results in the neocortex and other brain regions (p < 0.05), there was no significant difference between carriers and non-carriers on personality factors and no significant interactions were found between APOE ε4 carriage and personality factors on brain glucose metabolism. In conclusion, we found significant relationships between personality factors and glucose metabolism in neural regions more susceptible to AD neuropathology in older adults without clinically significant cognitive impairment. These findings support the need for longitudinal research into the potential mechanisms underlying the relationship between personality and dementia risk, including measurement of change in other AD biomarkers (amyloid and tau imaging) and how they correspond to change in personality factors. Future research is also warranted to determine whether timely psychological interventions aimed at personality facets (specific aspects or characteristics of personality factors) can affect imaging or other biomarkers of AD resulting in delay or ideally preventing the onset of the cognitive impairment.

Cognitive reserve predicts future executive function decline in older adults with Alzheimer's disease pathology but not age-associated pathology.

Cognitive reserve has been described as offering protection against Alzheimer's disease (AD) and other neurodegenerative conditions, but also against age-associated brain changes. Using data from the Alzheimer's Disease Neuroimaging Initiative, we defined cognitive reserve using the residual reserve index: episodic memory performance residualized for 3T MRI-derived brain volumes and demographics. We examined whether cognitive reserve predicted executive function (EF) decline equally across 2 groups of older adults-AD biomarker-positive (n = 468) and -negative (n = 402)-defined by the tau-to-amyloid ratio in cerebrospinal fluid. A significant interaction between the residual reserve index and biomarker group revealed that the effect of cognitive reserve on EF decline was dependent on pathology status. In the biomarker-positive group, higher cognitive reserve predicted EF decline over five years. However, cognitive reserve did not predict EF decline in the biomarker-negative group. These results suggest a certain level of AD pathology may be needed before cognitive reserve exerts its protective effects on future cognition; however, further research that tracks cognitive reserve longitudinally is needed.

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

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.

Influence of Comorbidity of Cerebrovascular Disease and Amyloid-ß on Alzheimer's Disease.

BACKGROUND: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer's disease is challenging. OBJECTIVE: We aimed to determine the influence of cerebrovascular disease, amyloid-ß (Aß), and their comorbidity on cognitive decline, hippocampal atrophy, and Aß deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing. METHODS: Two-hundred and eighteen participants underwent Aß PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aß status was determined on baseline PET. Participants were also classified as V+ on baseline MRI if they had≥1 large cortical infarcts, subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aß load between the four resultant groups. RESULTS: Mean age at baseline was 74 years (range 59-96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer's disease. Compared to the Aß-/V- group, the Aß+/V- and Aß+/V+ groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V+ status was associated with greater cognitive decline (Cohen's d = 0.85, p < 0.001) and hippocampal atrophy (d = 2.05, p < 0.001) in the Aß+ group but not in the Aß- group. V+ status was not associated with Aß accumulation in any group. CONCLUSION: Comorbidity of cerebrovascular disease and Aß was associated with cognitive decline and neurodegeneration. Cerebrovascular disease was not associated with the rate of Aß accumulation.

Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer's disease.

BACKGROUND: Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid ß (Aß) plaques accumulate in the decades prior to symptom onset. PURPOSE: To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aß burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65. STUDY TYPE: Cross-sectional. POPULATION: Forty-six CN subjects including 33 with low levels of Aß burden and 13 with high levels of Aß. FIELD STRENGTH/SEQUENCE: 3T/3D MP-PCASL. ASSESSMENT: The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction. STATISTICAL TESTS: General Linear Model. RESULTS: In CN subjects positive for Aß burden (n = 13), we observed a positive correlation between CBF and Aß burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05). DATA CONCLUSION: To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513.

Non-linear realignment improves hippocampus subfield segmentation reliability.

Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.

Comparison of 18F-florbetaben quantification results using the standard Centiloid, MR-based, and MR-less CapAIBL® approaches: Validation against histopathology.

INTRODUCTION: 18F-florbetaben is currently approved for the visual rule out of ß-amyloid (Aß) pathology. It is also used for recruitment and as an outcome measure in therapeutic trials, requiring accurate and reproducible quantification of Aß burden in the brain. METHODS: Data from eighty-eight subjects (52 male subjects, aged 79.8 ± 10.6 years) who underwent antemortem 18F-florbetaben positron emission tomography scan and magnetic resonance imaging less than a year before neuropathological assessment at autopsy were evaluated. Image analysis was performed using the standard Centiloid (CL) statistical parametric mapping approach and CapAIBL®. Imaging results were compared against autopsy data. RESULTS: Against combined Bielschowsky silver staining and immunohistochemistry histopathological scores, statistical parametric mapping had 96% sensitivity, 96% specificity, and 95% accuracy, whereas magnetic resonance-less CapAIBL standardized uptake value ratioWhole Cerebellum had 94% sensitivity, 96% specificity, and 95% accuracy. Based on the combined histopathological scores, a CL threshold band of 19 ± 7 CL was determined. DISCUSSION: Quantification of 18F-florbetaben positron emission tomography scans using magnetic resonance-based and magnetic resonance-less CapAIBL® approaches showed high agreement, establishing a pathology-based threshold in CL.

COMT val158met is not associated with Aß-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults.

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aß-amyloid (Aß) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer's disease (AD). In 598 cognitively normal older adults with known neocortical Aß levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aß-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.