Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging.

BACKGROUND: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. METHODS: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. FINDINGS: We found both tau metrics significantly elevated across increasing disease stages (p < 0.0001) and as a function of increasing amyloid burden for participants with preclinical (p < 0.0001, p = 0.0056) and symptomatic (p = 0.010, p = 0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p = 0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (ß = 0.59), but then tau burden elevated relative to spread (ß = 0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R = 0.83). INTERPRETATION: Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. FUNDING: This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease.

Off-target binding of [18F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-ß PET tracers [18F]florbetapir and [11C]Pittsburgh compound B (n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (∼16%) FTP scans had high levels of skull signal. Most were female (n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantially correlate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-ß-negative, but not -positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [11C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease.

APOE ε4 genotype, amyloid-ß, and sex interact to predict tau in regions of high APOE mRNA expression.

The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral ß-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-ß (Aß), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aß on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aß burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Beta-amyloid moderates the relationship between cortical thickness and attentional control in middle- and older-aged adults.

Although often unmeasured in studies of cognition, many older adults possess Alzheimer disease (AD) pathologies such as beta-amyloid (Aß) deposition, despite being asymptomatic. We were interested in examining whether the behavior-structure relationship observed in later life was altered by the presence of preclinical AD pathology. A total of 511 cognitively unimpaired adults completed magnetic resonance imaging and three attentional control tasks; a subset (n = 396) also underwent Aß-positron emissions tomography. A vertex-wise model was conducted to spatially represent the relationship between cortical thickness and average attentional control accuracy, while moderation analysis examined whether Aß deposition impacted this relationship. First, we found that reduced cortical thickness in temporal, medial- and lateral-parietal, and dorsolateral prefrontal cortex, predicted worse performance on the attention task composite. Subsequent moderation analyses observed that levels of Aß significantly influence the relationship between cortical thickness and attentional control. Our results support the hypothesis that preclinical AD, as measured by Aß deposition, is partially driving what would otherwise be considered general aging in a cognitively normal adult population.

Large-scale interventions may delay decline of the Great Barrier Reef.

On the iconic Great Barrier Reef (GBR), the cumulative impacts of tropical cyclones, marine heatwaves and regular outbreaks of coral-eating crown-of-thorns starfish (CoTS) have severely depleted coral cover. Climate change will further exacerbate this situation over the coming decades unless effective interventions are implemented. Evaluating the efficacy of alternative interventions in a complex system experiencing major cumulative impacts can only be achieved through a systems modelling approach. We have evaluated combinations of interventions using a coral reef meta-community model. The model consisted of a dynamic network of 3753 reefs supporting communities of corals and CoTS connected through ocean larval dispersal, and exposed to changing regimes of tropical cyclones, flood plumes, marine heatwaves and ocean acidification. Interventions included reducing flood plume impacts, expanding control of CoTS populations, stabilizing coral rubble, managing solar radiation and introducing heat-tolerant coral strains. Without intervention, all climate scenarios resulted in precipitous declines in GBR coral cover over the next 50 years. The most effective strategies in delaying decline were combinations that protected coral from both predation (CoTS control) and thermal stress (solar radiation management) deployed at large scale. Successful implementation could expand opportunities for climate action, natural adaptation and socioeconomic adjustment by at least one to two decades.

Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease.

PURPOSE: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues. METHODS: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7-2.9 min) and late phase (SUVRLP, 80-105 min) to approximate R1 and DVR, respectively. RESULTS: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals. CONCLUSION: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study.

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

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. APOE 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.

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease.

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

INTRODUCTION: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. METHODS: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. RESULTS: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. DISCUSSION: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease.

INTRODUCTION: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. METHODS: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. RESULTS: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. DISCUSSION: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.

Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. Successful use of this tool is limited by the lack of a common standard in the quantification of amyloid imaging data. The Centiloid approach was recently proposed to address this problem and in this work, we report our implementation of this approach and evaluate the impact of differences in underlying image analysis methodologies using both cross-sectional and longitudinal datasets. The Centiloid approach successfully converts quantitative amyloid burden measurements into a common Centiloid scale (CL) and comparable dynamic range. As expected, the Centiloid values derived from different analytical approaches inherit some of the inherent benefits and drawbacks of the underlying approaches, and these differences result in statistically significant (p < 0.05) differences in the variability and group mean values. Because of these differences, even after expression in CL, the 95% specificity amyloid positivity thresholds derived from different analytic approaches varied from 5.7 CL to 11.9 CL, and the reliable worsening threshold varied from -2.0 CL to 11.0 CL. Although this difference is in part due to the dependency of the threshold determination methodology on the statistical characteristics of the measurements. When amyloid measurements obtained from different centers are combined for analysis, one should not expect Centiloid conversion to eliminate all the differences in amyloid burden measurements due to variabilities in underlying acquisition protocols and analysis techniques.

Cross-sectional and longitudinal atrophy is preferentially associated with tau rather than amyloid ß positron emission tomography pathology.

INTRODUCTION: Structural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimer's disease pathology. Prior work has shown that both amyloid ß (Aß) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain. METHODS: Aß pathology was measured with [18F] AV-45 (florbetapir) positron emission tomography (PET) and tau was assessed with [18F] AV-1451 (flortaucipir) PET in a population of 178 older adults, of which 123 had longitudinal magnetic resonance imaging assessments (average of 5.7 years) that preceded the PET acquisitions. RESULTS: In cross-sectional analyses, greater tau PET pathology was associated with thinner cortices. When examined independently in longitudinal models, both Aß and tau were associated with greater antecedent loss of gray matter. However, when examined in a combined model, levels of tau, but not Aß, were still highly related to change in cortical thickness. DISCUSSION: Measures of tau PET are strongly related to gray matter atrophy and likely mediate relationships between Aß and gray matter.

Resident Preferences for Program Director Role in Wellness Management.

BACKGROUND: Burnout and depression are prevalent among resident physicians, though the supportive role of the program director (PD) is not well defined. OBJECTIVE: To understand the residents' view of the residency program director's role in assessing and promoting resident wellness. METHODS: A single institution survey of all house staff was conducted in 2017. Rates of burnout and depression were identified via the 2-item Maslach Burnout Inventory (MBI) and the Patient Health Questionaire-2 (PHQ-2), respectively. Residents then qualified their preferences for various assistance services and for the role of their program directors in assisting them. RESULTS: One-hundred sixty-one of 202 (79.7%) residents completed the survey. The rate of depression was 28%. Rates of emotional exhaustion and depersonalization (2-item MBI) were 44 and 62%, respectively. Only 4% of respondents had used the Employee Assistance Program (EAP) in the prior 12 months. Eighty-two percent of residents were in favor of PDs inquiring about wellness regardless of their job performance and only 1% of residents stated the PD should not inquire about wellness at all. Thirty-three percent of residents reported that they would be likely to contact EAP on their own if they felt unwell. Significantly more residents (62%) reported being more likely to contact EAP if recommended by their PD (33 vs 62%, p < 0.001%). Important perceived barriers to seeking assistance were lack of time (65%), lack of knowledge of how to contact EAP (41%), and concerns about appearing weak (35%). CONCLUSIONS: Despite a high prevalence of burnout and depression, residents are unlikely to seek help on their own. Program directors have an important role in assessing and promoting the wellness of their residents. The majority of residents wants their PD to inquire about wellness and may be more likely to seek and receive help if recommended and facilitated by their PD.

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study.

BACKGROUND: Models of Alzheimer's disease propose a sequence of amyloid ß (Aß) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. METHODS: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aß deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aß accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning). INTERPRETATION: Mutation carriers had elevations in Aß deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aß, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. FUNDING: US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.

Local and regional controls of phylogenetic structure at the high-latitude range limits of corals.

Understanding how range-edge populations will respond to climate change is an urgent research priority. Here, we used a phylogenetic community ecology approach to examine how ecological and evolutionary processes shape biodiversity patterns of scleractinian corals at their high-latitude range limits in eastern Australia. We estimated phylogenetic signal in seven ecologically important functional traits and conducted tests of phylogenetic structure at local and regional scales using the net relatedness (NRI) and nearest taxon indices (NTI) for the presence/absence and abundance data. Regional tests showed light phylogenetic clustering, indicating that coral species found in this subtropical-to-temperate transition zone are more closely related to each other than are species on the nearby, more northerly Great Barrier Reef. Local tests revealed variable patterns of phylogenetic clustering and overdispersion and higher than expected phylogenetic turnover among sites. In combination, these results are broadly consistent with the hierarchical filtering model, whereby species pass through a regional climatic filter based on their tolerances for marginal conditions and subsequently segregate into local assemblages according to the relative strength of habitat filtering and species interactions. Conservatism of tested traits suggests that corals will likely track their niches with climate change. Nevertheless, high turnover of lineages among sites indicates that range shifts will probably vary among species and highlights the vulnerability and conservation significance of high-latitude reefs.

Correction: Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group.

[This corrects the article DOI: 10.1371/journal.pone.0152082.].