Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Orthopaedic In-Training Examination (OITE) Preparation and Study Habits of Orthopaedic Residents: Revisited

Introduction: The Orthopaedic In-Training Examination (OITE) is well-established as the cornerstone for educational evaluation of orthopaedic surgery residents. Great significance has been placed on the OITE, particularly as it has been found to correlate closely with successful completion of the American Board of Orthopaedic Surgery Part I Exam (ABOS I). Our study correlated different aspects of OITE study preparation, including resources and habits, with OITE performance. Methods: An online survey was created to assess these different aspects and distributed to 163 programs across the United States for distribution to orthopedic residents in each program. Results: Data analysis showed a positive correlation between OITE ranking and greater total hours devoted to studying (r = 0.26, p= 0.0003), earlier start time for exam preparation (r = 0.25, p = 0.0005), orthopaedic journal review (including Journal of Bone and Joint Surgery[r = 0.17, p=0.02] and American Academy of Orthopaedic Surgeons [r = 0.15, p = 0.0475]), review of prior OITE examinations (r = 0.20, p = 0.0054), and use of Orthobullets (r = 0.31, p \u3c 0.0001). 58% of respondents changed their study habits significantly over the course of residency. Most respondents stated they were able to study most effectively on primarily outpatient rotations, as well as pediatrics, sports, and hand orthopaedic rotations. Conclusion: The results of this study may assist residents and residency directors to develop their curriculum and individual study plans to ensure success on the OITE, ABOS I, and, ultimately, their careers as orthopaedic surgeons

Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer’s disease

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer’s disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid–positive (Aβ+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.United States. National Institutes of Health (1K25EB013649-01)United States. National Institutes of Health (1R21AG050122-01A1)United States. National Institutes of Health (P01AG036694)United States. National Institutes of Health (F32AG044054

Neuroimage

The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the peripheral nervous system. Prior studies clearly show that the thalamus atrophies in cognitively unimpaired aging. However, the thalamus is comprised of multiple nuclei involved in a wide range of functions, and the age-related atrophy of individual thalamic nuclei remains unknown. Using a recently developed automated method of identifying thalamic nuclei (3T or 7T MRI with white-matter-nulled MPRAGE contrast and THOMAS segmentation) and a cross-sectional design, we evaluated the age-related atrophy rate for 10 thalamic nuclei (AV, CM, VA, VLA, VLP, VPL, pulvinar, LGN, MGN, MD) and an epithalamic nucleus (habenula). We also used T1-weighted images with the FreeSurfer SAMSEG segmentation method to identify and measure age-related atrophy for 11 extra-thalamic structures (cerebral cortex, cerebral white matter, cerebellar cortex, cerebellar white matter, amygdala, hippocampus, caudate, putamen, nucleus accumbens, pallidum, and lateral ventricle). In 198 cognitively unimpaired participants with ages spanning 20–88 years, we found that the whole thalamus atrophied at a rate of 0.45% per year, and that thalamic nuclei had widely varying age-related atrophy rates, ranging from 0.06% to 1.18% per year. A functional grouping analysis revealed that the thalamic nuclei involved in cognitive (AV, MD; 0.53% atrophy per year), visual (LGN, pulvinar; 0.62% atrophy per year), and auditory/vestibular (MGN; 0.64% atrophy per year) functions atrophied at significantly higher rates than those involved in motor (VA, VLA, VLP, and CM; 0.37% atrophy per year) and somatosensory (VPL; 0.32% atrophy per year) functions. A proximity-to-CSF analysis showed that the group of thalamic nuclei situated immediately adjacent to CSF atrophied at a significantly greater atrophy rate (0.59% atrophy per year) than that of the group of nuclei located farther from CSF (0.36% atrophy per year), supporting a growing hypothesis that CSF-mediated factors contribute to neurodegeneration. We did not find any significant hemispheric differences in these rates of change for thalamic nuclei. Only the CM thalamic nucleus showed a sex-specific difference in atrophy rates, atrophying at a greater rate in male versus female participants. Roughly half of the thalamic nuclei showed greater atrophy than all extra-thalamic structures examined (0% to 0.54% per year). These results show the value of white-matter-nulled MPRAGE imaging and THOMAS segmentation for measuring distinct thalamic nuclei and for characterizing the high and heterogeneous atrophy rates of the thalamus and its nuclei across the adult lifespan. Collectively, these methods and results advance our understanding of the role of thalamic substructures in neurocognitive and disease-related changes that occur with aging. © 2022Initiative d'excellence de l'Université de Bordeau

Preclinical Alzheimer's disease and longitudinal driving decline

Introduction: Links between preclinical Alzheimer's disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. Methods: One hundred four OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries, and self-reported their driving habits. Results: Higher values of cerebrospinal fluid (CSF) tau/Aβ42 and phosphorylated tau (ptau181)/Aβ42 ratios, but not uptake on Pittsburgh compound B amyloid imaging (P = .12), predicted time to a rating of marginal or fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70–19.53), P = .005 for CSF tau/Aβ42; 6.19 (1.75–21.88), and P = .005 for CSF ptau181/Aβ42. Discussion Preclinical AD predicted time to receiving a marginal or fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials

Genetic variants and functional pathways associated with resilience to Alzheimer\u27s disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer\u27s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer\u27s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values \u3c 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values \u3c 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer\u27s disease (P-values \u3e 0.42) nor associated with APOE (P-values \u3e 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer\u27s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Disrupted Thalamus White Matter Anatomy and Posterior Default Mode Network Effective Connectivity in Amnestic Mild Cognitive Impairment

Alzheimer’s disease (AD) and its prodromal state amnestic mild cognitive impairment (aMCI) are characterized by widespread abnormalities in inter-areal white matter fiber pathways and parallel disruption of default mode network (DMN) resting state functional and effective connectivity. In healthy subjects, DMN and task positive network interaction are modulated by the thalamus suggesting that abnormal task-based DMN deactivation in aMCI may be a consequence of impaired thalamo-cortical white matter circuitry. Thus, this article uses a multimodal approach to assess white matter integrity between thalamus and DMN components and associated effective connectivity in healthy controls (HCs) relative to aMCI patients. Twenty-six HC and 20 older adults with aMCI underwent structural, functional and diffusion MRI scanning using the high angular resolution diffusion-weighted acquisition protocol. The DMN of each subject was identified using independent component analysis (ICA) and resting state effective connectivity was calculated between thalamus and DMN nodes. White matter integrity changes between thalamus and DMN were investigated with constrained spherical deconvolution (CSD) tractography. Significant structural deficits in thalamic white matter projection fibers to posterior DMN components posterior cingulate cortex (PCC) and lateral inferior parietal lobe (IPL) were identified together with significantly reduced effective connectivity from left thalamus to left IPL. Crucially, impaired thalamo-cortical white matter circuitry correlated with memory performance. Disrupted thalamo-cortical structure was accompanied by significant reductions in IPL and PCC cortico-cortical effective connectivity. No structural deficits were found between DMN nodes. Abnormal posterior DMN activity may be driven by changes in thalamic white matter connectivity; a view supported by the close anatomical and functional association of thalamic nuclei effected by AD pathology and the posterior DMN nodes. We conclude that dysfunctional posterior DMN activity in aMCI is consistent with disrupted cortico-thalamo-cortical processing and thalamic-based dissemination of hippocampal disease agents to cortical hubs