Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

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Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationshipmanifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. Methods: Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. Results: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. Interpretation: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials.

Objective. To survey physicians' opinions concerning the relative importance of 5 clinical encounter components-vital signs, patient history, physical examination, laboratory tests, and ancillary studies-in the diagnosis and management of 8 chronic diseases. Methods. A SurveyMonkey internet survey was e-mailed to 7,265 US physicians, including 3,542 rheumatologists and 3,723 nonrheumatologists, with the following query: "Please indicate the relative importance of 5 sources of information-vital signs, patient history, physical examination, laboratory tests, and ancillary studies-in diagnosis of congestive heart failure (CHF), diabetes mellitus, hypercholesterolemia, hypertension, lymphoma, pulmonary fibrosis, rheumatoid arthritis (RA), and ulcerative colitis." The response options were 0 -20%, 21-40%, 41-60%, 61-80%, and 81-100%. A second query with an identical structure addressed management of the 8 diseases. The proportions of physicians who estimated each component as most (or tied for most) important in diagnosis or in management were computed. Results. The survey was completed by 313 physicians (154 rheumatologists and 159 nonrheumatologists). More than 90%estimated vital signs as most important for hypertension, and laboratory tests for diabetes mellitus and hypercholesterolemia. More than 70% estimated ancillary studies as most important for lymphoma, pulmonary fibrosis, and ulcerative colitis. Patient history and physical examination were estimated as most important for RA and CHF by >50% of nonrheumatologists. Conclusion. RA and CHF were the only 2 of the 8 diseases studied for which >50% of nonrheumatologists estimated a patient history and physical examination as most important for diagnosis and management. Confirmation and extension of these observations in actual care may have implications for reimbursement and organization of clinical care.

Low literacy is an important underrecognized problem in medical care, which may be assessed easily in standard care using the REALM or A-REALM. Further attention to literacy-associated barriers may reduce socioeconomic disparities in health.