Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease.

OBJECTIVE: 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 relationship - manifested 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. ANN NEUROL 2021;90:751-762.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

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, range 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 tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found 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.

Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau.

Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer's disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer's Association (NIA-AA) A/T/(N) [ß-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [ß-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of ß-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as "mismatch MCI" for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because ß-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or "prodromal AD") and A-T-(N+) MCI (or "neurodegeneration-only MCI") on cross-sectional and longitudinal cognition and neuroimaging characteristics. ß-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less "AD-like" than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that ß-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.

Cognitive Impairment Evaluation and Management.

Clinicians should use a systematic approach to evaluating patients presenting with a concern for cognitive impairment. This approach includes interviewing a knowledgeable informant and performing a thorough mental status examination in order to determine the presence of functional impairments and the domains of cognition that are impaired. The results of this interview and examination determine the next steps of the diagnostic work-up. The pattern of cognitive impairment shapes the differential diagnosis. Treatment should address symptoms, and environmental, psychological, and behavioral interventions are essential.

Importance of patient history and physical examination in rheumatoid arthritis compared to other chronic diseases: results of a physician survey.

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.

Screening for low literacy in a rheumatology setting: more than 10% of patients cannot read "cartilage," "diagnosis," "rheumatologist," or "symptom".

OBJECTIVES: The objectives of the study were to analyze literacy in 194 consecutive patients at an academic rheumatology setting with the Rapid Estimate of Adult Literacy in Medicine (REALM) and an "Arthritis-Adapted" REALM (A-REALM), and to compare responses to one another and to demographic and clinical measures. METHODS: The REALM and A-REALM are two 66-item word recognition tests. Both were administered to 194 consecutive patients in usual rheumatology care. Multidimensional Health Assessment Questionnaire (MDHAQ) scores for physical function, pain, fatigue, and global estimate, and laboratory assessments also were available. Descriptive statistics and analyses of agreement were computed. RESULTS: REALM and A-REALM administration involved 2 to 3 minutes each. Scores below 61, indicating a reading level at eighth grade or less, were seen in 35 (18%) of 194 patients on the REALM and 46 patients (24%) on the A-REALM. No patient was classified as having severely low literacy at or below a third-grade level. However, words not read correctly by 10% or more of the patients on the REALM included diagnosis (14%), osteoporosis (17%), and inflammatory (10%), and on the A-REALM, rheumatologist (11%), cartilage (14%), and symptom (14%). REALM and A-REALM scores were correlated significantly (Pearson r = 0.94, P < 0.001). Almost all patients (33/35) with REALM scores of less than 61 also had A-REALM scores of less than 61, less formal education, and poorer clinical status on all measures, most not statistically significant. CONCLUSION: 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.

A biopsychosocial model to complement a biomedical model: patient questionnaire data and socioeconomic status usually are more significant than laboratory tests and imaging studies in prognosis of rheumatoid arthritis.

Modern medical care is based largely on a paradigm known as a "biomedical model," in which a single "gold standard" high-technology test guides clinical care. Patients with hypertension, diabetes, osteoporosis, and many other conditions often are unaware of their status in the absence of data from "objective" tests. By contrast, in rheumatoid arthritis (RA) and most rheumatic diseases, patients generally are aware of symptoms, and information from patients often is as or more important to taking direct clinical decisions than laboratory tests, imaging studies, or even physical examination data. Physical function on a patient self-report questionnaire generally is as significant as, or more significant than laboratory, imaging, or physical examination data in predicting severe outcomes of RA, such as work disability, costs, and mortality. Patient questionnaires may be viewed as contributing to a complementary "biopsychosocial model" that can overcome limitations of the traditional "biomedical model" in RA and other chronic diseases. Further relevance of a "biopsychosocial model" in RA and other rheumatic diseases is seen in evidence that socioeconomic status, most easily assessed as formal education level, identifies favorable or unfavorable clinical status and prognosis at high levels of significance. Socioeconomic status may be regarded as a surrogate for the importance of patient actions, in addition to actions of health professionals, in the course and outcomes of rheumatic and other chronic diseases.