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.

Study protocol for "In-vehicle sensors to detect changes in cognition of older drivers".

BACKGROUND: Driving is a complex behavior that may be affected by early changes in the cognition of older individuals. Early changes in driving behavior may include driving more slowly, making fewer and shorter trips, and errors related to inadequate anticipation of situations. Sensor systems installed in older drivers' vehicles may detect these changes and may generate early warnings of possible changes in cognition. METHOD: A naturalistic longitudinal design is employed to obtain continuous information on driving behavior that will be compared with the results of extensive cognitive testing conducted every 3 months for 3 years. A driver facing camera, forward facing camera, and telematics unit are installed in the vehicle and data downloaded every 3 months when the cognitive tests are administered. RESULTS: Data processing and analysis will proceed through a series of steps including data normalization, adding information on external factors (weather, traffic conditions), and identifying critical features (variables). Traditional prediction modeling results will be compared with Recurring Neural Network (RNN) approach to produce Driver Behavior Indices (DBIs), and algorithms to classify drivers within age, gender, ethnic group membership, and other potential group characteristics. CONCLUSION: It is well established that individuals with progressive dementias are eventually unable to drive safely, yet many remain unaware of their cognitive decrements. Current screening and evaluation services can test only a small number of individuals with cognitive concerns, missing many who need to know if they require treatment. Given the increasing number of sensors being installed in passenger vehicles and pick-up trucks and their increasing acceptability, reconfigured in-vehicle sensing systems could provide widespread, low-cost early warnings of cognitive decline to the large number of older drivers on the road in the U.S. The proposed testing and evaluation of a readily and rapidly available, unobtrusive in-vehicle sensing system could provide the first step toward future widespread, low-cost early warnings of cognitive change for this large number of older drivers in the U.S. and elsewhere.

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.

Effectiveness of a Per-Meal Protein Prescription and Nutrition Education with versus without Diet Coaching on Dietary Protein Intake and Muscle Health in Middle-Aged Women.

Sufficient dietary protein intake is vital to maintaining muscle health with aging. Yet protein intake among adults is often inadequate. This study's main objective was to examine the impact of nutrition education (NE) and a per-meal protein prescription (PRx) with versus without diet coaching on protein intake. A secondary objective examined its effects on muscle health. Participants included 53 women, age 45-64 years. All participants received NE and PRx; those randomized to coached-group received 10-weeks of diet coaching. Assessments included: protein intake at baseline, weeks 4 and 12 and muscle health (muscle mass, grip strength, five-chair rise test, 4 mgait speed test). The Chi-square test examined percentages of participants meeting PRx between groups. Repeated measures analysis of variance assessed within group and intervention effects on protein intake and muscle health parameters. Protein intake (g/kg body weight) increased (p < 0.001): not-coached (n = 28) 0.8 ± 0.2 to 1.2 ± 0.3 and coached (n = 25) 1.0 ± 0.2 to 1.4 ± 0.3 with no significant difference between groups. A greater percentage of coached-group participants met (p = 0.04) breakfast (72%) and met (p < 0.001) three-meal (76%) PRx versus not-coached participants (25% and 53%, respectively). Participants in both groups exhibited significantly (p < 0.001) improved times for the five-chair rise test and 4 mgait speed test. Diet coaching in conjunction with a PRx and NE should be considered to assist individuals in improving protein intake through self-selection of protein-rich foods.

Choosing coaching frameworks for promoting diet modifications.

Theoretical frameworks have successfully guided researchers in implementing coaching interventions to effect dietary changes in adults for both prevention and management of chronic diseases. Three such frameworks include the Transtheoretical Model (TTM), Social Cognitive Theory (SCT), and the Theory of Integrative Nurse Coaching (TINC). This article introduces each theory, followed by an overview of the coaching interventions used to effect dietary behaviour changes within each theory. A condensed version of Turner's synthesis methodology is used to determine if a conceptual connection exists among the three models/theories. The condensed version includes synthesis preparation, synthesis (comparison of converging and diverging components), synthesis refinement (conceptual connection), and a concluding discussion of all three theories related to nursing practice. This synthesis will inform the focus of interventions that aim to promote dietary changes in adults at risk of developing sarcopenia.

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.

In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). METHODS: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). RESULTS: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). CONCLUSION: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure.

Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by ß-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and ß-amyloid PET imaging in a diseased population.

Tau-PET Binding Distinguishes Patients With Early-stage Posterior Cortical Atrophy From Amnestic Alzheimer Disease Dementia.

BACKGROUND: Flortaucipir (tau) positron emission tomography (PET) binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau-PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease. METHODS: Flortaucipir and florbetapir (ß-amyloid) PET imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and ß-amyloid deposition were quantified using standard uptake value ratios and compared at a voxelwise level, controlling for age. RESULTS: PCA patients [median age-at-onset, 59 (51 to 61) years] were younger at symptom onset than similarly staged individuals with amnestic AD [75 (60 to 85) years] or CN controls [73 (61 to 90) years; P=0.002]. Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients. CONCLUSIONS AND RELEVANCE: Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype.

Brief report: Under-representation of African americans in autism genetic research: a rationale for inclusion of subjects representing diverse family structures.

African American children with autism are seriously under-represented in existing genetic registries and biomedical research studies of autism. We estimated the number of African American children with autism in the St. Louis region using CDC surveillance data and present the outcomes of a concerted effort to enroll approximately one-third of that population into either of two large national genetic autism registries. The results revealed that even after traditional barriers to research participation were addressed and all contacted families expressed a willingness to participate, 67% of the reachable families were disqualified from participation because of family structure alone. Comprehensive efforts-including expansion of eligibility to families of diverse structure-are warranted to facilitate the inclusion of African American children in biomedical research.