Sex differences in Alzheimer's disease: do differences in tau explain the verbal memory gap?

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

Modeling the Role of Epitaxial Grain Structure of the Prior ß Phase and Associated Fiber Texture on the Strength Characteristics of Ti-6Al-4V Produced via Additive Manufacturing.

Due to the rapid cooling and directional heat flow inherent in metal-based additive manufacturing, Ti-6Al-4V results in epitaxial grain growth and a fiber texture of the prior ß phase. While Ti-6Al-4V produced via powder bed, electron beam melted processing can exhibit a range of strength characteristics, recent studies have shown superior strength properties, compared to similar orientations, of conventional plate material (AMS 4911) across a range of elevated temperatures (204 to 371 °C). To investigate this phenomenon, a series of crystal plasticity models was developed for the representative grain structures of Ti-6Al-4V to rationalize if the columnar, fiber texture produced by additive manufacturing (AM) was sufficient to explain the observed strength attributes. As a first step towards understanding this behavior, the grain structure was characterized via electron backscattering diffraction for AM material taken from four specimens (with different build directions), as well as material taken from baseline plate material (along and transverse to the rolling direction), and the resulting microstructures were modeled via a crystal plasticity framework. As expected, the results showed the AM material accounting for only the α grain structure was stronger in the vertical builds and weaker in the horizontal builds compared to the conventional plate counterparts. This suggested that grain morphology and α grain orientation alone provided some information about the relative strengths, but did not explain the overall trends observed from the experiments. To account for the role of texture, the characterized α phase was converted, via variant selection, to its prior ß phase for use in the simulations. The results showed that each simulation of the AM prior ß phase exhibited a higher strength compared to the baseline plate material, except for one specimen (horizontally built), which had large colonies of soft microtextured regions for the prior ß structure. This suggests that some variability was experienced (as anticipated), but the texture (especially of the prior ß macrozones) was a key contributor for the unusually high strength observed of the AM Ti-6Al-4V material.

Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau.

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-ß-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: ß = -5.960 ± 1.517, P < 0.001, Logical Memory Delay: ß = -5.703 ± 1.677, P = 0.002) and Braak 3/4 (Logical Memory Immediate: ß = -2.900 ± 0.938, P = 0.002, Logical Memory Delay: ß = -2.672 ± 0.955, P = 0.006) subgroups. There were no sex differences in Logical Memory performance within the Braak 5/6 subgroup (Logical Memory Immediate: ß = -0.314 ± 0.328, P = 0.34, Logical Memory Delay: ß = -0.195 ± 0.287, P = 0.50). Taken together, our results point to a sex-related verbal memory reserve.

Tau and atrophy: domain-specific relationships with cognition.

BACKGROUND: Late-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness. METHODS: We analyzed data from 131 amyloid-ß positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores. RESULTS: FTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition. CONCLUSIONS: Our findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness.

Learning from the design and development of the NHS Safety Thermometer.

QUALITY ISSUE: Research indicates that 10% of patients are harmed by healthcare but data that can be used in real time to improve safety are not routinely available. INITIAL ASSESSMENT: We identified the need for a prospective safety measurement system that healthcare professionals can use to improve safety locally, regionally and nationally. CHOICE OF SOLUTION: We designed, developed and implemented a national tool, named the NHS Safety Thermometer (NHS ST) with the goal of measuring the prevalence of harm from pressure ulcers, falls, urinary tract infection in patients with catheters and venous thromboembolism on one day each month for all NHS patients. IMPLEMENTATION: The NHS ST survey instrument was developed in a learning collaborative involving 161 organizations (e.g. hospitals and other delivery organizations) using a Plan, Do, Study, Act method. EVALUATION: Testing of operational definitions, technical capability and use were conducted and feedback systems were established by site coordinators in each participating organization. During the 17-month pilot, site coordinators reported a total of 73,651 patient entries. LESSONS LEARNED: It is feasible to obtain national data through standardized reporting by site coordinators at the point of care. Some caution is required in interpreting data and work is required locally to ensure data collection systems are robust and data collectors were trained. Sampling is an important strategy to optimize efficiency and reduce the burden of measurement.