Search

Cognitive resilience (CR) describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. This is especially true when information about CR is contained in the data the linear model was fitted to, either through inclusion of CR-associated variables or due to correlation. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and CR and achieves better estimation accuracy on simulated ground-truth data. [ABSTRACT FROM AUTHOR]

Remote, digital cognitive testing on an individual's own device provides the opportunity to deploy previously understudied but promising cognitive paradigms in preclinical Alzheimer's disease (AD). The Boston Remote Assessment for NeuroCognitive Health (BRANCH) captures a personalized learning curve for the same information presented over seven consecutive days. Here, we examined BRANCH multi-day learning curves (MDLCs) in 167 cognitively unimpaired older adults (age = 74.3 ± 7.5, 63% female) with different amyloid-β (A) and tau (T) biomarker profiles on positron emission tomography. MDLC scores decreased across ascending biomarker groups, with the A + T- group performing numerically worse (β = –0.24, 95%CI[–0.55,0.07], p = 0.128) and the A + T+ group performing significantly worse (β = –0.58, 95%CI[–1.06,–0.10], p = 0.018) than the A-T- group. Further, lower MDLC scores were associated with greater cortical thinning (β = 0.18, 95%CI[0.04,0.34], p = 0.013). Our results suggest that diminished MDLCs track with advanced AD pathophysiology, and demonstrate how a digital multi-day learning paradigm can provide novel insights about cognitive decline during preclinical AD. [ABSTRACT FROM AUTHOR]

Objective: Elevated entorhinal cortex (EC) tau in low beta‐amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)‐derived locus coeruleus integrity, neocortical beta‐amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta‐amyloid PET‐negative. Methods: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T‐MRI of the locus coeruleus, Pittsburgh compound‐B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB− sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR‐sum‐of‐boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. Results: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB− sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden‐index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut‐off, lower locus coeruleus integrity was associated with a two‐fold increase in clinical progression, including mild cognitive impairment. Interpretation: Locus coeruleus integrity has promise as a low‐cost, non‐invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta‐amyloid individuals. ANN NEUROL 2024;96:650–661 [ABSTRACT FROM AUTHOR]

As new synthetic methods for the preparation of solution processable electrochromic polymers are explored, including increasing synthetic scale beyond that of the research laboratory, it is expected that polymer intermolecular and intramolecular interactions will be affected. In this study, we explore the use of four different alkyl phosphonic acids of differing chain lengths as an interfacial treatment on ITO transparent electrodes to improve the polymer‐electrode interactions to mitigate the loss of film integrity and resulting electrochromic properties (current density, optical properties, and effective switch rates) during repeated oxidation/reduction and swelling/deswelling of the film. It was found that the phosphonic acid layer allows for a compatibilization of the polarity of the electrode surface with the polymer layer while also improving surface energy uniformity. We evaluated two electrochromic polymers (ECPs), and while a near complete delamination was observed on untreated ITO, film integrity was maintained beyond 25 repeated cycles, with polymer optical contrast maintained at all switching rates when coated onto dodecylphosphonic acid. Additionally, we show that electrochromic polymer film integrity is maintained over a range of film thicknesses. This method can be extended to applications using a variety of solution processable electroactive polymers in contact with metal oxide surfaces. [ABSTRACT FROM AUTHOR]

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = –0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = –0.035(0.009), p = 0.001), inferior temporal (β (SE) = –0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = –0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities. [ABSTRACT FROM AUTHOR]

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau. [ABSTRACT FROM AUTHOR]

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age. [ABSTRACT FROM AUTHOR]

Twentieth-century medical advances reduced the rate of maternal mortality by more than 99 percent. Yet recently we hear that there has been a substantial increase in the maternal mortality rate. This increase has been caused by contemporary researchers adopting much broader definitions for what counts as cases of maternal mortality. This example illustrations the importance of definitions in shaping statistics. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sleep is crucial for memory consolidation and the clearance of toxic proteins associated with Alzheimer's disease (AD). We examined the association between sleep characteristics and imaging biomarkers of early amyloid beta (Aβ) and tau pathology as well as neurodegeneration in brain regions known to be affected in the incipient stages of AD. METHODS: Thirty‐nine cognitively unimpaired (CU) participants of the Harvard Aging Brain Study underwent at‐home polysomnography as well as tau positron emission tomography (flortaucipir‐PET), amyloid PET (Pittsburgh compound B [PiB]‐PET), and magnetic resonance imaging–derived assessment of cortical thickness (CT). RESULTS: Increased N1 sleep was associated with a higher tau PET signal (β = 0.009, p = 0.001) and lower CT in the temporal composite region of interest (β = –0.017, p = 0.007). Decreased slow‐wave sleep (SWS) was associated with higher tau burden in the temporal composite (β = –0.008, p = 0.005) and lower CT (β = 0.008, p = 0.002), even after controlling for global PiB‐PET. DISCUSSION: In CU older adults, lower SWS and higher N1 sleep were associated with higher tau burden and lower CT in brain regions associated with early tau deposition and vulnerable to AD‐related neurodegeneration through mechanisms dissociable from amyloid deposition. Highlights: We report the results of an observational study, which leveraged ‐a well‐characterized cohort of healthy aging (Harvard Aging Brain Study) by adding in‐home full polysomnograms.By adding at‐home polysomnograms to this unique and deeply phenotyped cohort, we examined variations in sleep architecture that are associated with Alzheimer's disease (AD) pathologic changes.Our results confirmed the association of sleep changes with early tau and cortical neurodegenerative changes that were independent of amyloid.The results will be of importance in monitoring sleep‐related variations in relation to the natural history of AD pathology and in designing sleep‐focused clinical trials. [ABSTRACT FROM AUTHOR]

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer’s disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Results: Amyloid [unstandardized partial regression coefficient estimate (β) =-0.007, 95% confidence interval (95% CI) = (-0.013,-0.001)], and medial temporal tau [β =-0.013, 95% CI = (-0.022,-0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer’s disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages. [ABSTRACT FROM AUTHOR]

Background: Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. Methods: A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Results: Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Conclusions: Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging. [ABSTRACT FROM AUTHOR]

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system. The role of olfactory pathways in the development of neurodegeneration in Alzheimer's disease is not well understood. Here, the authors show odor identification deficits are predictive of tau accumulation and progression in olfactory pathways, and that tau spreads from medial temporal lobe structures towards the olfactory system. [ABSTRACT FROM AUTHOR]

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline. [ABSTRACT FROM AUTHOR]

Sorghum [Sorghum bicolor (L.) Moench] is a resilient forage crop due to its drought tolerance and adaptation to low‐N environments. Sorghum produces a cyanogenic glucoside called dhurrin. The breakdown of dhurrin leads to the release of hydrogen cyanide (HCN), which can cause cyanide toxicity in livestock. Dhurrin‐free sorghum lines have been developed through chemical mutagenesis by mutagenizing the gene for the first enzyme, CYP79A1, in the biosynthetic pathway. The CYP79A1 mutation was bred into sorghum lines to create a dhurrin‐free experimental hybrid. Grazing preference of ewes was assessed when allocated to the dhurrin‐free hybrid and three commercial hybrids. Near isogenic lines (NIL), contrasting in dhurrin production, were also compared for grazing preference. Forage mass was measured before and after grazing to determine the amount of forage mass grazed by the ewes. An unmanned aerial vehicle (UAV) was flown to quantify changes in normalized difference vegetation index (NDVI) over time for each hybrid. The nutritive values of the hybrids were also evaluated. The dhurrin‐free hybrid was grazed 19% and 13% more (p‐value ≤ 0.05) in comparison to the commercial hybrids for the second and third grazing cycles in 2019 and 2020. The NIL Tx623 bmr6 CYP79A1, was grazed 20% more than Tx623 bmr6 in two grazing cycles in 2020. Remote sensing data showed a similar pattern with the dhurrin‐free hybrid having the largest decline in NDVI for three grazing cycles in 2019. Nutritive value of the dhurrin‐free hybrid was similar to the two hybrids with the brown midrib (bmr) trait. Core Ideas: This study was conducted to quantify the palatability and quality of dhurrin‐free sorghum.Dhurrin‐free sorghum is of interest because it eliminates HCN toxicity risk in livestock.Palatability of dhurrin‐free sorghum was examined using ewes in a free‐choice study.This study demonstrated favorable feeding on dhurrin‐free sorghum lines with no reduction in nutritional quality. [ABSTRACT FROM AUTHOR]

Background: Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. Methods: 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. Results: At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. Conclusions: Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline. [ABSTRACT FROM AUTHOR]

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ–TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ–TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer. Synopsis: The YAP-TEAD transcriptional regulators play a pivotal role in tumorigenesis, but activation of this pathway remains incompletely understood at the molecular level. This study implicates nuclear inositol phospholipids as molecular glue mediating YAP-TEAD interaction, required for full activation of the YAP-TEAD complex in breast cancer. YAP binds to phosphoinositide species via a polybasic motif located in its TEAD-binding domain. Phosphoinositides generated by lipid kinases, i.e., PIPKIa and IPMK, facilitate the binding of YAP to TEAD. Inhibition of PIPKIa and IPMK, or blockade of phosphoinositide binding to YAP, diminishes the expression of YAP target genes. The phosphoinositide-driven enhancement of YAP-TEAD complex formation promotes breast cancer cell motility. Phosphoinositide products of lipid kinases PIPKIa and IPMK bind to the transcriptional co-activator YAP and enhance its interaction with the transcription factor TEAD. [ABSTRACT FROM AUTHOR]

Cerebrovascular dysfunction is a significant contributor to Alzheimer's disease (AD) progression. AD mouse models show altered capillary morphology, density, and diminished blood flow in areas of tau and beta-amyloid accumulation. The purpose of this study was to examine alterations in vascular structure and their contributions to perfusion deficits in the hippocampus in AD and mild cognitive impairment (MCI). Seven individuals with AD and MCI (1 AD/6 MCI), nine cognitively intact older healthy adults, and seven younger healthy adults underwent pseudo-continuous arterial spin labeling (PCASL) and gradient-echo/spin-echo (GESE) dynamic susceptibility contrast (DSC) MRI. Cerebral blood flow (CBF), cerebral blood volume, relative vessel size index (rVSI), and mean vessel density were calculated from model fitting. Lower CBF from PCASL and SE DSC MRI was observed in the hippocampus of AD/MCI group. rVSI in the hippocampus of the AD/MCI group was larger than that of the two healthy groups (FDR- P = 0.02). No difference in vessel density was detected between the groups. We also explored relationship of tau burden from 18F-flortaucipir positron emission tomography and vascular measures from MRI. Tau burden was associated with larger vessel size and lower CBF in the hippocampus. We postulate that larger vessel size may be associated with vascular alterations in AD/MCI. [ABSTRACT FROM AUTHOR]

Objective. Performing positron emission tomography (PET) denoising within the image space proves effective in reducing the variance in PET images. In recent years, deep learning has demonstrated superior denoising performance, but models trained on a specific noise level typically fail to generalize well on different noise levels, due to inherent distribution shifts between inputs. The distribution shift usually results in bias in the denoised images. Our goal is to tackle such a problem using a domain generalization technique. Approach. We propose to utilize the domain generalization technique with a novel feature space continuous discriminator (CD) for adversarial training, using the fraction of events as a continuous domain label. The core idea is to enforce the extraction of noise-level invariant features. Thus minimizing the distribution divergence of latent feature representation for different continuous noise levels, and making the model general for arbitrary noise levels. We created three sets of 10%, 13%–22% (uniformly randomly selected), or 25% fractions of events from 97 18F-MK6240 tau PET studies of 60 subjects. For each set, we generated 20 noise realizations. Training, validation, and testing were implemented using 1400, 120, and 420 pairs of 3D image volumes from the same or different sets. We used 3D UNet as the baseline and implemented CD to the continuous noise level training data of 13%–22% set. Main results. The proposed CD improves the denoising performance of our model trained in a 13%–22% fraction set for testing in both 10% and 25% fraction sets, measured by bias and standard deviation using full-count images as references. In addition, our CD method can improve the SSIM and PSNR consistently for Alzheimer-related regions and the whole brain. Significance. To our knowledge, this is the first attempt to alleviate the performance degradation in cross-noise level denoising from the perspective of domain generalization. Our study is also a pioneer work of continuous domain generalization to utilize continuously changing source domains. [ABSTRACT FROM AUTHOR]

Objective: Biomarkers of Alzheimer disease vary between groups of self‐identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. Methods: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z‐transformations. Results: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aβ42/40, total tau, p‐tau181, and neurofilament light. CSF Aβ42/40 was negatively correlated with total tau and p‐tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aβ42/40, total tau, and p‐tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aβ42/40, Aβ42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. Interpretation: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495–506 [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker‐related declines in memory consolidation that are otherwise undetectable with single time point assessments. Methods: Thirty‐six (21.9%) cognitively unimpaired older adults (aged 60–91 years) were classified with elevated β‐amyloid (Aβ+) and 128 (78%) were Aβ− using positron emission tomography with 11CPittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries‐Prices, Face‐Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in‐clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC‐5), with 123 participants undergoing PACC‐5 follow‐up after 1.07 (standard deviation = 0.25) years. Results: At the cross‐section, there were no statistically significant differences in performance between Aβ+/− participants on any standard in‐clinic cognitive tests (eg, PACC‐5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7‐day learning curves on multiday BRANCH after 4 days of testing relative to Aβ− participants (Cohen d = 0.49, 95% confidence interval = 0.10–0.87). Diminished learning curves were associated with greater annual PACC‐5 decline (r = 0.54, p < 0.001). Interpretation: Very early Aβ‐related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507–517 [ABSTRACT FROM AUTHOR]

This study describes the development of open educational resources (OER) course materials for three computer-aided design (CAD) courses and the evaluation of student and faculty perceptions after their first implementation. We used mixed-method research techniques which involved analysis of quantitative data, utilization of COUP (cost, outcomes, usage, and perception) framework and analysis of qualitative comments using thematic coding. Results suggest students find faculty developed OER materials are more useful and preferable to a traditional textbook without compromising student academic performance. Most students agreed or strongly agreed that the materials provided fair treatment, access, opportunity, and advancement for all students. Assessment of faculty data showed that faculty have positive views of OER, their accessibility, customization, and equity measures, and reported increased student engagement when using OER. Faculty also indicated challenges with OER such as time and effort required to create OER contents and the need for periodic update of dynamic courses like CAD as technology and industry needs change. Several recommendations are provided in support of OER for academic effectiveness and student success. [ABSTRACT FROM AUTHOR]

Purpose: Due to various physical degradation factors and limited counts received, PET image quality needs further improvements. The denoising diffusion probabilistic model (DDPM) was a distribution learning-based model, which tried to transform a normal distribution into a specific data distribution based on iterative refinements. In this work, we proposed and evaluated different DDPM-based methods for PET image denoising. Methods: Under the DDPM framework, one way to perform PET image denoising was to provide the PET image and/or the prior image as the input. Another way was to supply the prior image as the network input with the PET image included in the refinement steps, which could fit for scenarios of different noise levels. 150 brain [ 18 F]FDG datasets and 140 brain [ 18 F]MK-6240 (imaging neurofibrillary tangles deposition) datasets were utilized to evaluate the proposed DDPM-based methods. Results: Quantification showed that the DDPM-based frameworks with PET information included generated better results than the nonlocal mean, Unet and generative adversarial network (GAN)-based denoising methods. Adding additional MR prior in the model helped achieved better performance and further reduced the uncertainty during image denoising. Solely relying on MR prior while ignoring the PET information resulted in large bias. Regional and surface quantification showed that employing MR prior as the network input while embedding PET image as a data-consistency constraint during inference achieved the best performance. Conclusion: DDPM-based PET image denoising is a flexible framework, which can efficiently utilize prior information and achieve better performance than the nonlocal mean, Unet and GAN-based denoising methods. [ABSTRACT FROM AUTHOR]

We and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers. [ABSTRACT FROM AUTHOR]

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET. [ABSTRACT FROM AUTHOR]

Speech processing requires extracting meaning from acoustic patterns using a set of intermediate representations based on a dynamic segmentation of the speech stream. Using whole brain mapping obtained in fMRI, we investigate the locus of cortical phonemic processing not only for single phonemes but also for short combinations made of diphones and triphones. We find that phonemic processing areas are much larger than previously described: they include not only the classical areas in the dorsal superior temporal gyrus but also a larger region in the lateral temporal cortex where diphone features are best represented. These identified phonemic regions overlap with the lexical retrieval region, but we show that short word retrieval is not sufficient to explain the observed responses to diphones. Behavioral studies have shown that phonemic processing and lexical retrieval are intertwined. Here, we also have identified candidate regions within the speech cortical network where this joint processing occurs. The neural dynamics underlying speech comprehension are not well understood. Here, the authors show that phonemic-to-lexical processing is localized to a large region of the temporal cortex, and that segmentation of the speech stream occurs mostly at the level of diphones. [ABSTRACT FROM AUTHOR]

Speech processing requires extracting meaning from acoustic patterns using a set of intermediate representations based on a dynamic segmentation of the speech stream. Using whole brain mapping obtained in fMRI, we investigate the locus of cortical phonemic processing not only for single phonemes but also for short combinations made of diphones and triphones. We find that phonemic processing areas are much larger than previously described: they include not only the classical areas in the dorsal superior temporal gyrus but also a larger region in the lateral temporal cortex where diphone features are best represented. These identified phonemic regions overlap with the lexical retrieval region, but we show that short word retrieval is not sufficient to explain the observed responses to diphones. Behavioral studies have shown that phonemic processing and lexical retrieval are intertwined. Here, we also have identified candidate regions within the speech cortical network where this joint processing occurs. The neural dynamics underlying speech comprehension are not well understood. Here, the authors show that phonemic-to-lexical processing is localized to a large region of the temporal cortex, and that segmentation of the speech stream occurs mostly at the level of diphones. [ABSTRACT FROM AUTHOR]