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In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

To identify individual differences and potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT, index of processing speed) and paired-associate learning (PAL, index of verbal episodic memory). svRT and PAL results were combined with 22 survey questions. Analysis of MindCrowd’s svRT data revealed education and reported stroke as potential modifiers of changes in processing speed and memory from younger to older ages (ntotal=75,666,nwomen= 47,700,nmen= 27,966; ages 18-85 years old, mean (M)Age= 46.54, standard deviation(SD)Age= 18.40). To complement this work, we evaluated complex recognition reaction time (cvrRT) in the UK Biobank cohort (ntotal=158,249nwomen= 89,333nmen= 68,916; ages 40-70 years old,MAge= 55.81,SDAge= 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of the MindCrowd cohort. Labeled UKBb MindCrowd (ntotal=39,795,nwomen= 29,640,nmen= 10,155; ages 40-70 years old,MAge= 56.59,SDAge= 8.16), this subset was carefully selected to mirror the UK Biobank. An identical linear model (LM) was used to assess both cohorts. The LM revealed similarities between MindCrowd and the UK Biobank across most results, despite obvious cohort differences (e.g., US vs. the UK). Notable divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer’s disease (FHAD) was associated with longer RTs in only. (2) Compared to being a man with more education, being a woman was associated with longer cvrRT length differences observed from younger to older ages. Divergent results from UKBb MindCrowd include more education and reported smoking. More education was associated with shorter and smoking longer cvrRTs differences observed from younger to older ages. Collected with our prior work, MindCrowd is beginning to reveal the intricate network connecting processing speed, memory, and cognition to healthy and pathological brain aging.

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 were COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6±163 pg/ml) compared to COVID-neg ICU patients (19.3±5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3±3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

The COVID-19 pandemic has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. This study tested whether motor function can be assessed at home. One hundred seventy-seven older adults nationwide (recruited through the MindCrowd electronic cohort) completed a brief functional upper-extremity assessment at home and unsupervised. Performance data were compared to data from an independent sample of community-dwelling older adults (N=250) assessed by an experimenter in-lab. The effect of age on performance was similar between the in-lab and at-home groups for both the dominant and non-dominant hand. Practice effects were also similar between the groups. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution in response to the COVID-19 pandemic and telehealth practice and other research involving remote or geographically isolated individuals.

Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18–85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

Well-established literature indicates that older adults have poorer cerebral white matter integrity, as measured through diffusion tensor imaging (DTI). Age differences in DTI have been observed widely across white matter, although some tracts appear more sensitive to the effects of aging than others. Factors like APOE ε4 status and sex may contribute to individual differences in white matter integrity that also selectively impact certain tracts, and could influence DTI changes in aging. The present study explored the degree to which age, APOE ε4, and sex exerted global vs. tract specific effects on DTI metrics in cognitively healthy late middle-aged to older adults. Data from 49 older adults (ages 54–92) at two time-points separated by approximately 2.7 years were collected. DTI metrics, including fractional anisotropy (FA) and mean diffusivity (MD), were extracted from nine white matter tracts and global white matter. Results showed that across timepoints, FA and MD increased globally, with no tract-specific changes observed. Baseline age had a global influence on both measures, with increasing age associated with lower FA and higher MD. After controlling for global white matter FA, age additionally predicted FA for the genu, callosum body, inferior fronto-occipital fasciculus (IFOF), and both anterior and posterior cingulum. Females exhibited lower global FA on average compared to males. In contrast, MD was selectively elevated in the anterior cingulum and superior longitudinal fasciculus (SLF), for females compared to males. APOE ε4 status was not predictive of either measure. In summary, these results indicate that age and sex are associated with both global and tract-specific alterations to DTI metrics among a healthy older adult cohort. Older women have poorer white matter integrity compared to older men, perhaps related to menopause-induced metabolic changes. While age-related alterations to white matter integrity are global, there is substantial variation in the degree to which tracts are impacted, possibly as a consequence of tract anatomical variability. The present study highlights the importance of accounting for global sources of variation in DTI metrics when attempting to investigate individual differences (due to age, sex, or other factors) in specific white matter tracts.

Purpose of Review Precision Aging® is a novel concept that we have recently employed to describe how the model of precision medicine can be used to understand and define the multivariate risks that drive age-related cognitive impairment (ARCI). Hypertension and cardiovascular disease are key risk factors for both brain function and cognitive aging. In this review, we will discuss the common mechanisms underlying the risk factors for both hypertension and ARCI and how the convergence of these mechanisms may be amplified in an individual to drive changes in brain health and accelerate cognitive decline. Recent Findings Currently, our cognitive health span does not match our life span. Age-related cognitive impairment and preventing and treating ARCI will require an in-depth understanding of the interrelated risk factors, including individual genetic profiles, that affect brain health and brain aging. Hypertension and cardiovascular disease are important risk factors for ARCI. And, many of the risk factors for developing hypertension, such as diabetes, smoking, stress, viral infection, and age, are shared with the development of ARCI. We must first understand the mechanisms common to the converging risk factors in hypertension and ARCI and then design person-specific therapies to optimize individual brain health. Summary The understanding of the convergence of shared risk factors between hypertension and ARCI is required to develop individualized interventions to optimize brain health across the life span. We will conclude with a discussion of possible steps that may be taken to decrease ARCI and optimize an individual’s cognitive life span.

ABRSTACTBackgroundVascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating the risks associated with underlying vascular disease. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific impact of smoking on cognitive function and with contradictory results. This is an important topic since smoking and cardiovascular disease negatively impact health and possibly women have the greater lifetime risk of stroke and dementia than men. In this study, we sought to investigate the effect-modification of sex on the relationship between smoking, cardiovascular disease and verbal learning and memory function.MethodsUsing MindCrowd, a web-based cohort of over 70,000 people aged 18 - 85, we investigated whether sex modifies the impact of smoking and cardiovascular disease on verbal memory performance on a paired-associate learning task using both multiple regression and propensity matching approaches. Artificial error introduction and permutation testing underscored the stability of our results. To demonstrate the necessity of large sample sizes to detect an interaction of sex and smoking, we performed down sampling analyses.FindingsWe found significant interactions in that smoking impacts verbal learning performance more in women and cardiovascular disease more in men across a wide age range.InterpretationThese results suggest that smoking and cardiovascular disease impact verbal learning and memory throughout adulthood. Smoking particularly affects learning and memory in women and cardiovascular disease has a larger effect in men. Although the reasons for these sex-modification effects are not entirely understood, our findings highlight the importance of considering biological sex in VCID.FundingMueller Family Charitable Trust; Arizona Alzheimer’s Consortium; Flinn Foundation; The McKnight Brain Research Foundation; NIH-NIA grant R01-AG049465.

Prior research investigating associations between hypertension, obesity, and apolipoprotein (APOE) genotype status with memory performance among older adults has yielded inconsistent results. This may reflect, in part, a lack of first accounting for the effects these variables have on structural brain changes, that in turn contribute to age-related memory impairment. The current study sought to clarify the relationships between these factors via path modeling. We hypothesized that higher body mass index (BMI), hypertension, and being an APOE-e4 allele carrier would predict poorer memory scores, with much of these effects accounted for by indirect effects operating via differences in the integrity of temporal stem white matter. Participants included 125 healthy older adults who underwent neuropsychological assessment and diffusion-weighted MRI scanning. Direct effects were found for hypertension and demographic variables including age, sex, and education. Importantly, indirect effects were found for BMI, hypertension, APOE-e4 status, age, and sex, where these factors predicted memory scores via their impact on temporal stem diffusion measures. There was also a dual effect of sex, with a direct effect indicating that females had better memory performance overall, and an indirect effect indicating that females with greater temporal stem diffusion had poorer memory performance. Results suggest that changes to the integrity of temporal white matter in aging may underpin reduced memory performance. These results highlight that accounting for variables that not only directly impact cognition, but also for those that indirectly impact cognition via structural brain changes, is crucial for understanding the impact of risk factors on cognition.

Objectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer’s disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18–85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified. Copyright Talboom et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited

Among non-Hispanic whites, cardiovascular risk factors are associated with increased mortality and poorer cognition. Prevalence of cardiovascular risk factors among aging Hispanics is also high and Hispanics generally have poorer access to healthcare, yet they tend to have advantageous cardiovascular disease rates and outcomes and live longer than non-Hispanic whites, an epidemiological phenomenon commonly referred to as the Hispanic or Latino health paradox. Although robust data support these ethnic benefits on physical health and mortality, it is unknown if it extends to include cognition resilience advantages in older adulthood. The present study compared relationships between cardiovascular risk and cognition (executive functions and episodic memory) in late middle age and older Hispanics (n = 87) and non-Hispanic whites (n = 81). Participants were selected from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases. Hispanics and non-Hispanic white groups were matched on age (50–94 yr, mean age = 72 yr), education, gender, cognitive status (i.e., cognitively healthy versus mildly cognitively impaired), and apolipoprotein E4 status. History of hypertension and higher body mass index were both associated with poorer executive functions among Hispanics but not non-Hispanic whites. Our findings suggest greater vulnerability to impairments in executive functions among Hispanics with hypertension and obesity, contrary to the notion of a Hispanic health paradox for cognitive aging.

The resource modulation hypothesis suggests that the influence of genes on cognitive functioning increases with age. The KIBRA single nucleotide polymorphism rs17070145, associated with episodic memory and working memory, has been suggested to follow such a pattern, but few studies have tested this assertion directly. The present study investigated the relationship between KIBRA alleles (T carriers vs. CC homozygotes), cognitive performance, and brain volumes in three groups of cognitively healthy adults —middle aged (ages 52 - 64, n = 38), young old (ages 65 - 72, n = 45), and older old (ages 73 - 92, n = 62) – who were carefully matched on potentially confounding variables including apolipoprotein e4 status and hypertension. Consistent with our prediction, T carriers maintained verbal memory performance with increasing age while CC homozygotes declined. Voxel-based morphometric analysis of magnetic resonance images showed an advantage for T carriers in frontal white matter volume that increased with age. Focusing on the older old group, this advantage for T carriers was also evident in left lingual gyrus gray matter and several additional frontal white matter regions. Contrary to expectations, neither KIBRA nor the interaction between KIBRA and age predicted hippocampal volumes. None of the brain regions investigated showed a CC homozygote advantage. Taken together, these data suggest that KIBRA results in decreased verbal memory performance and lower brain volumes in CC homozygotes compared to T carriers, particularly among the oldest old, consistent with the resource modulation hypothesis.

Objective To assess whether the pattern of diffusion changes among a cohort of individuals showing BMI-related increases in white matter volume reflects healthy expansion of myelin or damaged white matter. Methods Diffusion MRI measures (axial, radial, and fractional anisotropy) were obtained from 94 females, aged 52-92. Relationships between BMI and diffusion measures were assessed controlling for age, hypertension, and diabetes status using general linear modeling. Associations between diffusion measures and cognitive status (memory, executive functions, and visuomotor speed) were assessed using multiple regressions, controlling for age, education, hypertension, and diabetes status. Results Higher levels of BMI were associated with lower axial diffusion in frontal, temporal, parietal, internal capsule, and cerebellar white matter. Lower fractional anisotropy was observed in bilateral temporal white matter and the right corticospinal tract, with higher radial diffusion in temporal and temporoparietal white matter. Importantly, diffusion measures predicted reductions in executive functioning, memory, and visuomotor speed. Conclusions The pattern of diffusion changes in regions of white matter showing BMI-related volume increases are not due to expansion of normal myelin, but instead suggests damage to white matter that has important consequences for cognitive functioning.

Diffusion tensor imaging (DTI) is a Magnetic Resonance Imaging (MRI) technique that can reveal in vivo tissue microstructure by measuring diffusion of water in tissue. DTI has become an important tool in many clinical applications, such as assessment of white matter maturation, locating white matter lesions, and providing anatomical connectivity information. However, DTI usually requires long examination times due to the repetitive nature of the acquisition and is very sensitive to motion. These drawbacks have become the largest obstacles to full utilization of DTI. In this work, we propose to overcome these obstacles by using a model-based compressive imaging approach. Our approach consist of models to efficiently represent diffusion-encoded images and the corresponding recovery schemes based on compressive sensing (CS) principles. Our results indicate that the proposed model-based approach can allow reliable recovery of DTI signal from undersampled measurements and outperforms conventional CS recovery.

To examine how feature-specific pattern-analysing processes affect implicit and explicit memory test performance, words were displayed for study and testing in 2 visually distinct formats: upside down vs. normal for Experiment 1, upside down vs. backward for Experiement 2, and in Applesoft pudgy vs. shadow typeface for Experiment 3. Implicit and explicit memory were assessed with word identification and recognition tests, respectively.

The speed and accuracy with which subjects can read words is enhanced or ‘‘primed’’ by a prior presentation of the same words. Moreover, priming effects are generally larger when the physical form of the words is maintained from the first to the second presentation. We investigated the neural basis of format-specific priming in a mirror word-reading task using event-related functional magnetic resonance imaging (fMRI). Participants read words that were presented either in mirror-image (M) orientation or in normal (N) orientation and were repeated either in the same or the alternate orientation, creating 4 study--test conditions, N-N, M-N, N-M, and M-M. Priming of N words resulted in reductions in fMRI signal in multiple brain regions, even though reading times (RTs) were unchanged. Priming of M words showed a pattern of RTs consistent with format-specific priming, with greater reductions when the prime matched the form of the test word. Primingrelated reductions in fMRI activity were evident in all regions involved in mirror-image reading, regardless of the orientation of the prime. Importantly, reductions in several posterior regions, including fusiform, superior parietal, and superior temporal regions were also format specific. That is, signal reductions in these regions were greatest when the visual form of the prime and target matched (M-M compared with N-M). The results indicate that, although there are global neural priming effects due to stimulus repetition, it is also possible to identify regional brain changes that are sensitive to the specific perceptual overlap of primes and targets.

Evidence from multiple paradigms has converged on the finding that stimulus repetition most often results in decreases in neural activity. The mechanisms of these decreases, however, are not yet well understood. The current study attempted to determine, through the use of masked word repetition priming, whether decreases in activity levels occur in response to pre- or post-prime identification processes, fMRI was performed while participants engaged in a lexical decision task where words were primed with a briefly presented and masked word. Masked word priming resulted in increased fMRI signal in regions of cortex associated with the perceptual identification of the target words. This finding provides evidence suggesting that the impact of repetition priming on the fMRI signal may depend upon whether or not the prime is identified.

A new low-temperature polycrystalline-silicon LTPS process was developed. The doping mask for p-type TFT was compared with PR mask and gate hard mask. The process and design challenge in gate hard mask was compared with the photo resist residues problem encountered in PR mask process. In the gate hard mask technology, the gates of p-type and n-type TFTs are etched in different steps for p-type TFT S/D doping and n-type TFT LDD doping. The results indicate the gate insulator loss and the CD loss due to these different etching steps can be controlled in the same magnitude, and the TFT electrical characteristics of NMOS and PMOS are good enough for pixel and driver applications.