Neurovascular Mechanisms of Cognitive Aging: Sex-Related Differences in the Average Progression of Arteriosclerosis, White Matter Atrophy, and Cognitive Decline.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data ( N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like causality inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT) temporally precedes an acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.

Age, sex, and apolipoprotein E isoform alter contextual fear learning, neuronal activation, and baseline DNA damage in the hippocampus.

Age, female sex, and apolipoprotein E4 (E4) are risk factors to develop Alzheimer's disease (AD). There are three major human apoE isoforms: E2, E3, and E4. Compared to E3, E4 increases while E2 decreases AD risk. However, E2 is associated with increased risk and severity of post-traumatic stress disorder (PTSD). In cognitively healthy adults, E4 carriers have greater brain activation during learning and memory tasks in the absence of behavioral differences. Human apoE targeted replacement (TR) mice display differences in fear extinction that parallel human data: E2 mice show impaired extinction, mirroring heightened PTSD symptoms in E2 combat veterans. Recently, an adaptive role of DNA double strand breaks (DSBs) in immediate early gene expression (IEG) has been described. Age and disease synergistically increase DNA damage and decrease DNA repair. As the mechanisms underlying the relative risks of apoE, sex, and their interactions in aging are unclear, we used young (3 months) and middle-aged (12 months) male and female TR mice to investigate the influence of these factors on DSBs and IEGs at baseline and following contextual fear conditioning. We assessed brain-wide changes in neural activation following fear conditioning using whole-brain cFos imaging in young female TR mice. E4 mice froze more during fear conditioning and had lower cFos immunoreactivity across regions important for somatosensation and contextual encoding compared to E2 mice. E4 mice also showed altered co-activation compared to E3 mice, corresponding to human MRI and cognitive data, and indicating that there are differences in brain activity and connectivity at young ages independent of fear learning. There were increased DSB markers in middle-aged animals and alterations to cFos levels dependent on sex and isoform, as well. The increase in hippocampal DSB markers in middle-aged animals and female E4 mice may play a role in the risk for developing AD.

Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function.

BACKGROUND: α-klotho might play a role in neurodegenerative diseases. OBJECTIVE: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). METHODS: All subjects were between age 39 to 83+ (n = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. RESULTS: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. CONCLUSION: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels.

Amifostine (WR-2721) Mitigates Cognitive Injury Induced by Heavy Ion Radiation in Male Mice and Alters Behavior and Brain Connectivity.

The deep space environment contains many risks to astronauts during space missions, such as galactic cosmic rays (GCRs) comprised of naturally occurring heavy ions. Heavy ion radiation is increasingly being used in cancer therapy, including novel regimens involving carbon therapy. Previous investigations involving simulated space radiation have indicated a host of detrimental cognitive and behavioral effects. Therefore, there is an increasing need to counteract these deleterious effects of heavy ion radiation. Here, we assessed the ability of amifostine to mitigate cognitive injury induced by simulated GCRs in C57Bl/6J male and female mice. Six-month-old mice received an intraperitoneal injection of saline, 107 mg/kg, or 214 mg/kg of amifostine 1 h prior to exposure to a simplified five-ion radiation (protons, 28Si, 4He, 16O, and 56Fe) at 500 mGy or sham radiation. Mice were behaviorally tested 2-3 months later. Male mice that received saline and radiation exposure failed to show novel object recognition, which was reversed by both doses of amifostine. Conversely, female mice that received saline and radiation exposure displayed intact object recognition, but those that received amifostine prior to radiation did not. Amifostine and radiation also had distinct effects on males and females in the open field, with amifostine affecting distance moved over time in both sexes, and radiation affecting time spent in the center in females only. Whole-brain analysis of cFos immunoreactivity in male mice indicated that amifostine and radiation altered regional connectivity in areas involved in novel object recognition. These data support that amifostine has potential as a countermeasure against cognitive injury following proton and heavy ion irradiation in males.

Apolipoprotein E levels in the amygdala and prefrontal cortex predict relative regional brain volumes in irradiated Rhesus macaques.

In the brain, apolipoprotein E (apoE) plays an important role in lipid transport and response to environmental and age-related challenges, including neuronal repair following injury. While much has been learned from radiation studies in rodents, a gap in our knowledge is how radiation might affect the brain in primates. This is important for assessing risk to the brain following radiotherapy as part of cancer treatment or environmental radiation exposure as part of a nuclear accident, bioterrorism, or a nuclear attack. In this study, we investigated the effects of ionizing radiation on brain volumes and apoE levels in the prefrontal cortex, amygdala, and hippocampus of Rhesus macaques that were part of the Nonhuman Primate Radiation Survivor Cohort at the Wake Forest University. This unique cohort is composed of Rhesus macaques that had previously received single total body doses of 6.5-8.05 Gy of ionizing radiation. Regional apoE levels predicted regional volume in the amygdala and the prefrontal cortex. In addition, apoE levels in the amygdala, but not the hippocampus, strongly predicted relative hippocampal volume. Finally, radiation dose negatively affected relative hippocampal volume when apoE levels in the amygdala were controlled for, suggesting a protective compensatory role of regional apoE levels following radiation exposure. In a supplementary analysis, there also was a robust positive relationship between the neuroprotective protein α-klotho and apoE levels in the amygdala, further supporting the potentially protective role of apoE. Increased understanding of the effects of IR in the primate brain and the role of apoE in the irradiated brain could inform future therapies to mitigate the adverse effects of IR on the CNS.

The Effect of High Fat Diet on Cerebrovascular Health and Pathology: A Species Comparative Review.

In both humans and animal models, consumption of a high-saturated-fat diet has been linked to vascular dysfunction and cognitive impairments. Laboratory animals provide excellent models for more invasive high-fat-diet-related research. However, the physiological differences between humans and common animal models in terms of how they react metabolically to high-fat diets need to be considered. Here, we review the factors that may affect the translatability of mechanistic research in animal models, paying special attention to the effects of a high-fat diet on vascular outcomes. We draw attention to the dissociation between metabolic syndrome and dyslipidemia in rodents, unlike the state in humans, where the two commonly occur. We also discuss the differential vulnerability between species to the metabolic and vascular effects of macronutrients in the diet. Findings from animal studies are better interpreted as modeling specific aspects of dysfunction. We conclude that the differences between species provide an opportunity to explore why some species are protected from the detrimental aspects of high-fat-diet-induced dysfunction, and to translate these findings into benefits for human health.

High-resolution magnetic resonance imaging-based atlases for the young and adolescent domesticated pig (Sus scrofa).

BACKGROUND: Neurodevelopmental studies utilize the pig as a translational animal model due to anatomical and morphological similarities between the pig and human brain. However, neuroimaging resources are not as well developed for the pig as they are for humans and other animal models. We established a magnetic resonance imaging-based brain atlas at two different ages for biomedical studies utilizing the pig as a preclinical model. NEW METHOD: Twenty artificially-reared domesticated male pigs (Sus scrofa) and thirteen sow-reared adolescent domesticated male pigs (Sus scrofa) underwent a series of scans measuring brain macrostructure, microstructure, and arterial cerebral blood volume. RESULTS: An atlas for the 4-week-old and 12-week-old pig were created along with twenty-six regions of interest. Normative data for brain measures were obtained and detailed descriptions of the data processing pipelines were provided. COMPARISON WITH EXISTING METHOD: Atlases at the two different ages were created for the pig utilizing newer imaging technology and software. This facilitates the performance of longitudinal studies and enables more precise volume measurements in pigs of various ages by appropriately representing the neuroanatomical features of younger and older pigs and accommodating the proportion differences of the brain over time. CONCLUSION: Two high-resolution MRI brain atlases specific to the domesticated young and adolescent pig were created using defined image acquisition and data processing methods to facilitate the generation of high-quality normative data for neurodevelopmental research.

Age-related changes in cerebrovascular health and their effects on neural function and cognition: A comprehensive review.

The process of aging includes changes in cellular biology that affect local interactions between cells and their environments and eventually propagate to systemic levels. In the brain, where neurons critically depend on an efficient and dynamic supply of oxygen and glucose, age-related changes in the complex interaction between the brain parenchyma and the cerebrovasculature have effects on health and functioning that negatively impact cognition and play a role in pathology. Thus, cerebrovascular health is considered one of the main mechanisms by which a healthy lifestyle, such as habitual cardiorespiratory exercise and a healthful diet, could lead to improved cognitive outcomes with aging. This review aims at detailing how the physiology of the cerebral vascular system changes with age and how these changes lead to differential trajectories of cognitive maintenance or decline. This provides a framework for generating specific mechanistic hypotheses about the efficacy of proposed interventions and lifestyle covariates that contribute to enhanced cognitive well-being. Finally, we discuss the methodological implications of age-related changes in the cerebral vasculature for human cognitive neuroscience research and propose directions for future experiments aimed at investigating age-related changes in the relationship between physiology and cognitive mechanisms.

Decreased resting perfusion in precuneus and posterior cingulate cortex predicts tinnitus severity.

Functional magnetic resonance imaging has been increasingly used to understand the mechanisms involved in subjective tinnitus; however, researchers have struggled to reach a consensus about a primary mechanistic model to explain tinnitus. While many studies have used functional connectivity of the BOLD signal to understand how patterns of activity change with tinnitus severity, there is much less research on whether there are differences in more fundamental physiology, including cerebral blood flow, which may help inform the BOLD measures. Here, arterial spin labeling was used to measure perfusion in four regions-of-interest, guided by current models of tinnitus, in a sample of 60 tinnitus patients and 31 control subjects. We found global reductions in cerebral perfusion in tinnitus compared with controls. Additionally, we observed a significant negative correlation between tinnitus severity and perfusion. These results demonstrate that examining perfusion from the whole brain may present a complementary tool for studying tinnitus. More research will help better understand the physiology underlying these differences in perfusion.

Longitudinal Effects of Immediate and Delayed Estradiol on Cognitive Performance in a Spatial Maze and Hippocampal Volume in Menopausal Macaques Under an Obesogenic Diet.

The consumption of a diet high in fat and refined sugars has several health risks, including the development of cognitive decline and neurodegeneration. For women, menopause carries additional health risks that may interact with a high-fat diet in negative ways. Some symptoms of menopause, including cognitive impairments, can be modulated by hormone replacement therapy (HRT), but the hormonal formulation and the timing of the treatment relative to the onset of menopause are critical factors determining its efficacy. Little is known about how obesogenic, high-fat, high-sugar diets interact with HRT in menopause to affect cognition and neurodegeneration. Given the high prevalence of the consumption of an obesogenic Western-style diet, understanding how the effects of HRT are modulated by an obesogenic diet is critical for developing optimized therapeutic strategies for peri- and post-menopausal women. In this study, we investigated by magnetic resonance imaging (MRI) the effects of either immediate or delayed estradiol hormone therapy on cognition and neuroanatomy following ovo-hysterectomy (OvH) of aged, female rhesus macaques on an obesogenic diet. The macaques were followed for 2.5 years after ovo-hysterectomy, with four time points at which anatomical MRIs were acquired. Analysis of hippocampal volumes revealed an interaction between time point and treatment; hippocampal volumes in the delayed estrogen group, but not the immediate estrogen group, increased over time compared to those in untreated controls. Performance on a hippocampal-dependent spatial maze task showed improved performance in estrogen treated animals compared to OvH macaques given placebo. These results indicate that HRT may contribute to beneficial cognitive outcomes after menopause under an obesogenic diet.

Age-related differences in functional brain network segregation are consistent with a cascade of cerebrovascular, structural, and cognitive effects.

Age-related declines in cognition are associated with widespread structural and functional brain changes, including changes in resting-state functional connectivity and gray and white matter status. Recently we have shown that the elasticity of cerebral arteries also explains some of the variance in cognitive and brain health in aging. Here, we investigated how network segregation, cerebral arterial elasticity (measured with pulse-DOT-the arterial pulse based on diffuse optical tomography) and gray and white matter status jointly account for age-related differences in cognitive performance. We hypothesized that at least some of the variance in brain and cognitive aging is linked to reduced cerebrovascular elasticity, leading to increased cortical atrophy and white matter abnormalities, which, in turn, are linked to reduced network segregation and decreases in cognitive performance. Pairwise comparisons between these variables are consistent with an exploratory hierarchical model linking them, especially when focusing on association network segregation (compared with segregation in sensorimotor networks). These findings suggest that preventing or slowing age-related changes in one or more of these factors may induce a neurophysiological cascade beneficial for preserving cognition in aging.

Optical measures of cerebral arterial stiffness are associated with white matter signal abnormalities and cognitive performance in normal aging.

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18-87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline.

Functional Brain Changes During Mindfulness-Based Cognitive Therapy Associated With Tinnitus Severity.

Mindfulness-based therapies have been introduced as a treatment option to reduce the psychological severity of tinnitus, a currently incurable chronic condition. This pilot study of twelve subjects with chronic tinnitus investigates the relationship between measures of both task-based and resting state functional magnetic resonance imaging (fMRI) and measures of tinnitus severity, assessed with the Tinnitus Functional Index (TFI). MRI was measured at three time points: before, after, and at follow-up of an 8-week long mindfulness-based cognitive therapy intervention. During the task-based fMRI with affective sounds, no significant changes were observed between sessions, nor was the activation to emotionally salient compared to neutral stimuli significantly predictive of TFI. Significant results were found using resting state fMRI. There were significant decreases in functional connectivity among the default mode network, cingulo-opercular network, and amygdala across the intervention, but no differences were seen in connectivity with seeds in the dorsal attention network (DAN) or fronto-parietal network and the rest of the brain. Further, only resting state connectivity between the brain and the amygdala, DAN, and fronto-parietal network significantly predicted TFI. These results point to a mostly differentiated landscape of functional brain measures related to tinnitus severity on one hand and mindfulness-based therapy on the other. However, overlapping results of decreased amygdala connectivity with parietal areas and the negative correlation between amygdala-parietal connectivity and TFI is suggestive of a brain imaging marker of successful treatment.

Assessing mindfulness-based cognitive therapy intervention for tinnitus using behavioural measures and structural MRI: a pilot study.

Objective: We used a minimally-modified version of Mindfulness-Based Cognitive Therapy (MBCT) to treat symptoms of distress associated with tinnitus.Design: Audiological screening (establishing a baseline) was conducted prior to treatment and at three time-points: pre-intervention, post-intervention and follow-up, 8 weeks after completion of training. MRI tests were also conducted at these three time-points.Study sample: Twenty-one participants were enrolled in the study, of whom 15 completed training and audiological testing and eight completed the MRI portion of the study.Results: Scores on tinnitus-related questionnaires showed a significant decline either from pre- to post-intervention or from pre-intervention to follow-up, despite no significant change during baseline. Voxel-based morphometric analysis of the structural MRI scans revealed clusters in bilateral superior frontal gyrus that exhibited significant increases in grey matter volume over the period of intervention and follow-up. Further, grey matter changes in occipital and cingulate regions correlated with declines in tinnitus handicap.Conclusions: This pilot study supports MBCT as an adequate approach for treating distressing tinnitus and suggests that neuroanatomical changes may reflect reductions in tinnitus-related severity. Although our small sample size precludes drawing strong conclusions, there is potential for assessing neuroanatomical changes due to mindfulness-based interventions in tinnitus.

Publisher Correction: Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring.

In Fig. 4c of this Article, the scale bar units were incorrectly stated as 'µV'; the correct units are 'mV'. The figure has now been amended accordingly.

Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring.

Skin-interfaced medical devices are critically important for diagnosing disease, monitoring physiological health and establishing control interfaces with prosthetics, computer systems and wearable robotic devices. Skin-like epidermal electronic technologies can support these use cases in soft and ultrathin materials that conformally interface with the skin in a manner that is mechanically and thermally imperceptible. Nevertheless, schemes so far have limited the overall sizes of these devices to less than a few square centimetres. Here, we present materials, device structures, handling and mounting methods, and manufacturing approaches that enable epidermal electronic interfaces that are orders of magnitude larger than previously realized. As a proof-of-concept, we demonstrate devices for electrophysiological recordings that enable coverage of the full scalp and the full circumference of the forearm. Filamentary conductive architectures in open-network designs minimize radio frequency-induced eddy currents, forming the basis for structural and functional compatibility with magnetic resonance imaging. We demonstrate the use of the large-area interfaces for the multifunctional control of a transhumeral prosthesis by patients who have undergone targeted muscle-reinnervation surgery, in long-term electroencephalography, and in simultaneous electroencephalography and structural and functional magnetic resonance imaging.

Publisher Correction: Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring.

In Fig. 4c of this Article originally published, the bottom y axis was incorrectly labelled as 'MRI-ECG (µV)'; the correct label is 'MRI/ECG'. In addition, in Fig. 4d, the bottom y axis was incorrectly labelled as 'ECG (µV)'; the correct label is 'ECG (mV)'. The scale bar units were also incorrectly stated as 'mV', the correct units are 'µV'. The figure has now been amended accordingly.

Dissociating tinnitus patients from healthy controls using resting-state cyclicity analysis and clustering.

Chronic tinnitus is a common and sometimes debilitating condition that lacks scientific consensus on physiological models of how the condition arises as well as any known cure. In this study, we applied a novel cyclicity analysis, which studies patterns of leader-follower relationships between two signals, to resting-state functional magnetic resonance imaging (rs-fMRI) data of brain regions acquired from subjects with and without tinnitus. Using the output from the cyclicity analysis, we were able to differentiate between these two groups with 58-67% accuracy by using a partial least squares discriminant analysis. Stability testing yielded a 70% classification accuracy for identifying individual subjects' data across sessions 1 week apart. Additional analysis revealed that the pairs of brain regions that contributed most to the dissociation between tinnitus and controls were those connected to the amygdala. In the controls, there were consistent temporal patterns across frontal, parietal, and limbic regions and amygdalar activity, whereas in tinnitus subjects, this pattern was much more variable. Our findings demonstrate a proof-of-principle for the use of cyclicity analysis of rs-fMRI data to better understand functional brain connectivity and to use it as a tool for the differentiation of patients and controls who may differ on specific traits.

Comparing Cyclicity Analysis With Pre-established Functional Connectivity Methods to Identify Individuals and Subject Groups Using Resting State fMRI.

The resting state fMRI time series appears to have cyclic patterns, which indicates presence of cyclic interactions between different brain regions. Such interactions are not easily captured by pre-established resting state functional connectivity methods including zero-lag correlation, lagged correlation, and dynamic time warping distance. These methods formulate the functional interaction between different brain regions as similar temporal patterns within the time series. To use information related to temporal ordering, cyclicity analysis has been introduced to capture pairwise interactions between multiple time series. In this study, we compared the efficacy of cyclicity analysis with aforementioned similarity-based techniques in representing individual-level and group-level information. Additionally, we investigated how filtering and global signal regression interacted with these techniques. We obtained and analyzed fMRI data from patients with tinnitus and neurotypical controls at two different days, a week apart. For both patient and control groups, we found that the features generated by cyclicity and correlation (zero-lag and lagged) analyses were more reliable than the features generated by dynamic time warping distance in identifying individuals across visits. The reliability of all features, except those generated by dynamic time warping, improved as the global signal was regressed. Nevertheless, removing fluctuations >0.1 Hz deteriorated the reliability of all features. These observations underscore the importance of choosing appropriate preprocessing steps while evaluating different analytical methods in describing resting state functional interactivity. Further, using different machine learning techniques including support vector machines, discriminant analyses, and convolutional neural networks, our results revealed that the manifestation of the group-level information within all features was not sufficient enough to dissociate tinnitus patients from controls with high sensitivity and specificity. This necessitates further investigation regarding the representation of group-level information within different features to better identify tinnitus-related alternation in the functional organization of the brain. Our study adds to the growing body of research on developing diagnostic tools to identify neurological disorders, such as tinnitus, using resting state fMRI data.