Higher Free Water Research Articles

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. Higher sOB-R was associated with lower fractional anisotropy (FA, β=-0.114±0.02, p<0.001), and higher free water (FW, β=0.091±0.022, p<0.001) and peak-width skeletonized mean diffusivity (PSMD, β=0.078±0.021, p<0.001). Correspondingly, higher FLI was associated with higher FA (β=0.115±0.027, p<0.001) and lower FW (β=-0.096±0.029, p=0.001) and PSMD (β=-0.085±0.028, p=0.002). Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Association of Blood Pressure With Brain White Matter Microstructural Integrity Assessed With MRI Diffusion Tensor Imaging in Healthy Young Adults.

High blood pressure (BP) in middle-aged and older adults is associated with a brain white matter (WM) microstructural abnormality. However, little evidence is available in healthy young adults. We investigated the associations between high BP and WM microstructural integrity in young adults. This study included 1015 healthy young adults (542 women, 22-37 years) from the Human Connectome Project. Brachial systolic and diastolic BP were measured using a semiautomatic or manual sphygmomanometer. Diffusion-weighted magnetic resonance imaging was acquired to obtain diffusion tensor imaging metrics of free water (FW) content, FW-corrected WM fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Using whole-brain voxel-wise linear regression models and ANCOVA, we examined associations of BP and hypertension stage with diffusion tensor imaging metrics after adjusting for age, sex, education, body mass index, smoking status, alcohol consumption history, and differences in the b value used for diffusion magnetic resonance imaging. Systolic and diastolic BP of the sample (mean±SD) were 122.8±13.0 and 76.0±9.9 mm Hg, respectively. Associations of BP with diffusion tensor imaging metrics revealed regional heterogeneity for FW-corrected fractional anisotropy. High BP and high hypertension stage were associated with higher FW and lower FW-corrected axial diffusivity, FW-corrected radial diffusivity, and FW-corrected mean diffusivity. Moreover, associations of high diastolic BP and hypertension stage with high FW were found only in men not in women. High BP in young adults is associated with altered brain WM microstructural integrity, suggesting that high BP may have damaging effects on brain WM microstructural integrity in early adulthood, particularly in men.

Heart-brain mapping: Cardiac atrial function is associated with distinct cerebral regions with high free water in older adults

Left atrial (LA) dysfunction has been linked to cognitive impairment and cerebrovascular dysfunction. Higher brain free-water (FW) derived from diffusion-MRI was associated with early and subtle cerebrovascular dysfunction and more severe cognitive impairment. We hypothesized that LA dysfunction would correlate with higher brain free-water (FW) among healthy older adults. 56 community older adults (73.13 ± 3.56 years; 24 female) with normal cognition and without known cardiovascular disease who had undergone cardiac-MRI, brain-MRI, and neuropsychological assessments were included. Whole-brain voxel-level general linear models were constructed to correlate brain FW measures with LA indices. We found lower scores in LA function measures were related to higher grey matter (GM) FW in regions including orbital frontal and right temporal regions (p < 0.01, family-wise error corrected). In parallel, LA dysfunction was associated with higher FW in white matter (WM) fibres including superior longitudinal fasciculus, internal capsule, and superior corona radiata. However, LA dysfunction was not related to WM tissue reduction and GM cortical thinning. Moreover, these cardiac-related higher brain FW were associated with lower executive function and higher serum B-type natriuretic peptide (p < 0.05, Holm–Bonferroni corrected). These findings may have implications for anti-ageing preventive strategies targeting cardiac and cerebral vascular functions to improve heart and brain outcomes.

Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder

BackgroundRestricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB.MethodsWe utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB.ResultsIndividuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes.LimitationsThe basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated.ConclusionsThese new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

Retinal perfusion is linked to cognition and brain MRI biomarkers in Black Americans.

We investigated whether retinal capillary perfusion is a biomarker of cerebral small vessel disease and impaired cognition among Black Americans, an understudied group at higher risk for dementia. We enrolled 96 Black Americans without known cognitive impairment. Four retinal perfusion measures were derived using optical coherence tomography angiography. Neurocognitive assessment and brain magnetic resonance imaging (MRI) were performed. Multiple linear regression analyses were performed. Lower retinal capillary perfusion was correlated with worse Oral Symbol Digit Test (P<=0.005) and Fluid Cognition Composite scores (P<=0.02), but not with the Crystallized Cognition Composite score (P>=0.41). Lower retinal perfusion was also correlated with higher free water and peak width of skeletonized mean diffusivity, and lower fractional anisotropy (all P<0.05) on MRI (N=35). Lower retinal capillary perfusion is associated with worse information processing, fluid cognition, and MRI biomarkers of cerebral small vessel disease, but is not related to crystallized cognition.

Assessing neuroinflammatory differences in FTLD‐Tau vs FTLD‐TDP using free water diffusion

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is associated with two pathological substrates: Tau and TAR‐DNA‐binding protein 43 (TDP‐43). In‐vivo detection of the pathological substrate is still not possible in FTLD‐related syndromes but progressive supranuclear palsy (PSP) is consistently associated with FTLD‐Tau while semantic‐variant primary progressive aphasia (svPPA) and FTD‐MND (FTD‐ALS) are associated with FTLD‐TDP. In the absence of disease‐specific markers in FTLD, it is necessary to identify biomarkers that can help distinguish FTLD‐Tau and FTLD‐TDP. Recent research has implicated neuroinflammation as a common feature across FTLD subtypes (Bright et al., 2019), however further research is required to investigate neuroinflammatory differences between FTLD‐Tau and FTLD‐TDP, given that microglial burden and activation may differ in FTLD subtypes (Woollacott et al., 2020). The free water fraction (FW), a metric generated from diffusion MRI (dMRI) (Pasternak et al., 2009), is a non‐specific marker of neuroinflammation (Bergamino, Walsh and Stokes, 2021). We will investigate differences in FW diffusion between patients with presumed FTLD‐Tau versus FTLD‐TDP. We hypothesize that differences in neuroinflammation between FTLD‐Tau and FTLD‐TDP can be identified using the free water measure, which may infer neuroinflammatory differences.MethodFree‐water maps were generated from dMRI datasets obtained from 43 subjects: 19 with presumed FTLD‐Tau (PSP, mean age = 70), 6 with presumed FTLD‐TDP (mean age = 67, 4 svPPA, 2 FTD‐ALS), and 19 healthy controls (mean age 63). Grey matter (GM) was segmented from T1‐weighted MRIs using FSL’s ‘fast’, projected onto the diffusion MRI space, where free‐water maps were averaged across the GM. The average free water estimates from FTLD‐Tau, FTLD‐TDP and control datasets were tested for group differences using student’s t‐tests and analysis of covariance (ANCOVA), with age as a covariate.ResultsANCOVA revealed significant differences between the groups (F = 6.47, p &lt; 0.01). Post‐hoc tests showed significantly higher free‐water in FTLD‐Tau (p&lt;0.01) and FTLD‐TDP (p&lt;0.01) compared to controls. There was also higher free water in FTLD‐TDP in comparison to FTLD‐Tau, approaching significance (p = 0.0503)ConclusionOur preliminary data shows significant differences between healthy controls and patients with FTLD‐Tau and FTLD‐TDP and a trend for increased free water in FTLD‐TDP patients vs FTLD‐Tau, which may be indicative of neuroinflammatory differences.

Associations of Blood Cardiovascular Biomarkers With Brain Free Water and Its Relationship to Cognitive Decline: A Diffusion-MRI Study.

There is an increasing awareness of the "Heart-Brain Connection", whereby cardiovascular function is connected with cognition. Diffusion MRI studies reported higher brain free-water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In current work, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition. Participants recruited from two Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15)) with brain white matter (WM) and cortical grey matter (GM) FW derived from diffusion-MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain-FW, and cognitive decline using path models. 308 older adults (76 no cognitive impairment, 134 cognitive impairment no dementia, and 98 Alzheimer's disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespread WM regions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p < 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: β=-0.115, SE=0.034, p=0.001; NT-proBNP: β=-0.154, SE=0.046, p=0.001; GDF-15: β=-0.073, SE=0.027, p=0.006); in contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: β=-0.126, SE=0.039, p=0.001; NT-proBNP: β=-0.110, SE=0.038, p=0.004; GDF-15: β=-0.117, SE=0.035, p=0.001). Similar full mediation effects of brain FW were also identified for baseline cognition. Results suggested a role of brain-FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.

Leveraging longitudinal, multi‐site diffusion MRI data in conjunction with free‐water analysis to characterize patterns of white matter neurodegeneration in aging

AbstractBackgroundSeveral prior studies have used diffusion MRI to investigate the relationship between white matter microstructure and aging; however, many of these studies used conventional diffusion MRI measures and single site data. The goal of the study is to leverage multi‐site harmonized diffusion MRI data in conjunction with a novel post‐processing technique [i.e., free‐water (FW) correction] to quantify the aging related tract‐specific changes in white matter microstructure.MethodThe dataset used in this study was collated using several well‐established longitudinal cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory &amp; Aging Project (VMAP)]. In total, this dataset included 1,909 participants (mean age at baseline: 72±9 years, 59% female) and 4,844 imaging sessions (mean number of visits: 4 ± 2 years, interval range: 1–12 years). Data was processed using standard approaches and uncorrected fractional anisotropy (FAU) was quantified with seven white matter tractography atlases (see Figure 1A). Data was then post‐processed using the FW correction technique and FW and FW‐corrected FA (FAT) values were quantified. Data were then harmonized using the ComBat technique and linear mixed‐effects regression was conducted on each microstructural measure, covarying for age at baseline, sex, cognitive status, education, APOE‐ε4 carrier status, and APOE‐ε2 carrier status. The effect of aging was modelled using an Age_at_Baseline x Interval interaction term.ResultAge was associated with lower FAU in all seven tracts (pFDR range: 4.77x10‐10 to ‐0.01). In the FW analysis, age was associated with higher FW in all seven tracts (pFDR range: 7.81x10‐12 to 1.33x10‐6). For FAT, however, age was only associated with lower FAT in the limbic tracts (pFDR=0.024) in addition to the occipital (pFDR=1.19x10‐8), parietal (pFDR=2.32x10‐4), and prefrontal (pFDR=0.024) TC tracts. Figure 1B‐D illustrates our findings.ConclusionThis study suggests that while there are global associations with FAU and age, these associations are attenuated once correcting for partial volume effects. Leveraging FW analysis, we found a global association with FW and age, whereby age is associated with higher FW. Further, we found that age is associated with reductions in FAT in the limbic and occipital/parietal/prefrontal TC tracts.

Leveraging longitudinal, multi‐site diffusion MRI data in conjunction with free‐water analysis to characterize patterns of white matter neurodegeneration in aging

AbstractBackgroundSeveral prior studies have used diffusion MRI to investigate the relationship between white matter microstructure and aging; however, many of these studies used conventional diffusion MRI measures and single site data. The goal of the study is to leverage multi‐site harmonized diffusion MRI data in conjunction with a novel post‐processing technique [i.e., free‐water (FW) correction] to quantify the aging related tract‐specific changes in white matter microstructure.MethodThe dataset used in this study was collated using several well‐established longitudinal cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory &amp; Aging Project (VMAP)]. In total, this dataset included 1,909 participants (mean age at baseline: 72±9 years, 59% female) and 4,844 imaging sessions (mean number of visits: 4 ± 2 years, interval range: 1–12 years). Data was processed using standard approaches and uncorrected fractional anisotropy (FAU) was quantified with seven white matter tractography atlases (see Figure 1A). Data was then post‐processed using the FW correction technique and FW and FW‐corrected FA (FAT) values were quantified. Data were then harmonized using the ComBat technique and linear mixed‐effects regression was conducted on each microstructural measure, covarying for age at baseline, sex, cognitive status, education, APOE‐ε4 carrier status, and APOE‐ε2 carrier status. The effect of aging was modelled using an Age_at_Baseline x Interval interaction term.ResultAge was associated with lower FAU in all seven tracts (pFDR range: 4.77x10‐10 to ‐0.01). In the FW analysis, age was associated with higher FW in all seven tracts (pFDR range: 7.81x10‐12 to 1.33x10‐6). For FAT, however, age was only associated with lower FAT in the limbic tracts (pFDR=0.024) in addition to the occipital (pFDR=1.19x10‐8), parietal (pFDR=2.32x10‐4), and prefrontal (pFDR=0.024) TC tracts. Figure 1B‐D illustrates our findings.ConclusionThis study suggests that while there are global associations with FAU and age, these associations are attenuated once correcting for partial volume effects. Leveraging FW analysis, we found a global association with FW and age, whereby age is associated with higher FW. Further, we found that age is associated with reductions in FAT in the limbic and occipital/parietal/prefrontal TC tracts.

Inhibitory effect of chitosan coating on oil absorption in French fries based on starch structure and morphology stability

The effect of chitosan (CS) coating on oil absorption, water migration, starch structure and morphology in French fries was evaluated. The penetrated surface oil, structure oil, total oil content, and a* of coated fries decreased, while the water content, L*, b*, and hardness significantly (P < 0.05) increased compared to uncoated samples. 1 % CS-coated fries had the lowest oil content, which decreased by 43.0 % compared to uncoated samples. CS-coated fries had higher free water, and lower T2 relaxation time, immobile and binding water than the control. CS coating reduced the pores on the fries' surface and the interaction between oil and the component of fries, which was observed by confocal laser scanning microscopy and scanning electron microscopy (SEM). As for starch morphology, the pores and cracks of starch granules in the coated samples reduced. As for the starch structure, the relative crystallinity, R1047/1022 respectively increased by 47.2 % and 2.35 times, and ΔH of CS-coated fries increased from 0 to 2.09 J/g, indicating that the long-range crystalline structure, short-range ordered structure, and hydrogen bonds between the double helices in starch increased. Therefore, CS coating reduced oil penetration into fries by reducing water migration and increasing starch ordered structure and morphological integrity.

Low Holding Densities Increase Stress Response and Aggression in Zebrafish.

Simple SummaryZebrafish are used as experimental animals in labs all around the world. To ensure that the health of zebrafish is maintained at the highest level, it is important to know the optimal housing conditions of the animals, including the housing density. Guidelines for housing densities of zebrafish can then be spread and followed globally, making it possible to compare research data from different facilities. To investigate the optimal housing densities of zebrafish and to better understand how holding density affects zebrafish behaviour and physiology, we evaluated the welfare of zebrafish housed at different densities for nine weeks. We observed that fish housed at the lowest holding density of 1 fish/L stood out from the rest of the experimental fish, showing higher levels of aggression, secreting more of the stress hormone cortisol in the water, and spending more time in the top zone of the tank, possibly reflecting the fact that fish in this density were hiding more behind the floating plants. Our data indicate that zebrafish should not be kept at 1 fish/L, or lower, to ensure good welfare of the animals.With laboratory zebrafish (Danio rerio) being an established and popular research model, there is a need for universal, research-based husbandry guidelines for this species, since guidelines can help promote good welfare through providing appropriate care. Despite the widespread use of zebrafish in research, it remains unclear how holding densities affect their welfare. Previous studies have mainly evaluated the effects of holding densities on a single parameter, such as growth, reproductive output, or social interactions, rather than looking at multiple welfare parameters simultaneously. Here we investigated how chronic (nine weeks) exposure to five different holding densities (1, 4, 8, 12, and 16 fish/L) affected multiple welfare indicators. We found that fish in the 1 fish/L density treatment had higher free water cortisol concentrations per fish, increased vertical distribution, and displayed aggressive behaviour more frequently than fish held at higher densities. On the other hand, density treatments had no effect on anxiety behaviour, whole-brain neurotransmitter levels, egg volume, or the proportion of fertilised eggs. Our results demonstrate that zebrafish can be held at densities between 4 and 16 fish/L without compromising their welfare. However, housing zebrafish in the density of 1 fish/L increased their stress level and aggressive behaviour.

Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract.

The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain. Diffusion MRI scans were collected on cognitively normal participants (CN) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 magnocellular regions of the basal forebrain (e.g., nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples. FW was significantly higher in patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05). These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and noninvasive early marker of structural changes related to cognitive impairment.

Abstract 13148: Cardiometabolic Risk Factors Partially Mediate the Association of Physical Inactivity With MRI Markers of Brain Aging

Introduction: Physical inactivity is associated with a higher risk of dementia, and has also been associated with unfavorable brain morphology. It is also clear that cardiometabolic risk factors accelerate the brain aging process. Hypothesis: Cardiometabolic risk factors mediate the association of physical inactivity with unfavorable brain morphology. Methods: Our investigation included participants from the Third Generation (exam 2) and Offspring (exam 9) cohorts of the Framingham Heart Study who wore an accelerometer for &amp;gte10 hours on &amp;gte3 days (to measure moderate to vigorous physical activity [MVPA] and steps walked per day), underwent brain MRI scans, and had no dementia, stroke, or missing cardiometabolic risk factor data (n=2416, 54% women, mean age 54.1 years). Higher levels of brain peak width of skeletonized mean (white matter) diffusivity, higher free water, and lower total cerebral brain volume were measured by MRI as markers of brain aging. We examined mediation by the 2017 revised version of the Framingham Stroke Risk Profile (FSRP, using weights for age, prevalent cardiovascular disease, atrial fibrillation, diabetes and smoking status, antihypertension medications and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of MVPA and steps with brain volume, white matter diffusivity, and free water, adjusting for age, age-squared, sex, wear time, smoking status (for HOMA-IR mediation analysis only), cohort, time from exam to MRI, and season of exam. Results: The associations of lower MVPA and steps with lower brain volume, higher white matter diffusivity, and higher free water were partially mediated through FSRP, accounting for 14.1-25.7% (p&amp;lt0.05) of the total association of physical inactivity with brain aging. The association of fewer steps (but not MVPA) with lower brain volume was mediated by HOMA-IR (20.1% of the total association, p&amp;lt0.05). Conclusions: Our results suggest that the associations of physical inactivity with lower brain volume, poorer white matter microstructure and aggregation of free water in the extracellular compartments of the brain are partially mediated by cardiometabolic risk factors.

The mechanism of low-level pressure coupled with heat treatment on water migration and gel properties of Nemipterus virgatus surimi

The effects of high-pressure processing (HPP) at different levels (0.1–600 MPa) and pressure coupled with two-stage heat treatment on the gel properties and water migration of Nemipterus virgatus surimi were studied. The gel prepared by HPP at 100 or 200 MPa for 15 min, followed by a two-stage heating, namely 100 P H and 200 P H respectively, showed the improved the gel strength, water-holding capacity (WHC) and whiteness (P < 0.05). The gel strength of the 100 P H sample was higher than that of the two-stage heated gel sample and the optimal HPP sample (300 MPa/15 min), increased by 124.14% and 131.43%, respectively. Under 100 MPa, HPP induced increased β-sheet and the exposure of reactive sulfhydryl groups, while the endogenous transglutaminase (TGase) of surimi maintained high activity. The subsequent heat treatment promoted the cross-linking induced by the endogenous TGase, the formation of protein-protein disulfide bonds and hydrophobic-hydrophobic interactions, forming a dense three-dimensional network. In addition, the enhanced interaction of protein-water restricted the migration of immobile water to free water. These ultimately rendered better gel properties. However, excessively high levels of pressures (300–600 MPa) coupled with heat treatment resulted in disordered gel structure, causing less immobile water with higher free water, leading to weak gels.

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FAT in adolescence, and 4% lower FAT by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FAT or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.

Cellular and Extracellular White Matter Abnormalities in Obsessive-Compulsive Disorder: A Diffusion Magnetic Resonance Imaging Study

BackgroundWhile previous studies have implicated white matter (WM) as a core pathology of obsessive-compulsive disorder (OCD), the underlying neurobiological processes remain elusive. This study used free-water (FW) imaging derived from diffusion magnetic resonance imaging to identify cellular and extracellular WM abnormalities in patients with OCD compared with control subjects. Next, we investigated the association between diffusion measures and clinical variables in patients. MethodsWe collected diffusion-weighted magnetic resonance imaging and clinical data from 83 patients with OCD (56 women/27 men, age 37.7 ± 10.6 years) and 52 control subjects (27 women/25 men, age 32.8 ± 11.5 years). Fractional anisotropy (FA), FA of cellular tissue, and extracellular FW maps were extracted and compared between patients and control subjects using tract-based spatial statistics and voxelwise comparison in FSL Randomise. Next, we correlated these WM measures with clinical variables (age of onset and symptom severity) and compared them between patients with and without comorbidities and patients with and without psychiatric medication. ResultsPatients with OCD demonstrated lower FA (43.4% of the WM skeleton), lower FA of cellular tissue (31% of the WM skeleton), and higher FW (22.5% of the WM skeleton) compared with control subjects. We did not observe significant correlations between diffusion measures and clinical variables. Comorbidities and medication status did not influence diffusion measures. ConclusionsOur findings of widespread FA, FA of cellular tissue, and FW abnormalities suggest that OCD is associated with microstructural cellular and extracellular abnormalities beyond the corticostriatothalamocortical circuits. Future multimodal longitudinal studies are needed to understand better the influence of essential clinical variables across the illness trajectory.

Cognitive status, brain amyloid pathology, and neurodegeneration are associated with altered white matter microstructure

AbstractBackgroundBrain amyloid (AB) and neurodegeneration (assessed using PET and MRI) are key AD pathology biomarkers, particularly during transitions from cognitively unimpaired (CU) to cognitively impaired (CI) states. Importantly, the role of brain white matter microstructural measures in these changes, such as those derived from neurite orientation dispersion and density imaging (NODDI), are poorly understood. We explored roles of cognitive status, brain amyloid pathology, and neurodegeneration on NODDI Free Water (FW), a potential neuroinflammation biomarker.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N=74, Table 1) underwent neuropsychological assessment, T1/NODDI MRI, and PiB PET. Participants were adjudicated as cognitively impaired (MCI or AD) or unimpaired using NIA‐AA criteria. T1 MRI were processed (FreeSurfer v5.3) to generate regions of interest (ROIs). An “AD‐signature” cortical thickness value was calculated, and thresholded to classify participants as neurodegeneration‐positive (N+) or ‐negative (N‐). A set of AD‐sensitive cortical ROIs was used to extract mean PET signal, which was thresholded to adjudicate AB positivity (AB‐/AB+). NODDI was processed to yield parameter maps using AMICO; mean isotropic volume fraction (FW) was calculated over a set of white matter tract ROIs. A two‐way ANOVA/ANCOVA (covariates: age, sex, education) assessed effects of neurodegeneration and AB on FW (N+/N‐ x AB+/AB‐), and a two‐way ANOVA/ANCOVA assessed effects of cognitive impairment and AB on FW (CU/CI x AB+/AB‐).ResultWe first examined effects of neurodegeneration and AB on NODDI FW. We found a significant main effect of neurodegeneration (p=.042), such that N+ had higher FW; this was marginal after adjustment (p=.07). We also observed a significant main effect of AB (p&lt;.001; adjusted p=.012), with AB+ having higher FW. There was no significant interaction. We next explored how cognitive status and AB interacted on FW. We found a significant main effect of cognitive impairment, with CI having higher FW (p=.018; adjusted p=.013). We also found an interaction between diagnosis and AB (p=.037; adjusted p=.044) such that among AB+ individuals, presence of CI related to increased FW (Figure 1).ConclusionNODDI FW increases were significantly affected by the presence of neurodegeneration, AB positivity, and cognitive impairment.

Stage‐dependent amyloid beta‐ and tau‐associated longitudinal white matter degeneration in early stages of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease(AD) is associated with pathological deposition of amyloid‐beta(Aβ) plaques and neurofibrillary tau tangles which have been shown to be related to poorer white‐matter(WM) integrity using diffusion‐MRI(dMRI) [Vipin et al.,2019;Jacobs et al.,2018]. However, possible interactive effects between Aβ and tau on microstructural WM changes remain unclear. Additionally, partial volume artefacts impact dMRI sensitivity but can be corrected through free‐water(FW) correction to provide FW and FW‐corrected tissue measures(FAt)[Pasternak et al.,2009]. Thus, we examined additive and interactive effects of Aβ and tau burden on temporal progression of FW‐corrected WM changes in temporoparietal WM fibres at baseline and over‐time in cognitively normal elderly(CN) and mild cognitive impairment(MCI). We hypothesize that MCI subjects would show more widespread Aβ and tau‐related temporoparietal WM alterations than CN. Additionally, based on prior evidence, Aβ and tau interactive effects would be more prevalent for FW than tissue‐based measures.MethodWe used dMRI data from 72 CN and 82 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative followed over 2‐4 time‐points(55‐90 years). Aβ burden was quantified using AV‐45 PET standardized uptake value and tau burden was quantified using cerebrospinal fluid phosphorylated‐tau(Ptau) levels. We derived subject‐specific FW and FAt fibre maps using the longitudinal TRActs‐Constrained‐by‐UnderLying‐Anatomy method[Yendiki et al.,2016].ResultCN with higher Aβ burden showed faster decline in RUNC FAt (uncorrected‐p=0.0055; Fig.1). However, in MCI, widespread Ptau effects were found(Fig.2) i.e. higher baseline Ptau burden was associated with lower fibre FAt in left superior longitudinal fasciculus parietal (SLFP; uncorrected‐p=0.039) and left(uncorrected‐p=0.0062) and right(uncorrected‐p=0.026) superior longitudinal fasciculus temporal(SLFT). Synergistic Aβ*Ptau effects were instead observed in right cingulum angular bundle(CAB) FW in CN at baseline and over‐time (FDR‐corrected:p&lt;0.05; Fig.3). This effect was more widespread in MCI‐ higher Aβ combined with higher Ptau associated with higher FW in right CAB, SLFP, SLFT and uncinate fasciculus fibres at baseline(Fig.4).ConclusionOur findings provide insights into stage‐dependent differences in additive and synergistic influences of Aβ and Ptau between tissue‐based and FW‐based WM metrics. Thus, together with Aβ and Ptau burden, FW‐corrected WM measures likely provide more detailed insight regarding the regions showing alterations related to the interaction between neuropathological hallmarks of AD to collectively inform regarding disease progression.

Cellular and extracellular white matter alterations indicate conversion to psychosis among individuals at clinical high-risk for psychosis

Objectives It is important to find biomarkers associated with transition to illness in individuals at clinical high-risk for psychosis (CHR). Here, we use free-water imaging, an advanced diffusion MRI technique, to identify white matter alterations in the brains of CHR subjects who subsequently develop psychosis (CHR-P) compared to those who do not (CHR-NP). Methods Twenty-four healthy controls (HC) and 30 CHR individuals, 8 of whom converted to schizophrenia after a mean follow-up of 15.16 months, received baseline MRI scans. Maps of fractional anisotropy (FA), FA of cellular tissue (FAT), and extracellular free-water (FW) were extracted using tract-based spatial statistics after which voxel-wise non-parametric group statistics and correlations with symptom severity were performed. Results There were no significant differences between HCs and the combined CHR group. However, prior to conversion, CHR-P showed widespread lower FA compared to CHR-NP (p FWE < 0.05). FA changes in CHR-P were associated with significantly lower FAT and higher FW, compared to CHR-NP. Positive symptoms correlated significantly with diffusion parameters in similar regions as those discriminating CHR-P from CHR-NP. Conclusions Our study suggests that cellular (FAT) and extracellular (FW) white matter alterations are associated with positive symptom severity and indicate an elevated illness risk among CHR individuals.