Pupillary response is associated with the reset and switching of functional brain networks during salience processing.

The interface between processing internal goals and salient events in the environment involves various top-down processes. Previous studies have identified multiple brain areas for salience processing, including the salience network (SN), dorsal attention network, and the locus coeruleus-norepinephrine (LC-NE) system. However, interactions among these systems in salience processing remain unclear. Here, we simultaneously recorded pupillometry, EEG, and fMRI during an auditory oddball paradigm. The analyses of EEG and fMRI data uncovered spatiotemporally organized target-associated neural correlates. By modeling the target-modulated effective connectivity, we found that the target-evoked pupillary response is associated with the network directional couplings from late to early subsystems in the trial, as well as the network switching initiated by the SN. These findings indicate that the SN might cooperate with the pupil-indexed LC-NE system in the reset and switching of cortical networks, and shed light on their implications in various cognitive processes and neurological diseases.

Evidence suggesting common mechanisms underlie contralateral and ipsilateral negative BOLD responses in the human visual cortex.

The task-evoked positive BOLD response (PBR) to a unilateral visual hemi-field stimulation is often accompanied by robust and sustained contralateral as well as ipsilateral negative BOLD responses (NBRs) in the visual cortex. The signal characteristics and the neural and/or vascular mechanisms that underlie these two types of NBRs are not completely understood. In this paper, we investigated the properties of these two types of NBRs. We first demonstrated the linearity of both NBRs with respect to stimulus duration. Next, we showed that the hemodynamic response functions (HRFs) of the two NBRs were similar to each other, but significantly different from that of the PBR. Moreover, the subject-wise expressions of the two NBRs were tightly coupled to the degree that the correlation between the two NBRs was significantly higher than the correlation between each NBR and the PBR. However, the activation patterns of the two NBRs did not show a high level of interhemispheric spatial similarity, and the functional connectivity between them was not different than the interhemispheric functional connectivity between the NBRs and PBR. Finally, while attention did modulate both NBRs, the attention-related changes in their HRFs were similar. Our findings suggest that the two NBRs might be generated through common neural and/or vascular mechanisms involving distal/deep brain regions that project to the two hemispheres.

Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics.

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-ß (Aß), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aß, measured using positron emission tomography (PET), examine the accuracy of plasma Aß to predict brain Aß positivity, and the relation of APOE ɛ4 with plasma Aß. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aß42/Aß40 ratio measured with Simoa. Brain Aß burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aß42/Aß40 ratio was inversely associated with global Aß SUVR (ß= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aß positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aß42/Aß40 ratio in relation to brain Aß positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aß42/Aß40 ratio and a higher Aß positivity determined with the Aß42/Aß40 ratio threshold of 0.060. CONCLUSION: Plasma Aß42/Aß40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

Landmark-guided region-based spatial normalization for functional magnetic resonance imaging.

As the size of the neuroimaging cohorts being increased to address key questions in the field of cognitive neuroscience, cognitive aging, and neurodegenerative diseases, the accuracy of the spatial normalization as an essential preprocessing step becomes extremely important. Existing spatial normalization methods have poor accuracy particularly when dealing with the highly convoluted human cerebral cortex and when brain morphology is severely altered (e.g., aging populations). To address this shortcoming, we propose a novel spatial normalization technique that takes advantage of the existing surface-based human brain parcellation to automatically identify and match regional landmarks. To simplify the nonlinear whole brain registration, the identified landmarks of each region and its counterpart are registered independently with topology-preserving deformation. Next, the regional warping fields are combined by an inverse distance weighted interpolation technique to have a global warping field for the whole brain. To ensure that the final warping field is topology-preserving, we used simultaneously forward and reverse maps with certain symmetric constraints to yield bijectivity. We have evaluated our proposed solution using both simulated and real (structural and functional) human brain images. Our evaluation shows that our solution can enhance structural correspondence compared to the existing methods. Such improvement also increases the sensitivity and specificity of the functional imaging studies, reducing the required number of subjects and subsequent study costs. We conclude that our proposed solution can effectively substitute existing substandard spatial normalization methods to deal with the demand of large cohorts which is now common in clinical and aging studies.

In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics.

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.

Metabolic syndrome and its components in relation to in vivo brain amyloid and neurodegeneration in late middle age.

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid ß (Aß) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aß or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aß burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.

Brain Amyloid Burden and Resting-State Functional Connectivity in Late Middle-Aged Hispanics.

Non-linear relations of brain amyloid beta (Aß) with task- based functional connectivity (tbFC) measured with functional magnetic resonance imaging (fMRI) have been reported in late middle age. Our objective was to examine the association between brain Aß and resting-state functional connectivity (rsFC) in late middle-aged adults. Global brain Aß burden was ascertained with 18F-Florbetaben Positron Emission Tomography (PET); rsFC was ascertained on 3T Magnetic Resonance Imaging (MRI) among 333 late middle-aged Hispanics adults without dementia in four major brain functional connectivity networks: default mode network (DMN), fronto-parietal control network (FPC), salience network (SAL) and dorsal attention network (DAN). We examined the relationship of global brain Aß with rsFC using multivariable linear regression adjusted for age, sex, education, and APOE-ε4 genotype. We quantified the non-linear associations both with quadratic terms and by categorizing Aß into three groups: low Aß, intermediate Aß, and positive Aß. We found no significant linear or non-linear associations between Aß, measured either continuously or categorically, with rsFC in the examined networks. Our null findings may be explained by the younger age of our participants in whom amyloid burden is relatively low. It is also possible that the recently reported non-linear relationship is exclusive to task fMRI and not rsfMRI.

Apolipoprotein E genotype and in vivo amyloid burden in middle-aged Hispanics.

OBJECTIVE: To examine in vivo amyloid burden in relation to APOEε4 genotype in middle-aged Hispanics. We hypothesize higher amyloid levels among APOE ε4 carriers vs APOE ε4 noncarriers. METHODS: This is a cross-sectional study in a community-based sample of 249 middle-aged Hispanics in New York City who underwent a 3T brain MRI and PET with the amyloid radioligand 18F-florbetaben. APOE genotype was the primary exposure. The primary outcome was amyloid positivity. The secondary outcome was subthreshold amyloid levels examined as a continuous variable. RESULTS: APOE ε4 carriers (n = 85) had a higher frequency (15.3%) of amyloid positivity compared to APOE ε4 noncarriers (n = 164, 1.8%). In the subthreshold group of amyloid-negative participants (n = 233), APOE ε4 carriers (n = 72) had a 0.02 (95% confidence interval [CI] 0.01-0.04) higher global brain amyloid standardized uptake value ratio (SUVR) compared to APOE ε4 noncarriers (n = 161). Compared to participants with the ε3/ε3 genotype, participants with ε4/ε4 had the highest frequency of amyloid positivity (28.6%), followed by those with ε3/ε4 (11%). Among amyloid-negative participants (n = 233), compared to participants with ε3/ε3 (n = 134), those with ε4/ε4 (n = 5) had a 0.12 (95% CI 0.07-0.17) higher global brain amyloid SUVR, and those with ε3/ε4 had a 0.02 higher SUVR (95% CI 0.003-0.04). Results were similar when a median split was used for elevated amyloid, when continuous amyloid SUVR was analyzed in all participants, and in nonparametric Mann-Whitney comparisons. CONCLUSION: Middle-aged Hispanic APOE ε4 carriers have higher in vivo brain amyloid burden compared with noncarriers, as reported in non-Hispanics.

Pre-Diabetes, but not Type 2 Diabetes, Is Related to Brain Amyloid in Late Middle-Age.

BACKGROUND: Type 2 diabetes is a dementia risk factor, but its relation to Alzheimer's disease (AD), the most common cause of dementia, is unclear. OBJECTIVE: Our primary objective was to examine the association of pre-diabetes and type 2 diabetes with brain amyloid-ß (Aß), the putative main culprit of AD. Our secondary objective was to examine the association of pre-diabetes and type 2 diabetes with neurodegeneration, cerebrovascular disease (CVD), and memory performance. METHODS: We conducted a cross-sectional study of 350 late middle-aged Hispanics without dementia in New York City. We classified diabetes status as normal glucose tolerance (NGT), pre-diabetes, and type 2 diabetes following American Diabetes Association criteria. Brain Aß was ascertained as global Aß standardized value uptake ratio using PET with 18F-Florbetaben. Neurodegeneration was operationalized as cortical thickness in regions affected by AD using MRI. CVD was operationalized as white matter hyperintensity volume (WMH) on MRI, and memory as performance with the selective reminding test (SRT). RESULTS: Mean age was 64.15±3.34 years, 72.00% were women, and 35.43% were APOEɛ4 carriers. Pre-diabetes, but not type 2 diabetes, was associated with higher Aß compared with NGT. Type 2 diabetes treatment was related to lower Aß. Type 2 diabetes was related to lower cortical thickness, higher WMH, and lower SRT score. CONCLUSION: Pre-diabetes, but not type 2 diabetes, is associated with higher brain Aß in late middle age, and this observation could be explained by the relation of diabetes treatment with lower brain Aß. Whether type 2 diabetes treatment lowers brain Aß requires further study.

Sex Differences in in vivo Alzheimer's Disease Neuropathology in Late Middle-Aged Hispanics.

BACKGROUND: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer's disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. OBJECTIVE: To examine sex differences in in vivo AD neuropathology in late middle age. METHODS: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio (SUVR) with18F-Florbetaben positron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 in 75 of the 266 participants. RESULTS: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. CONCLUSION: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males.

The influence of physique on dose conversion coefficients for idealised external photon exposures: a comparison of doses for Chinese male phantoms with 10th, 50th and 90th percentile anthropometric parameters.

For evaluating radiation risk, the construction of anthropomorphic computational phantoms with a variety of physiques can help reduce the uncertainty that is due to anatomical variation. In our previous work, three deformable Chinese reference male phantoms with 10th, 50th and 90th percentile body mass indexes and body circumference physiques (DCRM-10, DCRM-50 and DCRM-90) were constructed to represent underweight, normal weight and overweight Chinese adult males, respectively. In the present study, the phantoms were updated by correcting the fat percentage to improve the precision of radiological dosimetry evaluations. The organ dose conversion coefficients for each phantom were calculated and compared for four idealized external photon exposures from 15 keV to 10 MeV, using the Monte Carlo method. The dosimetric results for the three deformable Chinese reference male phantom (DCRM) phantoms indicated that variations in physique can cause as much as a 20% difference in the organ dose conversion coefficients. When the photon energy was <50 keV, the discrepancy was greater. The irradiation geometry and organ position can also affect the difference in radiological dosimetry between individuals with different physiques. Hence, it is difficult to predict the conversion coefficients of the phantoms from the anthropometric parameters alone. Nevertheless, the complex organ conversion coefficients presented in this report will be helpful for evaluating the radiation risk for large groups of people with various physiques.

Monte Carlo Simulations for Dosimetry in Prostate Radiotherapy with Different Intravesical Volumes and Planning Target Volume Margins.

In prostate radiotherapy, the influence of bladder volume variation on the dose absorbed by the target volume and organs at risk is significant and difficult to predict. In addition, the resolution of a typical medical image is insufficient for visualizing the bladder wall, which makes it more difficult to precisely evaluate the dose to the bladder wall. This simulation study aimed to quantitatively investigate the relationship between the dose received by organs at risk and the intravesical volume in prostate radiotherapy. The high-resolution Visible Chinese Human phantom and the finite element method were used to construct 10 pelvic models with specific intravesical volumes ranging from 100 ml to 700 ml to represent bladders of patients with different bladder filling capacities during radiotherapy. This series of models was utilized in six-field coplanar 3D conformal radiotherapy simulations with different planning target volume (PTV) margins. Each organ's absorbed dose was calculated using the Monte Carlo method. The obtained bladder wall displacements during bladder filling were consistent with reported clinical measurements. The radiotherapy simulation revealed a linear relationship between the dose to non-targeted organs and the intravesical volume and indicated that a 10-mm PTV margin for a large bladder and a 5-mm PTV margin for a small bladder reduce the effective dose to the bladder wall to similar degrees. However, larger bladders were associated with evident protection of the intestines. Detailed dosimetry results can be used by radiation oncologists to create more accurate, individual water preload protocols according to the patient's anatomy and bladder capacity.