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White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease. Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study, we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a 2-year follow-up. We found the following. First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (b = 7.7 × 1024; P = 0.025). Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (P < 0.05, when HbA1c >6.51%), and non-apolipoprotein E (APOE) e4 carriers had a stronger association between HbA1c and WMHV progression (b =22.59 × 1023; P = 0.004). Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (b = 7.17 × 10-4; P < 0.01) compared with periventricular WMHV change and, for frontal (b = 5.00 × 10-4; P < 0.001) and parietal (b = 1.53 × 10-4; P < 0.05) lobes, WMHV change compared with occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater 2-year WMHV progression, especially in non-APOE e4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and whitematter disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex‐dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. METHODS: Thirty‐three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face‐name associative memory functional magnetic resonance imaging (fMRI) task with a 2‐year follow‐up. We acquired baseline carbon 11‐labeled Pittsburgh compound B ([11C]PiB) positron emission tomography (PET) and T2‐weighted fluid‐attenuated inversion recovery (T2‐FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively. RESULTS: Males had increased hippocampal‐prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. DISCUSSION: These findings suggest sex‐dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females. [ABSTRACT FROM AUTHOR]

Background: Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don't provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes. Method: Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline). Result: Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women. Conclusion: We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: In this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA). Method: Our study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter. Result: As shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2). Conclusion: Our findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women. Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings. Reference: Li, Jiatai, et al. "VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images." Annual Meeting of the Organization for Human Brain Mapping. 2023 [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMHs) are neuroimaging features associated with Alzheimer's disease (AD). Ex‐vivo studies may enable better characterization of WMHs pathological substrates. In this work, we present a novel method that leverages in‐vivo and ex‐vivo MRIs and histopathology to analyze the progression of WMHs in AD. Method: A single subject's in‐vivo MRI scans at four different time points were analyzed. Ex‐vivo scans of the brain left hemisphere were done using 16‐Tx and 32‐Rx TicTacToe coil3 and a 3‐D printed enclosure with integrated cutting guides1 (Fig. 1). The WMHs were segmented on the T2‐weighted FLAIR in‐vivo MRI 2, and registered onto the final time point via SPM's normalized mutual information‐based algorithm. All four WMH segmentations were warped to the ex‐vivo MRI's space by applying the deformation field from the ITK in‐vivo to ex‐vivo registration. Result: The 3D printed enclosure achieved an accurate alignment between gross pathology, ex‐vivo and in‐vivo MRI (Fig. 1). Then, we computed the WMHs' growth over time warped onto the ex‐vivo MRI (Fig. 2). This growth was quantified as the total number of voxels in each segmentation longitudinally with a quadratic fit with an R2 =0.99 (Fig. 2). Lastly, we found a significant change in the distribution of WMH segmentations over time as evident by their normalized histograms (Fig. 3). Conclusion: We present a novel method to track the progression of WMHs in‐vivo to ex‐vivo MRI and gross pathology. Future studies will perform a voxel‐wise analysis on the WMHs in MRI scans, both in‐vivo and ex‐vivo, along with its histological correlates to gain insight into the underlying cellular mechanisms during the biomarker's development. References: 1. Nadim Farhat et al. "Reusable 3D printed enclosure with integrated cutting guides for the alignment of high resolution ex‐vivo MRI with ex‐vivo gross brain photographs." 2021 ISMRM Meeting (Under revision). 2. Wu, M. et al (2006). "A fully automated method for quantifying and localizing white matter hyperintensities on MR images." Psychiatry Research: Neuroimaging, 148(2‐3), 133‐142. 3. T. Santini et al., "In‐vivo and numerical analysis of the eigenmodes produced by a multi‐level Tic‐Tac‐Toe head transmit array for 7 Tesla MRI," PLoS One, vol. 13, no. 11, p. e0206127, Nov. 2018. [ABSTRACT FROM AUTHOR]

Pelvic target dose from intensity-modulated proton therapy (IMPT) is sensitive to patient bowel motion. Robustly optimized plans in regard to bowel filling may improve the dose coverage in the treatment course. Our purpose is to investigate the effect of air volume in large and small bowel and rectum on target dose from IMPT plans. Data from 17 cancer patients (11 prostate, 3 gynecologic, 2 colon, and 1 embryonal rhabdomyosarcoma) with planning CT (pCT) and weekly or biweekly scanned quality assurance CTs (QACTs; 82 QACT scans total) were studied. Air in bowels and rectum traversed by proton pencil beams was contoured. The robust treatment plan was made by using 3 CT sets: the pCT set and 2 virtual CT sets that were copies of pCT but in which the fillings of bowels and rectum were overridden to be either air or muscle. Each plan had 2–5 beams with a mean of 3 beams. Targets in the pCT were mapped to the QACTs by deformable image registration, and the dose in QACTs was calculated. Dose coverage (D99 and D95) and correlations between dose coverage and changes in air volume were analyzed. The significance of the correlation was analyzed by t test. Mean changes of D99 in QACTs were within 3% of those in the pCT for all prostate and colon cases but >3% in 2 of the 3 gynecologic cases and in the embryonal rhabdomyosarcoma case. Of these three cases with mean change of D99 > 3%, air volume may be the main cause in 2. For the prostate cases, correlation coefficients were <0.7 between change in air volume and change in D99 and D95, because other anatomy changes also contributed to dose deviation. Correlation coefficients in the non-prostate cases were >0.9 between D99 change and rectum and between D95 change and small bowel, indicating a greater effect of the air volume on target dose. The air volume may still have an important effect on target dose coverage in treatment plans using 3 CT sets, particularly when the air is traversed by multiple beams. [ABSTRACT FROM AUTHOR]

Objective: White matter hyperintensities (WMH) on brain MRI images are the most common feature of cerebral small vessel disease (CSVD). Studies have yielded divergent findings on the modifiable risk factors for WMH and WMH's impact on cognitive decline. Mounting evidence suggests sex differences in WMH burden and subsequent effects on cognition. Thus, we aimed to identify sex-specific modifiable risk factors for WMH. We then explored whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes., Methods: Participants aged 49-89 years were recruited at memory clinics and underwent a T2-weighted fluid-attenuated inversion recovery (FLAIR) 3T MRI scan to measure WMH volume. Participants were then recruited for two additional follow-up visits, 1-2 years apart, where clinical dementia rating sum of boxes (CDR-SB) scores were measured. We first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. We additionally tested which risk factors were significant when stratified by sex. We then tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific., Results: The study utilized data from 713 participants (241 males, 472 females) with a mean age of 72.3 years and 72.8 years for males and females, respectively. 57.3% and 59.5% of participants were diagnosed with mild cognitive impairment (MCI) for males and females, respectively. 40.7% and 39.4% were diagnosed with dementia for males and females, respectively. Of the 713 participants, 181 participants had CDR-SB scores available for three longitudinal time points. Compared to males, females showed stronger association of age to WMH volume. Type 2 Diabetes was associated with greater WMH burden in females but not males. Finally, baseline WMH burden was associated with worse clinical dementia outcomes longitudinally in females but not in males., Discussion: Elderly females have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Additionally, females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the consequences of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies., Clinical Trial Registration: The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391). Registration Date 2018/12/14., Competing Interests: Competing interests: Thurston: Astellas, Bayer, Hello Therapeutics (Advisory Board). All other authors declare no competing interests.

White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease. Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study, we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a 2-year follow-up. We found the following. First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (β = 7.7 × 10-4; P = 0.025). Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (P < 0.05, when HbA1c >6.51%), and non-apolipoprotein E (APOE) ε4 carriers had a stronger association between HbA1c and WMHV progression (β = -2.59 × 10-3; P = 0.004). Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (β = 7.17 × 10-4; P < 0.01) compared with periventricular WMHV change and, for frontal (β = 5.00 × 10-4; P < 0.001) and parietal (β = 1.53 × 10-4; P < 0.05) lobes, WMHV change compared with occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater 2-year WMHV progression, especially in non-APOE ε4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and white matter disease., (© 2024 by the American Diabetes Association.)

Introduction: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging., Methods: Thirty-three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face-name associative memory functional magnetic resonance imaging (fMRI) task with a 2-year follow-up. We acquired baseline carbon 11-labeled Pittsburgh compound B ([ 11 C]PiB) positron emission tomography (PET) and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively., Results: Males had increased hippocampal-prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume., Discussion: These findings suggest sex-dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)