Gray Matter Cerebral Blood Flow Research Articles

Cerebral blood flow and arterial transit time responses to exercise training in older adults

Brain vascular health worsens with age, as is made evident by resting grey matter cerebral blood flow (CBFGM) reductions and lengthening arterial transit time (ATTGM). Exercise training can improve aspects of brain health in older adults, yet its effects on CBFGM and ATTGM remain unclear. This randomised controlled trial assessed responses of CBFGM and ATTGM to a 26 week exercise intervention in 65 healthy older adults (control: n = 33, exercise: n = 32, aged 60–81 years), including whether changes in CBFGM or ATTGM were associated with cognitive function changes. Multiple-delay pseudo-continuous arterial spin labelling data were used to estimate resting global and regional CBFGM and ATTGM. Results showed no between-group differences in CBFGM or ATTGM following the intervention. However, exercise participants with the greatest cardiorespiratory gains (n = 17; ∆V̇O2peak >2 mL/kg/min) experienced global CBFGM reductions (-4.0 [-7.3, -0.8] mL/100 g/min). Cognitive functions did not change in either group and changes were not associated with changes in CBFGM or ATTGM. Our findings indicate that exercise training in older adults may induce global CBFGM reductions when high cardiorespiratory fitness gains are induced, but this does not appear to affect cognitive functions.

Phasic perfusion dynamics among migraine subtypes: a multimodel arterial spin labeling investigation

BackgroundMigraine-related perfusion changes are documented but inconsistent across studies due to limited sample size and insufficient phenotyping. The phasic and spatial dynamics across migraine subtypes remains poorly characterized. This study aimed to determine spatiotemporal dynamics of gray matter (GM) perfusion in migraine.MethodsWe prospectively recruited episodic (EM) and chronic migraine (CM) patients, diagnosed with the International Headache Society criteria and healthy controls (HCs) between 2021 and 2023 from the headache center in a tertiary medical center, and adjacent communities. Magnetic resonance (3-tesla) arterial spin labeling (ASL) was conducted for whole brain cerebral blood flow (CBF) in all participants. The voxel-wise and whole brain gray matter (GM) CBF were compared between subgroups. Spatial pattern analysis of CBF and its correlations with headache frequency were investigated regarding different migraine phases and subtypes. Sex- and age-adjusted voxel-wise and whole brain GM comparisons were performed between HCs and different EM and CM phases. Spatial pattern analysis was conducted by CBF clusters with phasic differences and spin permutation test. Correlations between headache frequency and CBF were investigated regarding different EM and CM phases.ResultsTotally 344 subjects (172 EM, 120 CM, and 52 HCs) were enrolled. Higher CBF in different anatomical locations was identified in ictal EM and CM. The combined panels of the specific locations with altered CBF in ictal EM on receiver operating characteristic curve analysis demonstrated areas under curve of 0.780 (vs. HCs) and 0.811 (vs. preictal EM). The spatial distribution of ictal-interictal CBF alteration of EM and CM were not correlated with each other (p = 0.665; r = − 0.018). Positive correlations between headache frequency and CBF were noted in ictal EM and CM regarding whole GM and specific anatomical locations.ConclusionsPatients with migraine exhibited unique spatiotemporal CBF dynamics across different phases and distinct between subtypes. The findings provide neurobiological insights into how selected anatomical structures engage in a migraine attack and adapt to plastic change of repeated attacks along with chronicity.

Comparing single- and multi-post labeling delays for the measurements of resting cerebral and hippocampal blood flow for cerebrovascular testing in midlife adults.

To assess the reliability and validity of measuring resting cerebral blood flow (CBF) and hippocampal CBF using a single-post-labeling delay (PLD) and a multi-PLD pseudo-continuous arterial spin labeling (pCASL) protocol for cerebrovascular reactivity (CVR) testing. 25 healthy, midlife adults (57 ± 4years old) were imaged in a Siemens Prisma 3T magnetic resonance imaging (MRI) scanner. Resting CBF and hippocampal CBF were assessed using two pCASL protocols, our modified single-PLD protocol (pCASL-MOD) to accommodate the needs for CVR testing and the multi-PLD Human Connectome Project (HCP) Lifespan protocol to serve as the reference control (pCASL-HCP). During pCASL-MOD, CVR was calculated as the change in CBF from rest to hypercapnia (+9mmHg increase in end-tidal partial pressure of carbon dioxide [PETCO2]) and then normalized for PETCO2. The reliability and validity in resting gray matter (GM) CBF, white matter (WM) CBF, and hippocampal CBF between pCASL-MOD and pCASL-HCP protocols were examined using correlation analyses, paired t-tests, and Bland Altman plots. The pCASL-MOD and pCASL-HCP protocols were significantly correlated for resting GM CBF [r = 0.72; F (1, 23) = 25.24, p < 0.0001], WM CBF [r = 0.57; F (1, 23) = 10.83, p = 0.003], and hippocampal CBF [r = 0.77; F (1, 23) = 32.65, p < 0.0001]. However, pCASL-MOD underestimated resting GM CBF (pCASL-MOD: 53.7 ± 11.1 v. pCASL-HCP: 69.1 ± 13.1mL/100g/min; p < 0.0001), WM CBF (pCASL-MOD: 32.4 ± 4.8 v. pCASL-HCP: 35.5 ± 6.9mL/100g/min; p = 0.01), and hippocampal CBF (pCASL-MOD: 50.5 ± 9.0 v. pCASL-HCP: 68.1 ± 12.5mL/100g/min; p < 0.0001). PETCO2 increased by 8.0 ± 0.7mmHg to induce CVR (GM CBF: 4.8% ± 2.6%; WM CBF 2.9% ± 2.5%; and hippocampal CBF: 3.4% ± 3.8%). Our single-PLD pCASL-MOD protocol reliably measured CBF and hippocampal CBF at rest given the significant correlation with the multi-PLD pCASL-HCP protocol. Despite the lower magnitude relative to pCASL-HCP, we recommend using our pCASL-MOD protocol for CVR testing in which an exact estimate of CBF is not required such as the assessment of relative change in CBF to hypercapnia.

Determinants of cerebral blood flow and arterial transit time in healthy older adults.

Cerebral blood flow (CBF) and arterial transit time (ATT), markers of brain vascular health, worsen with age. The primary aim of this cross-sectional study was to identify modifiable determinants of CBF and ATT in healthy older adults (n = 78, aged 60-81 years). Associations between cardiorespiratory fitness and CBF or ATT were of particular interest because the impact of cardiorespiratory fitness is not clear within existing literature. Secondly, this study assessed whether CBF or ATT relate to cognitive function in older adults. Multiple post-labelling delay pseudo-continuous arterial spin labelling estimated resting CBF and ATT in grey matter. Results from multiple linear regressions found higher BMI was associated with lower global CBF (β = -0.35, P = 0.008) and a longer global ATT (β = 0.30, P = 0.017), global ATT lengthened with increasing age (β = 0.43, P = 0.004), and higher cardiorespiratory fitness was associated with longer ATT in parietal (β = 0.44, P = 0.004) and occipital (β = 0.45, P = 0.003) regions. Global or regional CBF or ATT were not associated with processing speed, working memory, or attention. In conclusion, preventing excessive weight gain may help attenuate age-related declines in brain vascular health. ATT may be more sensitive to age-related decline than CBF, and therefore useful for early detection and management of cerebrovascular impairment. Finally, cardiorespiratory fitness appears to have little effect on CBF but may induce longer ATT in specific regions.

Hypertension and cerebral blood flow in the development of Alzheimer's disease.

We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n=138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n=78; ADNI: n=89). The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

Characterization of posterior circulation blood perfusion in patients with different degrees of basilar artery tortuosity.

The morphology of basilar artery (BA) may affect posterior circulation blood perfusion. We aimed to investigate whether different degrees of BA tortuosity could lead to the alterations of posterior circulation perfusion. We collected 138 subjects with different BA tortuosity scores, including 32 cases of score 0, 45 cases of score 1, 43 cases of score 2, and 18 cases of score 3. A higher score represented a higher degree of BA tortuosity. Ordered logistic regression analysis was performed to investigate the risk factors for BA tortuosity. We quantitatively measured the cerebral blood flow (CBF) in eight posterior circulation brain regions using arterial spin labeling. SPSS 25.0 was used for statistical analysis. The correlation between the CBF and BA tortuosity was corrected by the Bonferroni method. The significance level was set at 0.006 (0.05/8). Hypertension (HR: 2.39; 95%CI: 1.23-4.71; P = 0.01) and vertebral artery dominance (HR: 2.38; 95%CI: 1.10-4.67; P = 0.03) were risk factors for BA tortuosity. CBF in occipital gray matter (R = -0.383, P < 0.001), occipital white matter (R = -0.377, P < 0.001), temporal gray matter (R = -0.292, P = 0.001), temporal white matter (R = -0.297, P < 0.001), and cerebellum (R = -0.328, P < 0.001) were negatively correlated with BA tortuosity degree. No significant correlation was found between the BA tortuosity degree and CBF in hippocampus (R = -0.208, P = 0.014), thalamus (R = -0.001, P = 0.988) and brainstem (R = -0.204, P = 0.016). BA tortuosity could affect posterior circulation blood perfusion. CBF was negatively correlated with BA tortuosity degree. The morphology of BA may serve as a biomarker for posterior circulation and the severity of posterior circulation ischemia.

Hippocampal volume mediates the association of arterial stiffness with cognitive impairment in adult population.

To investigate the association of arterial stiffness with brain perfusion, brain tissue volume and cognitive impairment in the general adult population. This prospective study included 1488 adult participants (age range: 22.8-83.9 years) from the Kailuan study. All participants underwent brachial-ankle pulse wave velocity (PWV) measurement, brain MRI, and Montreal Cognitive Assessment (MoCA). The association of PWV with cerebral blood flow (CBF), brain tissue volume and MoCA score was investigated. Mediation analysis was used to determine whether CBF and brain tissue volume changes mediated the associations between PWV and MoCA score. A 1 standard deviation (SD) increase in PWV was associated with lower total brain CBF [ β (95% CI) -0.67 (-1.2 to -0.14)], total gray matter CBF [β (95% CI) -0.7 [-1.27 to -0.13)], frontal lobe CBF [ β (95% CI) -0.59 (-1.17 to -0.01)], parietal lobe CBF [ β (95% CI) -0.8 (-1.43 to -0.18)], and temporal lobe CBF [ β (95% CI) -0.68 (-1.24 to -0.12)]. Negative associations were found for PWV and total brain volume [ β (95% CI) -4.8 (-7.61 to -1.99)] and hippocampus volume [ β (95% CI) -0.08 (-0.13 to -0.04)]. A 1 SD increase PWV was significantly associated with elevated odds of developing cognitive impairment [odds ratio (95% CI) 1.21 (1.01-1.45)]. Mediation analysis showed that hippocampal volume partially mediated the negative association between PWV and MoCA scores (proportion: 14.173%). High arterial stiffness was associated with decreased total and regional CBF, brain tissue volume, and cognitive impairment. Hippocampal volume partially mediated the effects of arterial stiffness on cognitive impairment.

Is cerebral blood flow altered by anxiety and depression in a sex-dependent manner?

Background: It is well-known that premenopausal females have greater cerebral blood flow (CBF) than age-matched males. People with anxiety and/or depression (A/D) have altered CBF compared to those without A/D. For example, males with depression may have greater CBF, and females with depression may have lower CBF, than their healthy counterparts. In contrast, anxiety may be correlated with higher CBF in certain brain regions such as the amygdala and hippocampus in both sexes. However prior studies assessing the effect of sex and A/D on CBF did not control for the menstrual cycle, something which is known to influence CBF in females. Objective: To determine if A/D is linked to CBF alterations in young healthy adults, in a sex-specific pattern, while controlling for menstrual cycle and hormonal contraception (HC). Hypothesis: As most of our subjects had depression, we hypothesized that CBF would be higher in control (CON) females than CON males and this difference will be abolished in A/D subjects, due to a greater CBF in A/D males compared to CON males and a lower CBF in A/D females compared to CON females. Methods: Twenty females (4 A/D) and 21 males (8 A/D) had their CBF (ml/100gm/min) measured using magnetic resonance imaging (MRI, 3T) with arterial spin labelling (ASL). A/D was diagnosed by a physician. Subjects in all 4 groups were matched for age (mean ± SD; 21 ± 2 y). Females were studied during days 1-5 of the menstrual cycle and were not taking HC. CBF data were tested using 2-way mixed effects analyses (sex*group (i.e., CON vs. A/D)) in: grey matter (GM), white matter (WM), and 8 emotional/memory regions of the brain, including the accumbens, amygdala, caudate, anterior cingulate, hippocampus, entorhinal, parahippocampus, and precuneus. Results: A trend for significant sex*group interaction (all p ≥ 0.052) but not group main effects (all p ≥ 0.100) was observed. CBF in GM and WM as well as in the 8 emotional/memory regions was higher in females compared to males (main effect of sex, p ≤ 0.004). This sex effect appeared to be driven by the CON groups ( p &lt; 0.0001 for all areas), as there were no CBF differences in any area between males and females in the A/D group (all p ≥ 0.089).Exploratory analyses showed significantly greater CBF in A/D males compared to CON males in GM as well as the accumbens, caudate, hippocampus, precuneus, and anterior cingulate gyrus (all p ≤ 0.049). No differences were observed for any outcome. Conclusion: These data suggest that while CON females have greater CBF than CON males at rest, this sex difference may be abolished in those with A/D. Albeit preliminary, these data are in line with previous findings whereby CBF appears to decrease more in females with depression and either remain unchanged or increase in males with depression. The higher CBF in certain regions in A/D males is interesting and in line with previous research showing increased CBF in the hippocampus with anxiety. As our sample size was small and included a mix of people with either anxiety or depression, future research should be conducted to assess the differential effects of these conditions in young adults. Support by NIH (HL150361). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pathologic burden goes with the flow: MRI perfusion and pathologic burden in frontotemporal lobar degeneration due to tau

Abstract Regional cerebral blood flow (CBF) changes quantified using arterial spin labeling (ASL) are altered in neurodegenerative disorders such as frontotemporal lobar degeneration due to tau (FTLD-tau), but the relationship between ASL CBF and pathologic burden has not been assessed. Our objective was to determine whether regional ASL CBF acquired antemortem in patients with FTLD-tau is related to pathologic burden measured at autopsy in those same regions in the same patients to directly test the imaging-pathology relationship. In this case-control study, data were acquired between 3/4/2010 and 12/16/2018. Data processing and analysis were completed in 2023. Twenty-one participants with autopsy-confirmed FTLD-tau (N = 10 women, mean[SD] age 67.9[7.56] years) along with 25 control participants (N = 15 women, age 64.7[7.53]) were recruited through the cognitive neurology clinic at the University of Pennsylvania. All participants had ASL and T1-weighted images collected antemortem. ASL images were processed to estimate CBF and T1-weighted images were processed to estimate gray matter (GM) volumes in regions corresponding to regions sampled postmortem. Digital quantification of pathologic burden was performed to find the percent area occupied (%AO) of pathologic FTLD-tau at autopsy. Regional CBF and GM volumes were both related to pathologic burden in the same regions from the same participants. Strengths of model fits of imaging measures to pathologic burden were compared. CBF in FTLD-tau and controls were compared, with results considered significant at p &amp;lt; 0.05 after Bonferroni correction. We found that relative to controls, FTLD-tau displayed hypoperfusion in anterior cingulate, orbitofrontal, middle frontal, and superior temporal regions, as well as angular gyrus. For patients with FTLD-tau regional CBF was significantly associated with pathologic burden (beta = -1.07, t = -4.80, p &amp;lt; 0.005). Models including both GM volume and CBF provided significantly better fits to pathologic burden data than single modality models (p &amp;lt; 0.05, Bonferroni-corrected). Our results indicate that reduced CBF measured using ASL MRI is associated with increased pathologic burden in FTLD-tau and adds complementary predictive value of pathologic burden to structural MRI.

Abstract P327: Examination of Cardiometabolic Health Status, Obesity, and Brain Health in Community-Dwelling Older Adults

Introduction: Mid-life and late-life obesity have been associated with changes in brain structure and function, though the exact nature of this dynamic relationship is not well understood. Purpose: To determine whether associations between measures of obesity and neuroimaging biomarkers are independent of cardiometabolic health status in older adults. Methods: Adults 55 and older were recruited into the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center (ADRC) between 2016 and 2023 and underwent standard evaluation in accordance with the National Alzheimer’s Coordinating Center protocols. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were measured to assess obesity. Cardiometabolic health was determined by the presence of impaired glucose tolerance (IGT) and hypertension (HTN). Brain MRI scans were conducted to assess cerebral blood flow (CBF) in white matter (WM) and gray matter (GM), WM microstructure using neurite orientation dispersion and density imaging (NODDI) of free water (FW), total brain volume (GM+WM), and temporal lobe cortical thickness. Linear regression was used to examine associations between anthropometric and neuroimaging measures, controlling for demographics (age, gender, race, education) in model 1 and demographics plus cardiometabolic health (HTN and IGT) in model 2. Results: A total of 647 Clinical Core participants with anthropometric, MRI, cardiometabolic, and demographic data available were analyzed. Mean age of participants was 70.1±8.2 years, 19% were African American, 48% had adjudicated cognitive impairment (35% mild cognitive impairment, 13% dementia), 76% had HTN, and 69% had IGT. BMI (p&lt;0.001), WC (p&lt;0.001), and WHR (p=0.006) were positively associated with WM CBF in models 1 and 2. BMI (p=0.039) was also positively associated with GM CBF in model 2. All three obesity measures were positively associated with NODDI FW in model 1: BMI (p=0.006), WC (p=0.007), and WHR (p=0.039), and WHR was negatively associated with total brain volume (p=0.043). However, these associations were attenuated after further adjustment. Cortical thickness was not significantly associated with obesity in any model. Conclusion: These results demonstrate that, among community-dwelling older adults, having higher BMI, WHR, and WC is associated with higher WM CBF even after adjusting for demographics, HTN and IGT, suggesting that obesity may be a risk factor for impaired brain perfusion in late life.

An Investigation of Cerebral Vascular Functional Properties in Middle-to-Old Age Community People With High Vascular Risk Profiles.

Vascular degeneration is an important cause of brain damage in aging. Assessing the functional properties of the cerebral vascular system may aid early diagnosis and prevention. To investigate the relationships between potential vascular functional markers and vascular risks, brain parenchymal damage, and cognition. Retrospective. Two hundred two general community subjects (42-80 years, males/females: 127/75). 3 T, spin echo T1W/T2W/FLAIR, resting-state functional MRI with an echo-planar sequence (rsfMRI), pseudo-continuous arterial spin labeling (pCASL) with a three-dimensional gradient-spin echo sequence. Cerebral blood flow (CBF) in gray matter calculated using pCASL, blood transit times calculated using rsfMRI, and the SD of internal carotid arteries signal (ICAstd) calculated using rsfMRI; visual assessment for lacunes; quantification of white matter hyperintensity volume; permutation test for quality control; collection of demographic and clinical data, Montreal Cognitive Assessment, Mini-Mental State Examination. Kolmogorov-Smirnov test; Spearman rank correlation analysis; Multivariable linear regression analysis controlling for covariates; The level of statistical significance was set at P < 0.05. Age was negatively associated with ICAstd (β = -0.180). Diabetes was associated with longer blood transit time from large arteries to capillary bed (β = 0.185, adjusted for age, sex, and intracranial volume). Larger ICAstd was associated with less presence of lacunes (odds ratio: 0.418, adjusted for age and sex). Higher gray matter CBF (β = 0.154) and larger ICAstd (β = 0.136) were associated with better MoCA scores (adjusted for age, sex, and education). Prolonged blood transit time, decreased ICAstd, and diminished CBF were associated with vascular dysfunction and cognitive impairment. They may serve as vascular functional markers in future studies. 3 TECHNICAL EFFICACY: Stage 3.

Abstract WP218: Risk Factors for Cerebral Aneurysms in Sickle Cell Disease

Introduction: Cerebral aneurysm frequency in sickle cell disease (SCD) is higher than in the general population. Specific risk factors explaining this difference have not been previously explored. We hypothesize that increased cerebral blood flow (CBF), low hemoglobin (Hb) levels, and documented risk factors for aneurysms in the general population would be associated with aneurysm development in SCD. Methods: Children and young adults with SCD defined as HbSS and HbSβ0 thalassemia were recruited from SCD clinics at an academic medical center and a community health clinic from 2014-2022 along with age and race-matched controls. Written consent and assent were required. Inclusion: ages 6-45 years, study MRI and MRA of the brain, risk factor data collected. MRAs were reviewed and aneurysms were confirmed by consensus of 2 neuroradiologists. CBF was assessed via MRI with pseudo-continuous arterial spin labeling. Results: The study population included 183 SCD participants, including 13 (7.1%) with aneurysms. The healthy control group included 77 participants, 3 (3.9%) of these participants had aneurysms, all women. In the SCD sample, 10 of 13 (76.9%) aneurysms occurred in males while 76 of 170 (44.7%) without aneurysms were male (p=0.025). In the aneurysm group, 3 of 13 (23.1%) were smokers versus 8 of 170 (4.7%) without aneurysms (p=0.035). In the SCD aneurysm group, median age was older, 30.9 years versus 17.2 years without aneurysm, (p&lt;0.001). Systolic blood pressure and Hb levels were not different in SCD participants with and without aneurysms, p=0.074 and p=0.358, respectively. However, SBP was 119.7±14.9 with aneurysms vs 113.2±12.3mmHg without aneurysms. Mean gray matter CBF for the SCD group with aneurysms was higher at 86.7± 25.9ml/100g/min compared to 80.8 ± 20.3ml/100g/min in the SCD group without aneurysms, though not significantly (p=0.325). Discussion: Increased CBF and low hemoglobin levels were not risk factors for cerebral aneurysms in SCD in this relatively small cohort. Like the general population, age and smoking are risk factors for aneurysm development in SCD. In contrast to the general population, male sex rather than female sex in SCD is an aneurysm risk factor. Based on these data, a larger consortium to study aneurysms in SCD is needed.

Abstract TMP10: Children With Sickle Cell Anemia Have Impaired Cerebrovascular Reactivity

Introduction: Sickle Cell Anemia (SCA) causes lower hemoglobin, leading to increased cerebral blood flow (CBF) to maintain cerebral oxygen metabolism (CMRO 2 ). Although CBF rises in childhood to meet higher CMRO 2 demands, further compensatory increases in CBF in children with SCA may tap into a limited hemodynamic reserve, increasing risk for infarct. Cerebrovascular reactivity (CVR) reflects hemodynamic reserve by measuring the vasculature’s response to vasoactive stimuli, particularly in the gray matter (GM). We hypothesized that children with SCA have lower GM CVR, regardless of CMRO 2 . Methods: We used magnetic resonance imaging of children with and without SCA to collect pseudocontinuous arterial spin labeling (pCASL) for CBF, asymmetric spin echo for oxygen extraction fraction (OEF) and blood oxygen level dependent (BOLD) data correlated with hypercapnic challenges for CVR. Lab draws confirmed Hemoglobin (Hb) values. CMRO 2 was calculated as CBF x OEF x Arterial Oxygen Content (1.36 x Hb x SpO 2 ). Continuous variable differences between groups were analyzed using the Mann-Whitney U test, and categorical variables using the Fisher’s exact test. Linear regression assessed the relationship between CVR and Hb. Reported significant relationships survived multiple comparisons correction. Results: A total of 35 participants, ages 8–22 years had quality CVR data [9 SCA subjects (5 male) and 26 controls (9 male)]. Of these, 8 SCA and 20 controls had adequate quality metabolic data. The groups are matched by age (p=0.56) and sex (p=0.43). Children with SCA had higher GM CBF (62.0 v 49.3 mL/100g/min; p=0.03), but similar GM CMRO 2 (1.81 v 1.42 mL/100g/min; p=0.07) than controls. GM CVR was significantly lower in SCA than controls (0.17 v 0.27 %/mmHg; p=0.0003). Lower CVR was associated with lower Hb (Figure) after adjusting for age and sex (p &lt;0.0001). Conclusion: Lower GM CVR in children with SCA indicates a lower hemodynamic reserve, likely related to the degree of anemia.

Associations of Intracranial Artery Length and Branch Number on Time-of-Flight MRA With Cognitive Impairment in Hypertensive Older Males.

Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment. To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort. Prospective observational study. 189 hypertensive older males (mean age 64.9 ± 7.2 years). TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T. The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment. Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance. TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF. The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects. 2 TECHNICAL EFFICACY: Stage 3.

Investigating the impact of APOE4 genotype on the association between cerebral blood flow and haematological properties in mid‐life adults

AbstractBackgroundCarriership of the apolipoprotein ε4 (APOE4) allele confers a heightened risk for the development of Alzheimer’s disease (AD). Cerebral blood flow (CBF) is decreased in prodromal and established AD, however findings in the preclinical stage are mixed, with some studies reporting increases. CBF can be impacted by many factors including the haematocrit. We investigated in a cohort at risk of developing AD how haematological variables relate to CBF and if this relationship is differentially moderated by APOE4.Method375 participants from the PREVENT‐Dementia study underwent arterial spin labelling (ASL) and structural 3Tesla MRI. ASL data were analysed using BASIL/FSL and structural scans with SPM12. CBF maps were corrected for partial volume effects. A vascular territory mask with nine territories, the middle, proximal and distal branches of the anterior, middle and posterior cerebral arteries (ACA, MCA, PCA) was used for region‐of‐interest analysis and registered to the native ASL space. Regional gray matter (GM) CBF values were harmonised using COMBAT. Linear regression was used to examine differences between APOE4 carriers and non‐carriers controlling for age, sex and years of education. Associations between haematological properties and CBF were examined with Pearson’s correlations. Differential relationships between CBF, haematocrit, and measures of red blood cell size and shape (distribution width (RDW) and mean corpuscular volume (MCV)) were investigated by including interaction terms of APOE4 and haematological variables in the models.ResultAPOE4 carriers had significantly higher CBF in the proximal MCA (t = 2.54, p = 0.01). Across all subjects, RDW and MCV were not associated with GM CBF, though several significant interactions were observed between APOE4 and RDW in predicting CBF (Figure 1). Haematocrit was associated with GM CBF (ρ = ‐0.19, p &lt; 0.01). No significant interactions were seen between APOE4 and haematocrit or MCV in predicting CBF.ConclusionThe variability of the size and shapes of erythrocytes was differentially associated with CBF between APOE4 carriers and non‐carriers suggesting a different response to morphological erythrocyte alterations. This could further relate to underlying factors such as inflammation, which is associated with a higher RDW. Such associations should be examined in further studies.

Investigating the impact of APOE4 genotype on the association between cerebral blood flow and haematological properties in mid‐life adults

AbstractBackgroundCarriership of the apolipoprotein ε4 (APOE4) allele confers a heightened risk for the development of Alzheimer’s disease (AD). Cerebral blood flow (CBF) is decreased in prodromal and established AD, however findings in the preclinical stage are mixed, with some studies reporting increases. CBF can be impacted by many factors including the haematocrit. We investigated in a cohort at risk of developing AD how haematological variables relate to CBF and if this relationship is differentially moderated by APOE4.Method375 participants from the PREVENT‐Dementia study underwent arterial spin labelling (ASL) and structural 3Tesla MRI. ASL data were analysed using BASIL/FSL and structural scans with SPM12. CBF maps were corrected for partial volume effects. A vascular territory mask with nine territories, the middle, proximal and distal branches of the anterior, middle and posterior cerebral arteries (ACA, MCA, PCA) was used for region‐of‐interest analysis and registered to the native ASL space. Regional gray matter (GM) CBF values were harmonised using COMBAT. Linear regression was used to examine differences between APOE4 carriers and non‐carriers controlling for age, sex and years of education. Associations between haematological properties and CBF were examined with Pearson’s correlations. Differential relationships between CBF, haematocrit, and measures of red blood cell size and shape (distribution width (RDW) and mean corpuscular volume (MCV)) were investigated by including interaction terms of APOE4 and haematological variables in the models.ResultAPOE4 carriers had significantly higher CBF in the proximal MCA (t = 2.54, p = 0.01). Across all subjects, RDW and MCV were not associated with GM CBF, though several significant interactions were observed between APOE4 and RDW in predicting CBF (Figure 1). Haematocrit was associated with GM CBF (ρ = ‐0.19, p &lt; 0.01). No significant interactions were seen between APOE4 and haematocrit or MCV in predicting CBF.ConclusionThe variability of the size and shapes of erythrocytes was differentially associated with CBF between APOE4 carriers and non‐carriers suggesting a different response to morphological erythrocyte alterations. This could further relate to underlying factors such as inflammation, which is associated with a higher RDW. Such associations should be examined in further studies.

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values&gt;0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Regional cerebral blood flow is associated with PET and plasma biomarkers of tau pathology in middle age

AbstractBackgroundCerebrovascular dysfunction and vascular brain injury are associated with risk and progression of clinical Alzheimer’s disease (AD), but it is unclear whether they contribute directly to disease pathogenesis. Animal models of small vessel cerebrovascular disease suggest that transient cerebral hypoperfusion may promote tau pathology independent of amyloidosis. In the current study, we used pulsed arterial spin labeling (PASL) magnetic resonance imaging (MRI) to examine the association of regional cerebral blood flow (CBF) with two biomarkers of tau pathology, plasma phosphorylated tau 181 (ptau181) concentrations and PET MK6240 SUVR, in middle aged adult participants from the Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease.MethodAt the time of analysis, 469 Offspring Study participants (54.0±10.6‐years‐old; 64% women; 67% Latinx, 22% non‐Latinx Black, 6% non‐Latinx white) had available PASL and ptau181 plasma concentrations (Quanterix Simoa HDx platform). Sixty‐four participants (59.9±5.4‐years‐old age; 67% women; 64% Latinx, 22% non‐Latinx Black, 8% Latinx white) with PASL CBF data received tau PET imaging with MK6240 and mean SUVR was computed across all grey matter regions for each participant. Voxelwise correlational analyses were run to examine the relationship between ptau181 concentrations and regional CBF and between tau PET SUVR and regional CBF.ResultIncreased ptau181 concentrations were associated with clusters of decreased CBF in frontal grey matter, striatum, hippocampus, and periventricular white matter. These correlations were asymmetrical, with the largest clusters found in the left hemisphere. Higher PET SUVR was associated with clusters of lower CBF in frontal, parietal, and occipital grey matter.ConclusionThese findings demonstrate a codependency between regional blood flow and tau pathology, indexed by fluidic and imaging biomarkers. Future studies will clarify the directionality and possible causality of these associations, but these cross‐sectional findings are consistent with a hypothesis that subtle diminished blood flow gives rise to tau abnormalities.