White Matter Cerebral Blood Flow Research Articles

Regional cerebral blood flow reflects both neurodegeneration and microvascular integrity across the Alzheimer's continuum.

Alzheimer's disease (AD) typically involves both neurodegenerative and vascular pathologies, each associated with reductions in cerebral blood flow (CBF). However, it remains unclear whether vascular and neural contributions to regional CBF can be differentiated. Using 3D background-suppressed arterial spin labeled perfusion magnetic resonance imaging, we evaluated regional CBF in a cohort of 257 participants across the AD continuum and assessed the impact of risk factors for both AD and small vessel disease (SVD) on regional CBF. Vascular risk factors (VRFs) were associated with reduced CBF in normal-appearing periventricular white matter, while amyloid positivity was associated with reduced CBF in the posterior cingulate cortex and precuneus. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes comparable to those in typical AD cortical regions. Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects on regional CBF. Our findings also support the contribution of SVD in AD pathogenesis. We used 3D background-suppressed pCASL MRI to evaluate CBF across the AD continuum. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes. AD and/or SVD risk correlated with reduced CBF in AD and/or SVD-related regions. VRFs were associated with more widespread CBF reductions than amyloid positivity. Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects.

Short‐term Sirolimus Treatment Increases Cerebral Blood Flow in Asymptomatic APOE4 Females Determined by 3T MRI

AbstractBackgroundApolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) with females having higher risk than males. Compared with non‐carriers, cognitively normal, middle‐aged APOE4 carriers have lower cerebral blood flow (CBF) decades before clinical symptoms appear. Early intervention to protect CBF would be critical for APOE4 carriers to mitigate AD progression. We have shown in APOE4 mice that Rapamycin (a.k.a. Sirolimus), a FDA‐approved mTOR‐inhibitor, can restore CBF. Here, in the first human study, our goal is to determine whether the findings translate to human APOE4 carriers by measuring CBF with MRI.MethodThe study was performed at the University of Missouri. Low dose Sirolimus (1 mg/day) was given for 4 weeks to two middle‐aged, cognitively normal APOE4 females (45‐65 yrs; MOCA>28). APOE status was determined by oral swabs. 3T MRI‐based pseudo‐continuous arterial spin‐labeled (PCASL, 1.7x1.7x4mm resolution) images were acquired at four time‐points: baseline (pre‐treatment), 2nd and 4th week into treatment, and washout (2 weeks post‐treatment). PCASL data was processed with FSL BASIL toolbox and regionally analyzed using FreeSurfer segmentation of T1‐weighted images.ResultAverage values of CBF (ml/100g/min) increased in all areas of investigation. When compared to baseline values, we observed an average 34.8±2.1% increase in washout CBF in the cortex across subjects (Figure 1). Within the cortex, there was an average increase of 41.5±8.9, 28.2±6.2, 37.4±1.7, and 33.1±0.3% in the frontal, parietal, temporal and occipital lobes, respectively. White matter CBF showed a similar trend, increasing by 33.7±4.9% across subjects from baseline to washout (Figure 2). Smaller AD‐associated regions were evaluated and also showed CBF improvement: the entorhinal cortex showed a 25.1±4.3% increase, while the hippocampus and amygdala showed a 21.4±1.1 and 23.6±9.8% increase, respectively (Figure 3). No side effects were observed, and no changes in blood glucose and HbAc1 levels were found in the participants.ConclusionShort‐term Sirolimus treatment can effectively increase CBF for asymptomatic APOE4 females, who have the highest risk for AD. Future work will include APOE4 males, increase the sample size and compare CBF with non‐carriers (e.g., APOE3/APOE2). Restoration of CBF may pave a way to mitigate or prevent AD developments for APOE4 carriers.

Associations of life-course cardiovascular risk factors with late-life cerebral haemodynamics.

While the associations of mid-life cardiovascular risk factors with late-life white matter lesions (WMH) and cognitive decline have been established, the role of cerebral haemodynamics is unclear. We investigated the relation of late-life (69-71 years) arterial spin labelling (ASL) MRI-derived cerebral blood flow (CBF) with life-course cardiovascular risk factors (36-71 years) and late-life white matter hyperintensity (WMH) load in 282 cognitively healthy participants (52.8% female). Late-life (69-71 years) high systolic (B = -0.15) and diastolic (B = -0.25) blood pressure, and mean arterial pressure (B = -0.25) were associated with low grey matter (GM) CBF (p < 0.03), and white matter CBF (B = -0.25; B = -0.15; B = -0.13, p < 0.03, respectively). The association between systolic blood pressure and GM CBF differed between sexes (male/female B = -0.15/0.02, p = 0.04). No associations were found with early- or mid-life cardiovascular risk factors. Furthermore, WMHs were associated with cerebral haemodynamics but not cardiovascular risk factors. These findings suggest that cerebral blood flow autoregulation is able to maintain stable global cerebral haemodynamics until later in life. Future studies are encouraged to investigate why cardiovascular risk factors have differential effects on haemodynamics and WMH, and their implications for cognitive decline.

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.

Detectability of white matter cerebral blood flow using arterial spin labeling MRI in patients with sickle cell disease: Relevance of flow territory, bolus arrival time, and hematocrit.

Sickle cell disease (SCD) is the most common genetic blood disorder, characterized by red cell hemolysis, anemia, and corresponding increased compensatory cerebral blood flow (CBF). SCD patients are at high risk for cerebral infarcts and CBF quantification is likely critical to assess infarct risk. Infarcts primarily localize to white matter (WM), yet arterial spin labeling (ASL) MRI, the most common non-invasive CBF approach, has poor WM CBF sensitivity owing to low WM CBF and long WM bolus arrival time (BAT). We hypothesize that anemia, and associated cerebral hyperemia, in SCD leads to improved WM detection with ASL. We performed 3-Tesla multi-delay pulsed ASL in SCD (n = 35; age = 30.5 ± 8.3 years) and control (n = 15; age = 28.7 ± 4.5 years) participants and applied t-tests at each inversion time within different flow territories, and determined which regions were significantly above noise floor (criteria: one-sided p < 0.05). Total WM CBF-weighted signal was primarily detectable outside of borderzone regions in SCD (CBF = 17.7 [range = 12.9-25.0] mL/100 g/min), but was largely unphysiological in control (CBF = 8.1 [range = 7.6-9.9)] mL/100 g/min) participants. WM BAT was reduced in SCD versus control participants (ΔBAT = 37 [range = 46-70] ms) and BAT directly correlated with hematocrit (Spearman's-ρ = 0.62; p < 0.001). Findings support the feasibility of WM CBF quantification using ASL in SCD participants for appropriately parameterized protocols.

Cerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

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.

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.

Abstract WMP63: Oxygen Metabolic Stress Attributes Intrinsic Vulnerability to Watershed Regions in Healthy Individuals

Introduction: Physiological imaging studies in patients with severe steno-occlusive carotid disease (SSCD) reveal hemodynamic compromise as a mechanism underlying watershed infarcts (WI). However, it is unclear if the watershed region (WR) is intrinsically vulnerable in healthy individuals. We measured cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in healthy individuals to determine if the WR was under metabolic stress, and therefore an intrinsically vulnerable region. Methods: To define a common WR, we created an “average WI density map” using MRIs from patients with diffusion restriction ipsilateral to SSCD from a single academic center (7/10 to 8/20). WI density maps were created using 5%, 10% and 15% incidence thresholds. Maps were overlaid onto coregistered CBF and OEF maps generated from pseudo-continuous arterial spin labeling (pCASL) and asymmetric spin echo sequences, respectively, performed on healthy controls aged &lt;55 with no vascular risk factors. OEF was normalized to whole brain values. White matter OEF and CBF was compared within vs. outside the WR using the Kruskal Wallis test. Results: 47 MRIs (mean age 62 years, 55 % females) were used to create average WI density maps using 3 thresholds (Fig A). Average CBF and OEF maps were created from 29 healthy volunteers (mean age 39 years, 59 % females). WI maps were superimposed on the CBF and OEF maps from healthy controls. OEF was higher (p&lt;0.001), and CBF lower (p&lt;0.001) within compared to outside the watershed regions, regardless of incidence threshold used (10% threshold shown in Fig. B-C). Conclusion: Increased OEF and decreased CBF suggest oxygen metabolic stress in the WR, suggesting that the deep white matter may be intrinsically vulnerable even in healthy individuals. Indeed, several brain pathologies (WI, white matter hyperintensities of presumed vascular origin, and multiple sclerosis lesions) are known to fall within this region.

MRI Assessment of Cerebral White Matter Microvascular Hemodynamics Across the Adult Lifespan.

Changes in cerebral hemodynamics with aging are important for understanding age-related variation in neuronal health. While many prior studies have focused on gray matter, less is known regarding white matter due in part to measurement challenges related to the lower vascular density in white matter. To investigate the impact of age and sex on white matter hemodynamics in a Human Connectome Project in Aging (HCP-A) cohort using tract-based spatial statistics (TBSS). Retrospective cross-sectional. Six hundred seventy-eight typically aging individuals (381 female), aged 36-100 years. Multi-delay pseudo-continuous arterial spin labeling (ASL) and diffusion-weighted pulsed-gradient spin-echo echo planar imaging sequences at 3.0 T. A skeleton of mean fractional anisotropy (FA) was produced using TBSS. This skeleton was used to project ASL-derived cerebral blood flow (CBF) and arterial transit time (ATT) measures onto white matter tracts. General linear models were applied to white matter FA, CBF, and ATT maps, while covarying for age and sex. Threshold-free cluster enhancement multiple comparisons correction was performed for the effects of age and sex, thresholded at PFWE < 0.05. CBF, ATT, and FA were compared between sex for each tract using analysis of covariance, with multiple comparisons correction for the number of tracts at PFDR < 0.05. Significantly lower white matter CBF and significantly prolonged white matter ATTs were associated with older age. These effects were widespread across tracts for ATT. Significant (PFDR < 0.05) sex differences in ATT were observed across all tracts, and significant sex differences in CBF were observed in all tracts except the bilateral uncinate fasciculus. Females demonstrated significantly higher CBF compared to males across the lifespan. Few tracts demonstrated significant sex differences in FA. This study identified significant sex- and age-associated differences in white matter hemodynamics across tracts. 3 TECHNICAL EFFICACY: Stage 3.

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.

Neurohormonal response patterns to hunger, satiation, and postprandial fullness in normal weight, anorexia nervosa, and obesity.

Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN. During an adlibitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs). A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK. Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO2 also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.

Cerebral blood flow in patients recovered from mild COVID-19.

Cerebral hypoperfusion has been described in both severe and mild forms of symptomatic Coronavirus Disease 2019 (COVID-19) infection. The purpose of this study was to investigate global and regional cerebral blood flow (CBF) in asymptomatic COVID-19 patients. Cases with mild COVID-19 infection and age-, sex-, and race-matched healthy controls were drawn from the Aging Brain Consortium at The University of South Carolina data repository. Demographics, risk factors, and data from the Montreal Cognitive Assessment were collected. Mean CBF values for gray matter (GM), white matter (WM), and the whole brain were calculated by averaging CBF values of standard space-normalized CBF image values falling within GM and WM masks. Whole brain region of interest-based analyses were used to create standardized CBF maps and explore differences between groups. Twenty-eight cases with prior mild COVID-19 infection were compared with 28 controls. Whole-brain CBF (46.7±5.6 vs. 49.3±3.7, p=.05) and WM CBF (29.3±2.6 vs. 31.0±1.6, p = .03) were noted to be significantly lower in COVID-19 cases as compared to controls. Predictive models based on these data predicted COVID-19 group membership with a high degree of accuracy (85.2%, p<.001), suggesting CBF patterns are an imaging marker of mild COVID-19 infection. In this study, lower WM CBF, as well as widespread regional CBF changes identified using quantitative MRI, was found in mild COVID-19 patients. Further studies are needed to determine the reliability of this newly identified COVID-19 brain imaging marker and determine what drives these CBF changes.

Vascular and microstructural markers of cognitive pathology

AbstractBackgroundArterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension, metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.MethodArterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer’s Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses.ResultAmong 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (&lt;70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected.ConclusionsArterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function.

Mean Arterial Pressure and Cerebral Hemodynamics Across The Lifespan: A Cross-Sectional Study From Human Connectome Project-Aging.

Cerebral perfusion is directly affected by systemic blood pressure, which has been shown to be negatively correlated with cerebral blood flow (CBF). The impact of aging on these effects is not fully understood. To determine whether the relationship between mean arterial pressure (MAP) and cerebral hemodynamics persists throughout the lifespan. Retrospective, cross-sectional study. Six hundred and sixty-nine participants from the Human Connectome Project-Aging ranging between 36 and 100+ years and without a major neurological disorder. Imaging data was acquired at 3.0 Tesla using a 32-channel head coil. CBF and arterial transit time (ATT) were measured by multi-delay pseudo-continuous arterial spin labeling. The relationships between cerebral hemodynamic parameters and MAP were evaluated globally in gray and white matter and regionally using surface-based analysis in the whole group, separately within different age groups (young: <60 years; younger-old: 60-79 years; oldest-old: ≥80 years). Chi-squared, Kruskal-Wallis, ANOVA, Spearman rank correlation and linear regression models. The general linear model setup in FreeSurfer was used for surface-based analyses. P < 0.05 was considered significant. Globally, there was a significant negative correlation between MAP and CBF in both gray (ρ = -0.275) and white matter (ρ = -0.117). This association was most prominent in the younger-old [gray matter CBF (β = -0.271); white matter CBF (β = -0.241)]. In surface-based analyses, CBF exhibited a widespread significant negative association with MAP throughout the brain, whereas a limited number of regions showed significant prolongation in ATT with higher MAP. The associations between regional CBF and MAP in the younger-old showed a different topographic pattern in comparison to young subjects. These observations further emphasize the importance of cardiovascular health in mid-to-late adulthood for healthy brain aging. The differences in the topographic pattern with aging indicate a spatially heterogeneous relationship between high blood pressure and CBF. 3 TECHNICAL EFFICACY STAGE: 3.

Abstract 109: Regional Cerebral Hypoperfusion In Patients Recovered From Mild COVID-19

Background: Cerebral hypoperfusion have been described in both severe and mild forms of symptomatic coronavirus disease 2019 (COVID-19) infection. The purpose of this study was to investigate global and regional gray matter (GM) and white matter (WM) cerebral blood flow (CBF) in asymptomatic COVID-19 infection patients compared with age-gender-race matched controls. Methods: Cases with mild COVID-19 infection and age-gender-race matched healthy controls, were drawn from the ABC@UofSC data repository. Demographics, risk factors and data from the Montreal Cognitive Assessment (MOCA score) were collected within a week of magnetic resonance imaging (MRI) perfusion image acquisition using pseudo-continuous arterial spin labeling. Mean CBF values for GM, WM and whole brain were calculated by averaging CBF values of standard space normalized CBF image values falling within GM and WM masks. Whole-brain, region of interest (ROI) based analyses were used to create standardized cerebral blood flow maps and further explore differences between the two groups. Results: Twenty-eight cases with prior mild COVID-19 infection were compared with 28 age-, gender-, race-matched controls. The MOCA score was similar between cases and controls. Whole-brain CBF (46.7±5.6 vs. 49.3±3.7, p=0.05), GM-specific CBF (64.2±8.9 vs. 67.6±6.0, p=0.10), and WM-specific CBF (29.3±2.6 vs. 31.0±1.6, p=0.03) were noted to be lower in COVID-19 cases as compared to controls. Further analysis identified several brain regions with lower CBF than the CONTROL group colors representing Z-scores shown in the figure. Predictive models based on these data predicted COVID-19 group membership with a high degree of accuracy (85.2%) suggesting CBF patterns as a key imaging marker of mild infection. Conclusion: In this study, lower white matter CBF, as well as widespread regional CBF changes identified using quantitative MRI, were found in patients recovered from mild to moderate COVID-19 infection.

Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease

AbstractBackgroundBrain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.Method76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.Result185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.ConclusionSignificant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.

Vascular and Microstructural Markers of Cognitive Pathology

AbstractBackgroundArterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension , metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.MethodArterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer’s Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses.ResultAmong 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (&lt;70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected.ConclusionsArterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function.

Brain Differences in Adolescents Living With Perinatally Acquired HIV Compared With Adoption Status Matched Controls: A Cross-sectional Study.

Background and ObjectivesDespite effective combination antiretroviral therapy (cART), adolescents with perinatally acquired HIV (PHIV) exhibit cognitive impairment, of which structural changes could be the underlying pathophysiologic mechanism. Prior MRI studies found lower brain volumes, higher white matter (WM) hyperintensity (WMH) volume, lower WM integrity, and differences in cerebral blood flow (CBF). However, these findings may be confounded by adoption status, as a large portion of adolescents with PHIV have been adopted. Adoption has been associated with malnutrition and neglect, which, in turn, may have affected brain development. We investigated the long-term effects of PHIV on the brain, while minimizing the confounding effect of adoption status.MethodsWe determined whole-brain gray matter (GM) and WM volume with 3D T1-weighted scans; total WMH volume with fluid-attenuated inversion recovery; CBF in the following regions of interest (ROIs): WM, GM, and subcortical GM with arterial spin labeling; and whole-brain WM microstructural markers: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) with diffusion tensor imaging in cART-treated adolescents with PHIV visiting our outpatient clinic in Amsterdam and controls matched for age, sex, ethnic origin, socioeconomic status, and adoption status. We assessed differences in neuroimaging parameters between adolescents with PHIV and controls using linear regression models adjusted for age and sex and applied multiple comparison correction.ResultsThirty-five adolescents with PHIV and 38 controls were included with a median age of 14.9 (interquartile range [IQR]: 10.7–18.5) and 15.6 (IQR: 11.1–17.6) years, respectively, with a similar rate of adoption. We found a lower overall FA (beta = −0.012; p < 0.014, −2.4%), a higher MD (beta = 0.014, p = 0.014, 1.3%), and a higher RD (beta = 0.02, p = 0.014, 3.3%) in adolescents with PHIV vs adoption-matched controls, but no differences in AD. We found comparable GM, WM, and WMH volume and CBF in ROIs between adolescents with PHIV and controls. We did not find an association between cognitive profiles and WM microstructural markers in adolescents with PHIV.DiscussionIrrespective of adoption status, adolescents with PHIV exhibited subtle lower WM integrity. Our findings may point toward early-acquired WM microstructural alterations associated with HIV.