Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.

CSF-to-blood toxins clearance is modulated by breathing through cranio-spinal CSF oscillation.

Clearance of brain toxins occurs during sleep, although the mechanism remains unknown. Previous studies implied that the intracranial aqueductal cerebrospinal fluid (CSF) oscillations are involved, but no mechanism was suggested. The rationale for focusing on the aqueductal CSF oscillations is unclear. This study focuses on the cranio-spinal CSF oscillation and the factors that modulate this flow. We propose a mechanism where increased cranio-spinal CSF movements enhance CSF-to-blood metabolic waste clearance through the spinal CSF re-absorption sites. A recent study demonstrating that disturbed sleep impairs CSF-to-blood but not brain-to-CSF clearance, supports the fundamentals of our proposed mechanism. Eight healthy subjects underwent phase-contrast magnetic resonance imaging to quantify the effect of respiration on the cranio-spinal CSF oscillations. Maximal CSF volume displaced from the cranium to the spinal canal during each respiration and cardiac cycle were derived as measures of cranio-spinal CSF mixing level. Transition from normal to slow and abdominal breathing resulted in a 56% increase in the maximal displaced CSF volume. Maximal change in the arterial-venous blood volume, which is the driving force of the CSF oscillations, was increased by 41% during slow abdominal breathing. Cranio-spinal CSF oscillations are driven by the momentary difference between arterial inflow and venous outflow. Breathing modulates the CSF oscillation through changes in the venous outflow. The amount of toxins being transferred to the spinal canal during each respiratory cycle is significantly increased during slow and deeper abdominal breathing, which explains enhanced CSF-to-blood toxins clearance during slow-wave sleep and poor clearance during disrupted sleep.

Early Amnestic Mild Cognitive Impairment Is Associated with Reduced Total Cerebral Blood Flow with no Brain Tissue Loss.

BACKGROUND: Lower cerebral blood flow (CBF) and excessive brain atrophy are linked to Alzheimer's disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. OBJECTIVE: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. METHODS: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. RESULTS: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stß) = 0.324 and stß= 0.326) and with memory scores (stß≥0.297 and stß≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stß= 0.327 and stß= 0.284) and in aMCI (stß= 0.627 and stß= 0.485). CONCLUSION: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss.

Blood and cerebrospinal fluid flow oscillations measured with real-time phase-contrast MRI: breathing mode matters.

BACKGROUND: Cervical blood and cerebrospinal fluid (CSF) flow rates can be quantified with Phase-contrast (PC) MRI, which is routinely used for clinical studies. Previous MRI studies showed that venous and CSF flow alterations are linked to various pathological conditions. Since it is well known that, besides the heart beating, the thoracic pump influences the blood and CSF dynamics, we studied the effect of different respiration modes on blood and CSF flow rates using a real-time (RT)-PC prototype. METHODS: Thirty healthy volunteers were examined with a 3 T scanner. A RT-PC sequence was acquired at the first cervical level to quantify the flow rates of internal carotid arteries, internal jugular veins (IJVs) and CSF. Each RT-PC acquisition was repeated three times, while the subjects were asked to breathe in three different ways for 60 s each: freely (F), with a constant rate (PN) and with deep and constant respiration rate (PD). The average flow rates were computed, they were removed from the respective signals and integrated in the inspiratory and expiratory phases (differential volumes). Finally, the power spectral density was computed for each detrended flow rate. High- and very-high frequency peaks were identified on the spectra while their frequencies were compared to the respiratory and cardiac frequencies estimated using a thoracic belt and a pulse oximeter. The area under the spectra was computed in four 0.5 Hz-wide ranges, centered on the high-frequency peak, on very-high frequency peak and its 2nd and 3rd harmonics, and then they were normalized by the flow rate variance. The effect of breathing patterns on average flow rates, on systolic and diastolic peaks, and on the normalized power was tested. Finally, the differential volumes of inspiration were compared to those of expiration. RESULTS: The frequencies of the high- and very-high spectral peaks corresponded to the respiratory and cardiac frequencies. The average flow rate progressively decreased from F to PN to PD breathing, and the cardiac modulations were less predominant especially for the IJVs. The respiratory modulation increased with PD breathing. The average volumes displaced in the inspiratory phases were not significantly different from those of the expiratory one. CONCLUSIONS: The spectral analyses demonstrated higher respiratory modulations in PD compared to free breathing, even prevailing the cardiac modulation in the IJVs, showing an increment of the thoracic pump affecting the flow rate shape.

Cardiac and Respiratory Influences on Intracranial and Neck Venous Flow, Estimated Using Real-Time Phase-Contrast MRI.

The study of brain venous drainage has gained attention due to its hypothesized link with various neurological conditions. Intracranial and neck venous flow rate may be estimated using cardiac-gated cine phase-contrast (PC)-MRI. Although previous studies showed that breathing influences the neck's venous flow, this aspect could not be studied using the conventional segmented PC-MRI since it reconstructs a single cardiac cycle. The advent of real-time PC-MRI has overcome these limitations. Using this technique, we measured the internal jugular veins and superior sagittal sinus flow rates in a group of 16 healthy subjects (12 females, median age of 23 years). Comparing forced-breathing and free-breathing, the average flow rate decreased and the respiratory modulation increased. The flow rate decrement may be due to a vasoreactive response to deep breathing. The respiratory modulation increment is due to the thoracic pump's greater effect during forced breathing compared to free breathing. These results showed that the breathing mode influences the average blood flow and its pulsations. Since effective drainage is fundamental for brain health, rehabilitative studies might use the current setup to investigate if respiratory exercises positively affect clinical variables and venous drainage.

Structural Basal Ganglia Correlates of Subjective Fatigue in Middle-Aged and Older Adults.

OBJECTIVE: Fatigue is among the most common complaints in community-dwelling older adults, yet its etiology is poorly understood. Based on models implicating frontostriatal pathways in fatigue pathogenesis, we hypothesized that smaller basal ganglia volume would be associated with higher levels of subjective fatigue and reduced set-shifting in middle-aged and older adults without dementia or other neurologic conditions. METHODS: Forty-eight non-demented middle-aged and older adults (Mage = 68.1, SD = 9.4; MMMSE = 27.3, SD = 1.9) completed the Fatigue Symptom Inventory, set-shifting measures, and structural MRI as part of a clinical evaluation for subjective cognitive complaints. Associations were examined cross-sectionally. RESULTS: Linear regression analyses showed that smaller normalized basal ganglia volumes were associated with more severe fatigue (ß = -.29, P = .041) and poorer Trail Making Test B-A (TMT B-A) performance (ß = .30, P = .033) controlling for depression, sleep quality, vascular risk factors, and global cognitive status. Putamen emerged as a key structure linked with both fatigue (r = -.43, P = .003) and TMT B-A (ß = .35, P = .021). The link between total basal ganglia volume and reduced TMT B-A was particularly strong in clinically fatigued patients. CONCLUSION: This study is among the first to show that reduced basal ganglia volume is an important neurostructural correlate of subjective fatigue in physically able middle-aged and older adults without neurological conditions. Findings suggest that fatigue and rapid set-shifting deficits may share common neural underpinnings involving the basal ganglia, and provide a framework for studying the neuropathogenesis and treatment of subjective fatigue.

Poor sleep accelerates hippocampal and posterior cingulate volume loss in cognitively normal healthy older adults.

Poor sleep quality is a known risk factor for Alzheimer's disease. This longitudinal imaging study aimed to determine the acceleration in the rates of tissue loss in cognitively critical brain regions due to poor sleep in healthy elderly individuals. Cognitively-normal healthy individuals, aged ≥60 years, reported Pittsburgh Sleep Quality Index (PSQI) and underwent baseline and 2-year follow-up magnetic resonance imaging brain scans. The links between self-reported sleep quality, rates of tissue loss in cognitively-critical brain regions, and white matter hyperintensity load were assessed. A total of 48 subjects were classified into normal (n = 23; PSQI score <5) and poor sleepers (n = 25; PSQI score ≥5). The two groups were not significantly different in terms of age, gender, years of education, ethnicity, handedness, body mass index, and cognitive performance. Compared to normal sleepers, poor sleepers exhibited much faster rates of volume loss, over threefold in the right hippocampus and fivefold in the right posterior cingulate over 2 years. In contrast, there were no significant differences in the rates of volume loss in the cerebral and cerebellar grey and white matter between the two groups. Rates of volume loss in the right posterior cingulate were negatively associated with global PSQI scores. Poor sleep significantly accelerates volume loss in the right hippocampus and the right posterior cingulate cortex. These findings demonstrate that self-reported sleep quality explains inter-individual differences in the rates of volume loss in cognitively-critical brain regions in healthy older adults and provide a strong impetus to offer sleep interventions to cognitively normal older adults who are poor sleepers.

Cognitive and Neuroimaging Correlates of the Insomnia Severity Index in Obstructive Sleep Apnea: A Pilot-Study.

We aim to determine the sleep correlates of age-related brain loss in a sample of middle-aged to older males with obstructive sleep apnea (OSA). We recruited consecutive treatment naïve male patients with moderate to severe OSA from January to November of 2019. We excluded participants if they had dementia, stroke or heart disease. We collected demographic variables and vascular risk factors. We also obtained the insomnia severity index, the Epworth sleepiness scale and the Pittsburgh sleep quality index. We also obtained computerized neurocognitive testing with the go-no-go response inhibition test, Stroop interference test, catch game test, staged information processing speed test, verbal memory test and non-verbal memory test. We derived age and education adjusted domain-specific Z-scores for global cognition, memory, attention, processing speed and executive function. We used brain MRI T1-weighted images to derive total hippocampal and gray matter volumes. Partial correlations evaluated associations between variables from sleep questionnaires (e.g., insomnia severity index score), and polysomnographic variables (the apnea-hypopnea index, average oxygen levels during sleep) with cognitive domains and brain volumes. We examined 16 participants with an age range of 40-76 years, 73% Hispanic/Latino. The mean apnea-hypopnea index was 48.9 ± 25.5 and average oxygen saturation during sleep was 91.4% ± 6.9%. Hypertension was seen in 66% and diabetes mellitus in 27%. We found that the insomnia severity index score and average oxygen levels during sleep had the strongest correlations with brain volumes and cognition. These preliminary findings may aid in developing future strategies to improve age-related brain loss in patients with OSA.

MRI Volumetrics and Image Texture Analysis in Assessing Systemic Treatment Response in Extra-Abdominal Desmoid Fibromatosis.

Purpose To determine whether MRI volumetric and image texture analysis correlates with treatment-induced biologic changes in desmoid fibromatosis (DF) earlier than conventional response criteria. Materials and Methods This retrospective study included 27 patients with histologically proven extra-abdominal DF who were managed with active surveillance or systemic therapy (from 2004 to 2016). MRI volumetric and image texture parameters were derived from manual tumor segmentations, and tumor signal intensity was normalized to muscle. Results were compared with objective response rates based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, World Health Organization (WHO) lesion response, volumetrics, and MRI-modified Choi criteria. Correlation coefficients (r) between image texture features and maximum tumor diameters were obtained by using a meta-analysis approach. Results The 27 included patients (mean age, 39 years; 74% women) were followed for an average of 4 years, comprising 207 distinct time-point assessments. The mean baseline tumor maximum diameter was 7.9 cm (range, 3.4-15.2 cm). Partial response (PR) rates as best response were 37%, 44%, 70%, and 81% by RECIST, WHO, volumetrics, and MRI-modified Choi criteria, respectively. Among the 10 tumors showing RECIST PR, a preceding MRI-modified Choi PR was observed in 70% (seven of 10), on average 1.3 years earlier. Multiple image texture parameters showed associations with objective measurements of tumor diameter including mean tumor-to-muscle signal ratio (r = 0.51; P = .004), median tumor-to-muscle signal ratio (r = 0.52; P = .003), energy (r = 0.48; P < .001), run entropy (r = 0.32, P = .04), and gray-level nonuniformity (r = 0.54; P ≤ .001). Conclusion Volumetric signal and image texture assessment allows more comprehensive analysis of DF biologic change and may permit early prediction of DF behavior and therapeutic response. Keywords: MR Imaging, Soft Tissues/Skin, Neoplasms-Primary © RSNA, 2021.

Poor sleep is associated with small hippocampal subfields in cognitively normal elderly individuals.

Recent studies demonstrated reduced hippocampal volumes in elderly healthy individuals who are cognitively normal but poor sleepers. The association between sleep quality and the pattern of volume loss across hippocampal subfields (HSs) is not well known. Thus, it is the focus of the present study. Sleep quality was self-assessed using the Pittsburgh Sleep Quality Index (PSQI). The HS volumes were measured using sub-millimetre in-plane resolution T2-weighted magnetic resonance imaging data. A total of 67 cognitively normal elderly individuals aged 60-83 years were classified into 30 normal sleepers with a PSQI <5 and 37 poor sleepers with a PSQI ≥5. The two groups were equivalent in age, gender distribution, ethnicity, education attainment, handedness and cognitive performance. Compared to normal sleepers, poor sleepers exhibited significantly lower normalised volumes in the left cornu ammonis field 1 (CA1), dentate gyrus (DG) and subiculum. In contrast, there were no significant differences in normalised grey and white matter volumes between the two groups. The global PSQI was negatively associated with the normalised volumes of the left CA1, DG and subiculum. Sleep duration was associated with the normalised volumes of the bilateral CA1, DG, left CA2 and subiculum. Verbal memory scores were associated with the left CA1 volume. In conclusion, poor sleep quality, especially insufficient sleep duration, was associated with volume loss in several HSs that are involved in specific learning and memory tasks. As the hippocampus does not regulate sleep, it is more likely that poor sleep leads to small hippocampi. Thus, based on this assumption, improving sleep quality of poor sleeper elderly individuals could benefit hippocampal health.

Quantification of Regional Cerebral Blood Flow Using Diffusion Imaging With Phase Contrast.

BACKGROUND: The perfusion-related diffusion coefficient obtained from triexponential diffusion analysis is closely correlated with regional cerebral blood flow (rCBF), as assessed by arterial spin labeling (ASL) methods. However, this provides only a semiquantitative measure of rCBF, thereby making absolute rCBF quantification challenging. PURPOSE: To obtain rCBF in a noninvasive manner using a novel diffusion imaging method with phase contrast (DPC), in which the total CBF from phase-contrast (PC) MRI was utilized to convert perfusion-related diffusion coefficients to rCBF values. STUDY TYPE: Prospective. SUBJECTS: Eleven healthy volunteers (nine men and two women; mean age, 23.9 years) participated in this study. FIELD STRENGTH/SEQUENCE: A 3.0 T, single-shot diffusion echo-planar imaging with multiple b-values (0-3000 s/mm2 ), PC-MRI, pulsed continuous ASL, and 3D T1 -weighted fast field echo. ASSESSMENT: rCBF and its correlations in the gray matter (GM) and white matter (WM) were compared between DPC and ASL methods. rCBF in the GM and WM and the GM/WM ratio were compared with the literature values obtained using [15 O]-water positron emission tomography (15 O-H2 O PET). STATISTICAL TESTS: Spearman's correlation coefficient and Wilcoxon signed-rank test were used. Significance was set at P < 0.05. RESULTS: A significant positive correlation between DPC and ASL in terms of rCBF was observed in GM (R = 0.9), whereas the correlation between the two methods was poor in WM (R = 0.09). The rCBF in GM and WM and the GM/WM ratio obtained using DPC were consistent with the literature values assessed using 15 O-H2 O PET. The rCBF value obtained using DPC was significantly higher in the GM and WM than that using ASL. DATA CONCLUSION: DPC enabled noninvasive quantification of rCBF. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Role of the spinal canal compliance in regulating posture-related cerebrospinal fluid hydrodynamics in humans.

Mechanical compliance of a compartment is defined by the change in its volume with respect to a change in the inside pressure. The compliance of the spinal canal regulates the intracranial pressure (ICP) under postural changes. Understanding how gravity affects ICP is beneficial for poorly understood cerebrospinal fluid (CSF)-related disorders. The aim of this study was to evaluate postural effects on cranial hemo- and hydrodynamics. This was a prospective study, which included 10 healthy volunteers (three males, seven females, mean ± standard deviation age: 29 ± 7 years). Cine gradient-echo phase-contrast sequence acquired at 0.5 T, "GE double-doughnut" scanner was used. Spinal contribution to overall craniospinal compliance (CSC), craniospinal CSF stroke volume (SV), magnetic resonance (MR)-derived ICP (MR-ICP), and total cerebral blood flow (TCBF) were measured in supine and upright postures using automated blood and CSF flows quantification. Statistical tests performed were two-sided Student's t-test, Cohen's d, and Pearson correlation coefficient. MR-ICP and the craniospinal CSF SV were significantly correlated with the spinal contribution to the overall CSC (r = 0.83, p < 0.05) and (r = 0.62, p < 0.05), respectively. Cranial contribution to CSC increased from 44.5% ± 16% in supine to 74.9% ± 8.4% in upright posture. The average MR-ICP dropped from 9.9 ± 3.4 mmHg in supine to -3.5 ± 1.5 mmHg. The CSF SV was over 2.5 times higher in the supine position (0.55 ± 0.14 ml) than in the upright position (0.21 ± 0.13 ml). In contrast, TCBF was slightly higher in the supine posture (822 ± 152 ml/min) than in the upright posture (761 ± 139 ml/min), although not statistically significant (p = 0.16). The spinal-canal compliance contribution to CSC is larger than the cranial contribution in the supine posture and smaller in the upright posture. Thereby, the spinal canal plays a role in modulating ICP upon postural changes. The lower pressure craniospinal CSF system was more affected by postural changes than the higher-pressure cerebral vascular system. Craniospinal hydrodynamics is affected by gravity and is likely to be altered by its absence in space. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Machine learning-based estimation of cognitive performance using regional brain MRI markers: the Northern Manhattan Study.

High dimensional neuroimaging datasets and machine learning have been used to estimate and predict domain-specific cognition, but comparisons with simpler models composed of easy-to-measure variables are limited. Regularization methods in particular may help identify regions-of-interest related to domain-specific cognition. Using data from the Northern Manhattan Study, a cohort study of mostly Hispanic older adults, we compared three models estimating domain-specific cognitive performance: sociodemographics and APOE ε4 allele status (basic model), the basic model and MRI markers, and a model with only MRI markers. We used several machine learning methods to fit our regression models: elastic net, support vector regression, random forest, and principal components regression. Model performance was assessed with the RMSE, MAE, and R2 statistics using 5-fold cross-validation. To assess whether prediction models with imaging biomarkers were more predictive than prediction models built with randomly generated biomarkers, we refit the elastic net models using 1000 datasets with random biomarkers and compared the distribution of the RMSE and R2 in models using these random biomarkers to the RMSE and R2 from observed models. Basic models explained ~ 31-38% of the variance in domain-specific cognition. Addition of MRI markers did not improve estimation. However, elastic net models with only MRI markers performed significantly better than random MRI markers (one-sided P < .05) and yielded regions-of-interest consistent with previous literature and others not previously explored. Therefore, structural brain MRI markers may be more useful for etiological than predictive modeling.

Fast Phase-Contrast Cine MRI for Assessing Intracranial Hemodynamics and Cerebrospinal Fluid Dynamics.

We propose fast phase-contrast cine magnetic resonance imaging (PC-cine MRI) to allow breath-hold acquisition, and we compared intracranial hemo- and hydrodynamic parameters obtained during breath holding between full inspiration and end expiration. On a 3.0 T MRI, using electrocardiogram (ECG)-synchronized fast PC-cine MRI with parallel imaging, rectangular field of view, and segmented k-space, we obtained velocity-mapped phase images at the mid-C2 level with different velocity encoding for transcranial blood flow and cerebrospinal-fluid (CSF) flow. Next, we calculated the peak-to-peak amplitudes of cerebral blood flow (ΔCBF), cerebral venous outflow, intracranial volume change, CSF pressure gradient (ΔPG), and intracranial compliance index. These parameters were compared between the proposed and conventional methods. Moreover, we compared these parameters between different utilized breath-hold maneuvers (inspiration, expiration, and free breathing). All parameters derived from the fast PC method agreed with those from the conventional method. The ΔPG was significantly higher during full inspiration breath holding than at the end of expiration and during free breathing. The proposed fast PC-cine MRI reduced scan time (within 30 s) with good agreement with conventional methods. The use of this method also makes it possible to assess the effects of respiration on intracranial hemo- and hydrodynamics.

Diastolic Blood Pressure Is Associated With Regional White Matter Lesion Load: The Northern Manhattan Study.

Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures (DBP) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and DBP, defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. DBP levels were significantly related to WMHV differentially across regions (P for interaction<0.05). Relative to those with DBP 90+ mm Hg, participants with DBP <80 mm Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with DBP 80 to 89 mm Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with DBP 90≥ mm Hg. Post hoc pairwise t tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted P<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower DBP levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.

Cholinergic White Matter Lesions, AD-Signature Cortical Thickness, and Change in Cognition: The Northern Manhattan Study.

BACKGROUND: How cerebrovascular disease and neurodegeneration affect each other to impact cognition is not yet known. We aimed to test whether Alzheimer's disease-signature (AD) cortical thickness mediates the association between cholinergic white matter lesion load and change in domain-specific cognition. METHODS: Clinically stroke-free participants from the Northern Manhattan Study with both regional white matter hyperintensity volume (WMHV) and gray matter measurements were included (N = 894). Tract-specific WMHVs were quantified through FSL using the Johns Hopkins University white matter tract atlas. We used Freesurfer 5.1 to estimate regional cortical thickness. We fit structural equation models, including multiple indicator latent change score models, to examine associations between white matter hyperintensity volume (WMHV) in cholinergic tracts, AD-signature region cortical thickness (CT), and domain-specific cognition. RESULTS: Our sample (N = 894) had a mean (SD) age = 70 (9) years, years of education = 10 (5), 63% women, and 67% Hispanics/Latinos. Greater cholinergic WMHV was significantly related to worse processing speed at baseline (standardized ß = -0.17, SE = 0.05, p = .001) and over time (standardized ß = -0.28, SE = 0.09, p = .003), with a significant indirect effect of AD-signature region CT (baseline: standardized ß = -0.02, SE = 0.01, p = .023; change: standardized ß = -0.03, SE = 0.02, p = .040). CONCLUSIONS: Cholinergic tract WMHV is associated with worse processing speed, both directly and indirectly through its effect on AD-signature region CT.

Measures of Adiposity and Alzheimer's Disease-Related MRI Markers: The Northern Manhattan Study.

BACKGROUND: Adiposity may increase risk for dementia and Alzheimer's disease (AD), but mechanisms are unclear. OBJECTIVE: To examine associations between measures of adiposity with AD-signature region cortical thickness and hippocampal volume. METHODS: We used data from the Northern Manhattan Study, a clinically stroke-free cohort of mostly Hispanic participants. Exposures of interest included body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC), and adiponectin concentration, measured at study entry. AD-signature region cortical thickness and hippocampal volume were obtained using Freesurfer. We estimated associations using multivariable linear regression, adjusting for sociodemographics and health behaviors. We re-examined estimates after adjustment for APOEɛ4 allele status or carotid intima-media thickness (cIMT), among those cognitively unimpaired, and after weighting for the inverse probability of selection into the MRI sub-study. We also repeated analyses for cortical thickness in non-AD signature regions. RESULTS: The sample (N = 947, 63% women, 66% Hispanic/Latino, 26% obese) had a mean (SD) age = 63 (8) years. Greater BMI and WC (both z-scored) were associated with thinner AD-signature region cortex (also z-scored) (BMI: ß [95% CI] = -0.09 [-0.18, -0.01], WC: ß [95% CI] = -0.11 [-0.20, -0.02]). We did not find evidence that adiposity was related to hippocampal volume. Results were consistent after adjustment for APOEɛ4 allele status or cIMT, after weighting for selection, among those cognitively unimpaired, and for non-AD signature region cortical thickness. CONCLUSION: Greater BMI and WC were related to cortical thinning within and outside the AD-signature region, suggesting a global effect not specific to AD.

Measures of obesity are associated with MRI markers of brain aging: The Northern Manhattan Study.

OBJECTIVE: To examine associations between measures of obesity in middle to early-old age with later-life MRI markers of brain aging. METHODS: We analyzed data from the Northern Manhattan MRI Sub-Study (n = 1,289). Our exposures of interest were body mass index (BMI), waist circumference (WC), waist-to-hip ratio, and plasma adiponectin levels. Our outcomes of interest were total cerebral volume (TCV), cortical thickness, white matter hyperintensity volume (WMHV), and subclinical brain infarcts (SBI). Using multivariable linear and logistic regression models adjusted for sociodemographics, health behaviors, and vascular risk factors, we estimated ß coefficients (or odds ratios) and 95% confidence intervals (CIs) and tested interactions with age, sex, and race/ethnicity. RESULTS: On average at baseline, participants were aged 64 years and had 10 years of education; 60% were women and 66% were Caribbean Hispanic. The mean (SD) time lag between baseline and MRI was 6 (3) years. Greater BMI and WC were significantly associated with thinner cortices (BMI ß [95% CI] -0.089 [-0.153, -0.025], WC ß [95% CI] -0.103 [-0.169, -0.037]) in fully adjusted models. Similarly, compared to those with BMI <25, obese participants (BMI ≥30) exhibited smaller cortical thickness (ß [95% CI] -0.207 [-0.374, -0.041]). These associations were particularly evident for those aged <65 years. Similar but weaker associations were observed for TCV. Most associations with WMHV and SBI did not reach statistical significance. CONCLUSIONS: Adiposity in early-old age is related to reduced global gray matter later in life in this diverse sample. Future studies are warranted to elucidate causal relationships and explore region-specific associations.

Brain arterial dilatation modifies the association between extracranial pulsatile hemodynamics and brain perivascular spaces: the Northern Manhattan Study.

Pulsatile hemodynamics are associated with brain small perivascular spaces (SPVS). It is unknown whether the stiffness of intermediary arteries connecting the aorta and brain modifies this association. Participants from the Northern Manhattan Study were assessed for SPVS (defined as ≤3 mm T1 voids) and white matter hyperintensity volume (WMH) using MRI. Middle (MCA) and anterior cerebral arterial (ACA) diameters (measured on time-of-flight MRA) and CCA strain (assessed by ultrasound) were used as surrogates of stiffness. Brachial and aortic pulse pressure (PP) and aortic augmentation index (Aix, assessed by applanation tonometry) were used as markers of pulsatility. We tested whether stiffness in intermediary arteries modifies the association between extracranial pulsatility with SPVS and WMH. We found that among 941 participants (mean age 71 ± 9 years, 60% women, 66% Hispanic), the right MCA/ACA diameter was associated with right anterior SPVS (B = 0.177, P = 0.002). Brachial PP was associated with right anterior SPVS (B = 0.003, P = 0.02), and the effect size was bigger with right MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). The association between right CCA strain and ipsilateral SPVS was modified by MCA/ACA diameter, with the largest effect size in those with ipsilateral MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). Similar dose-effects and statistical interactions were replicated using aortic AIx or aortic PP. We found no evidence of effect modification between pulsatile measures and WMH by stiffness measures. In summary, pulsatile hemodynamics relate to brain SPVS, and the association is the strongest among individuals with dilated brain arteries.