Neurofluid dynamics are crucial for maintaining brain homeostasis and facilitating the clearance of brain metabolites through the coupling of arterial and venous blood with cerebrospinal fluid (CSF). Two-dimensional phase contrast (PC) magnetic resonance imaging (MRI) is frequently used to study neurofluids; however, separate examinations are typically required for assessing blood and CSF flow, which can confound analyses due to asynchronous physiological measurements. To enable simultaneous assessment of neurofluid dynamics, we describe and evaluate a 2D PC MRI approach in human participant experiments. An interleaved multi-point velocity encoding scheme was integrated into a 2D golden angle spiral PC MRI scan to facilitate synchronous characterization of neurofluids. Two multi-point schemes, including interleaved dual-venc (DV) and triple-venc (MV) scans, were evaluated and compared with standard asynchronous single-venc (SV) scans. Data and repeated scans were collected on a clinical 3.0T scanner at the level of the C1/C2 vertebrae in 10 human participants. From cardiac-resolved images, the relationship between net blood flow and CSF flow pulsatile volume change was characterized using regression modeling. Temporal lags between cardiac-driven arterial blood (vertebral arteries (VAs) and internal carotid arteries (ICAs)) and spinal canal (SC) CSF were estimated with cross-correlation. SV, DV, and MV flow mean, range, and volume changes were studied and compared using linear mixed effect models, intraclass correlation coefficients, Bland–Altman, and Pearson correlations. A strong relationship was measured between net blood flow and CSF flow pulsatile volume change from SV (R 2 = 0.71, P = 0.002), DV (R 2 = 0.70, P = 0.003), and MV (R 2 = 0.78, P < 0.001) scans. SC-VAs temporal lags were statistically longer than SC-ICAs lags across all scans (P < 0.001 for SV, DV, and MV). Bland–Altman analyses and repeatability coefficients indicated that DV and MV scans had the highest repeatability. MV scans generally underestimated SC CSF flow markers relative to SV and DV scans. A more pronounced flow offset in venous measures was identified between SV scans and the DV and MV scans. In conclusion, this study introduced a method for simultaneous imaging of cranio-spinal arterial, venous, and CSF flow, enabling the synchronous assessment of neurofluid dynamics. The results indicated that interleaved DV and MV scans could improve the evaluation of neurofluid coupling compared with asynchronous SV scans.

Large-scale clinical research studies often incorporate neuroimaging biomarkers to understand underlying pathologic changes that occur in aging and neurodegenerative disease and are associated with cognitive decline and clinical impairment. Of particular interest are neuroimaging methods designed to understand various aspects of cerebrovascular disease that can lead to dementia and also co-occur with neurodegenerative diseases such as Alzheimer’s disease. Neurovascular 4D flow magnetic resonance imaging is one such method that measures hemodynamic characteristics of medium-large cerebral vessels, but it remains unclear how measures derived from 4D flow imaging including pulsatility index, cerebral blood flow, and cross-sectional area relate to underlying pathologic changes in cerebral arteries and downstream cerebrovascular pathology. For example, pulsatility index is thought to be a marker of vessel compliance, which may be due to fibrotic and/or atherosclerotic changes. This observational study investigates imaging-pathologic correlates of cerebral artery 4D flow MRI in 20 initial brain donors (mean (SD) age at death 78.2 (10.3) years; 3.2 (1.4) years from MRI to autopsy) from the Wisconsin Alzheimer’s Disease Research Center who underwent antemortem imaging and postmortem assessment of cerebral artery and brain pathology to identify possible pathologic correlates of 4D flow MRI. Our results suggest that 4D flow MRI measures recapitulate expected hemodynamic and structural relationships across cerebral arteries, but also that measures like MRI cross-sectional area may reflect arterial fibrosis whereas mean blood flow may indicate downstream cerebrovascular disease, including white matter rarefaction and arteriolosclerosis. In contrast, associations were minimal with pulsatility index and cerebral artery or brain pathology across participants but were moderate across arterial segments. To our knowledge, this is the first study to investigate pathologic correlates of antemortem 4D flow MRI in cerebral arteries. These results provide preliminary insights regarding the pathologic processes contributing to cerebral artery hemodynamics measured with 4D flow MRI that will help inform interpretation of large-scale clinical aging and dementia studies utilizing this method. Future work with larger samples is needed to confirm these findings.

[F-18]MK6240 is a Positron Emission Tomography (PET) radioligand with favorable imaging characteristics for measuring tau aggregation in Alzheimer’s disease (AD). In this study, we investigated the impact of extra-cerebral off-target binding (ECB) in the meninges and sinus present in [F-18]MK6240 PET scans on quantifying tau burden in preclinical AD. Based on large cohort data from 433 [F-18]MK6240 scans acquired at the University of Wisconsin-Madison, simulations were conducted to examine the range of effects of ECB by varying the ECB profile and input radiotracer concentration curves on areas of early tau accumulation in AD. The range and patterning of ECB in the imaging cohort had high variability between participants; however, 35% revealed moderate to high meningeal signal that could influence quantification. Partial volume effects, which can lead to measured PET signal from neighboring regions influencing signal in adjacent areas of interest, were examined in the simulated images. The simulations demonstrate that signal from the sinus increases the neighboring entorhinal cortex region (ERC) signal and activity detected from the meninges can similarly influence the inferior cerebellar grey matter reference region. ECB effects from the sinus were the most prevalent in our cohort, and simulations with the average ECB profile had ERC uptake (SUV) 23% higher than simulations with no ECB. Spill-in effects from the sinus, which increases the medial and ventral temporal cortex standardized uptake value ratio (SUVR), and spill-in from the meninges into the cerebellar reference region, which leads to a reduction in global SUVR, act in opposite directions, complicating the interpretation of the derived SUVR of [F-18]MK6240 images. These simulation results quantify the effects of ECB in [F-18]MK6240 scans and introduce correction factors to minimize bias of the SUVR measure.