CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2 ) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2 -induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2 ) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

Different profiles of neurocognitive functioning in patients with brain metastases prior to brain radiotherapy.

OBJECTIVE: Patients with brain metastases (BrMs) are a heterogeneous population, with almost 50% experiencing cognitive impairment before brain radiotherapy. Defining pre-radiotherapy cognitive profiles will aid in understanding of the cognitive vulnerabilities and offer valuable insight and guidance for tailoring interventions. METHODS: The study population consisted of 58 adult patients with BrMs referred for radiotherapy. A semi-structured interview and comprehensive battery including 10 neuropsychological tests were used to assess subjective and objective cognitive performance prior to radiotherapy. RESULTS: A majority (69%) of patients report decline in cognitive performance compared to their premorbid level (i.e. pre-cancer). Objective testing revealed memory (52%), processing speed (33%) and emotion recognition (29%) deficits were most frequent. 21% of patients had no cognitive deficits while 55% had deficits (-1.5SD) in at least two cognitive domains. Hierarchical cluster analysis based on patient deficit profiles identified four clusters: (I) no or limited cognitive deficits selectively restricted to processing speed or executive function, (II) psychomotor speed deficits, (III) memory deficits and (IV) extensive cognitive deficits including memory. No patient or clinical-related (e.g. age, number of BrMs, previous treatment) differences were found between clusters. CONCLUSIONS: Patterns of cognitive performance in patients with BrMs are heterogeneous, with most experiencing at least some degree of neurocognitive dysfunction. We identified four meaningful cognitive clusters. Stability of these clusters over time and in different samples should be assessed to advance understanding of the cognitive vulnerability of this patient population.

Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report.

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = -0.286, p < 0.001), CMRO2 (rrm = -0.254, p < 0.001), and CVR (rrm = -0.346, p < 0.001), but not in OEF (rrm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.

Hemodynamic imaging parameters in brain metastases patients - Agreement between multi-delay ASL and hypercapnic BOLD.

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = -0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.