Alexander K. Song

Understanding age-related changes in cerebral blood flow (CBF, rate of blood delivery to brain tissue) in sickle cell anemia (SCA) is a prerequisite to incorporating CBF as a marker of brain health. CBF decreases from school-age through adulthood in nonanemic people. In SCA, CBF is generally increased to compensate for anemia, but knowledge of age-related norms is limited. We hypothesized that age-related CBF trajectories differ for SCA vs nonanemic healthy persons: CBF increases from childhood to early adulthood in SCA to compensate for reduced blood oxygen content and then plateaus because of reduced vasodilatory capacity with older age. Children and adults with SCA and race-matched controls (hemoglobin [Hb] AA) aged 6-45 years were enrolled in an observational cross-sectional study from 2014 to 2023 at an academic and community health center. History of overt stroke or arterial stenosis >50% were exclusions. Brain MRIs were performed at 3T with arterial-spin-labeling measurements of gray matter CBF. Regression analyses assessed how age, imaging markers of ischemia, Hb, and arterial oxygen saturation (SpO₂) related to CBF. In 192 Black participants with SCA (N = 126; mean age = 18.7 ± 9.0 years, 52.4% female) or without SCA (N = 66; mean age = 22.4 ± 9.7 years, 54.5% female), total Hb was lower in SCA (mean Hb = 8.9 ± 1.3 g/dL) vs control (mean Hb = 13.4 ± 1.5 g/dL) participants (p < 0.001) and did not differ with age in the SCA group. SpO₂ was reduced in SCA (median SpO₂ = 96%; interquartile range [IQR] = 94-97.4%) vs controls (median SpO₂ = 98%, IQR = 97-99%, p < 0.001). In SCA participants, SpO₂ was lower in adults (median SpO₂ = 95%, IQR = 94%-97%, p = 0.001) compared with children (SpO₂ = 96.5%, IQR = 95%-98.2%). Regression analyses, including an interaction between age and group (SCA vs control), showed that CBF increases in SCA by 5.03 mL/100 g/min per decade (95% CI 1.70-8.37) and plateaus at approximately age 30-35 years. In controls, CBF decreased by -5.20 mL/100 g/min per decade (95% CI -8.96 to -1.94). The divergent age dependency of CBF between SCA and non-anemic persons may be explained by a gradient of increasing CBF with age required to compensate for reductions in blood oxygen content in SCA, with possible exhaustion of cerebral vasodilatory abilities in the fourth decade of life. Longitudinal studies are needed.

Dysregulated dopamine (DA) release in the mesocorticolimbic circuit is noted in Parkinson’s disease (PD) patients with impulsive and compulsive behaviors (ICBs). However, the effect of acute DA release on mood, the localization of this process, and the phenotypic differences in patients with ICB remain unknown. We applied a placebo-controlled dextro-amphetamine (dAMPH) study in 20 PD patients: 10 with ICBs (PD-ICB) and 10 without (PD-C). Subjective mood experiences were measured with well-described self-reported measures including the Positive and Negative Affect Scale (PANAS), Drug Effects Questionnaire (DEQ), and Amphetamine Interview Rating Scale (AIRS). D2-like receptor availability was measured as non-displaceable binding potential (BP_ND) using PET imaging with the high-affinity D2/3 receptor ligand [¹⁸F]-fallypride. Among all the subjects, dAMPH increased the PANAS positive, DEQ feel, DEQ high, and AIRS total scores. Increases in the PANAS positive and AIRS total scores were greater in the PD-ICB cohort. A mixed-effects model correlated these questionnaire changes with dAMPH-induced reductions in BP_ND in the ventral striatum (VS), caudate, amygdala, and caudo-medial orbitofrontal cortex. The baseline caudate, VS, and amygdala BP_ND positively correlated with lower on-dAMPH PANAS positive scores. Elevated mood symptoms of acute dAMPH administration in PD are linked to DA release in the mesocorticolimbic regions. Distinctions in behavioral effects among PD-ICB subjects emphasize that dysregulated striatal and extra-striatal DA-ergic networks alter mood responses to stimulated DA release and may also contribute to behavioral changes resulting from DA-targeting therapies in PD.

Patients with sickle cell disease (SCD) are at elevated risk of silent cerebral infarcts and strokes; however, they frequently lack established stroke risk factors (eg, macrovascular arterial steno-occlusion) and the mechanisms underlying such events are incompletely characterized. This study evaluated cerebral hemometabolism with respect to imaging markers of vascular shunting in 143 participants with SCD, including 73 pediatric (aged 6-17 years) and 70 adult (aged 18-40 years) participants using 3-Tesla brain magnetic resonance imaging (MRI). Vascular shunting was assessed in each patient using a previously published ordinal venous hyperintensity score (VHS) of 0, 1, or 2 on cerebral blood flow-weighted MRI. Participants with VHS of 2, indicative of the most rapid arteriovenous transit, had significantly reduced blood oxygen content (CaO2; 10.90 ± 1.69 mL O2/100 mL blood), oxygen extraction fraction (OEF; 33.52% ± 5.54%), and cerebral metabolic rate of oxygen consumption (CMRO2; 2.91 ± 0.69 mL O2/100 g tissue per minute) compared with their counterparts with VHS = 0 (CaO2 = 12.42 ± 1.58 mL O2/100 mL blood; OEF = 39.03% ± 3.80%; CMRO2 = 3.77 ± 0.84 mL O2/100 g tissue per minute) or VHS = 1 (CaO2 = 11.86 ± 1.73 mL O2/100 mL blood; OEF = 36.37% ± 5.11%; CMRO2 = 3.59 ± 0.78 mL O2/100 g tissue per minute). Both pediatric and adult patients with SCD presenting with greater imaging evidence of vascular shunting had mildly reduced OEF and CMRO2. These findings highlight that imaging markers of vascular shunting are associated with significant, albeit mild, evidence of reduced OEF and CMRO2 in patients with SCD.

Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Treatments include oral hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation (HSCT). Our objective was to evaluate the neurologic relevance of these therapies by characterizing how treatment-induced changes in hemoglobin (Hb) affect brain health biomarkers. In this interventional study, adults with and without SCD underwent a 3T-MRI at Vanderbilt University Medical Center at 2 time points before and after clinically indicated transfusion or HSCT or at 2 time points without the introduction of a new Hb-altering therapy (adult controls and patients with SCD on hydroxyurea). Cerebral blood flow (CBF; mL/100 g/min) and cerebral venous blood relaxation rate (s^-1; a marker of Hb and blood oxygen content) responses were assessed to understand how these markers of brain health vary with Hb modulation. CBF was assessed with arterial spin labeling MRI, and blood relaxation rate was assessed using T₂ relaxation under spin tagging MRI. Measures were pairwise compared within each cohort using a 2-tailed Wilcoxon signed-rank test, and regression was applied to evaluate the parameter and Hb change relationships. The significance criterion was 2-sided p < 0.05. Adults with (n = 43; age 28.7 ± 7.7 years; 42% male) and without (n = 13; age 33.5 ± 12.2 years; 46% male) SCD were evaluated. In adults receiving hydroxyurea (n = 10), neither Hb, CBF, nor venous relaxation rate changed between time 1 (Hb = 8.6 ± 1.2 g/dL) and time 2 (Hb = 9.0 ± 1.8 g/dL) (all p > 0.05). In transfusion patients (n = 19), Hb increased from 8.2 ± 1.4 g/dL to 9.3 ± 1.3 g/dL before vs after transfusion (p < 0.001), paralleling a CBF decrease of 14.2 mL/100 g/min (p < 0.001) toward control levels. The venous relaxation rate did not change after transfusion (p = 0.71). In HSCT patients (n = 14), Hb increased from 8.9 ± 1.9 g/dL to 12.9 ± 2.7 g/dL (p < 0.001) before vs after transplant, paralleling CBF decreases from 68.16 ± 20.24 to 47.43 ± 12.59 mL/100 g/min (p < 0.001) and increase in venous relaxation rate (p = 0.004). Across the Hb spectrum, a CBF decrease of 5.02 mL/100 g/min per g/dL increase in Hb was observed. Findings demonstrate improvement in cerebral hemodynamics after transfusion and transplant therapies compared with hydroxyurea therapy; quantitative relationships should provide a framework for using these measures as trial end points to assess how new SCD therapies affect brain health.

Preliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

One of the pathological hallmarks of Alzheimer’s and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively in vivo. Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow, and egress in the context of independent PET measures of amyloid-β accumulation in older adults. Participants (N = 23) were scanned at 3.0T with 3D T₂-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labeling, and phase contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion, and net CSF flow through the aqueduct of Sylvius respectively. All participants also underwent dynamic PET imaging with amyloid-β tracer ¹¹C-Pittsburgh Compound B to quantify global cerebral amyloid-β accumulation. Spearman’s correlation analyses revealed a significant relationship between global amyloid-β accumulation and parasagittal dural space volume (rho = 0.529, p = 0.010), specifically in the frontal (rho = 0.527, p = 0.010), and parietal (rho = 0.616, p = 0.002) subsegments. No relationships were observed between amyloid-β and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-β accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-β aggregation and clearance via neurofluids.

Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson’s disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D₂ autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson’s disease population. Here, we applied ¹⁸F-fallypride PET studies to assess striatal and extrastriatal D₂-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson’s disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D₂ autoreceptors would underlie this response. Twenty patients with Parkinson’s disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with ¹⁸F-fallypride, a high-affinity D₂-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson’s disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D₂ receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson’s disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.