Projects

Neurological complications and stroke mechanisms in sickle cell disease

Chronically low arterial oxygen content caused by hemolytic anemia in sickle cell disease leads the heart and brain to engage several compensatory mechanisms which lead to elevation in cerebral oxygen delivery to meet cerebral metabolic demands.  We are examining how global and regional cerebral hemodynamics and oxygen metabolism provide patient and tissue specificity for predicting risk for cerebral ischemic injury and cognitive impairment in pediatric and adult sickle cell disease.  Using both old and new imaging techniques, we are investigating the interaction of hypoxia-ischemia with endothelial and blood-brain barrier disruption on progressive cerebral injury and cognitive decline.  We are linking our imaging and cognitive findings to genomic and proteomic pathways across a population with varying levels of disease severity to help understand which pathways are protective and which are harmful.

Guilliams, Fields et al. Blood 2018: Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) maps from a child with Sickle Cell Disease.
Guilliams, Fields et al. Blood 2018: Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) maps from a child with Sickle Cell Disease.
Hulbert et al. Blood 2023: Comparison of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) between chronic red blood cell transfusion therapy (CRTT) and hematopoietic stem cell transplant (HSCT) in sickle cell disease (SCD) participants and children in the control group.
Hulbert et al. Blood 2023: Comparison of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) between chronic red blood cell transfusion therapy (CRTT) and hematopoietic stem cell transplant (HSCT) in sickle cell disease (SCD) participants and children in the control group.
Fields, Guilliams et al. Blood 2019: Percentage of patients with brain tissue experiencing increased metabolic stress decreases with HU.
Fields, Guilliams et al. Blood 2019: Percentage of patients with brain tissue experiencing increased metabolic stress decreases with HU.
Wang, Fellah et al. Neurology 2021: (A) Infarct density map, (B) Map of voxels with elevated mean diffusivity (MD) was overlaid onto the map of voxels with elevated oxygen extraction fraction (OEF), (C) Infarct density map was overlaid onto the map of voxels with elevated MD.
Wang, Fellah et al. Neurology 2021: (A) Infarct density map, (B) Map of voxels with elevated mean diffusivity (MD) was overlaid onto the map of voxels with elevated oxygen extraction fraction (OEF), (C) Infarct density map was overlaid onto the map of voxels with elevated MD.

Natural history of inherited small vessel diseases: RVCL-S and CADASIL

Our lab is investigating the influence of oxygen metabolic stress with respect to ischemic vulnerability in patients with active cSVD who have or are at risk for vascular contributions to cognitive impairment and dementia (VCID). One inherited cSVD of particular interest is retinal vasculopathy with cerebral leukoencephalopathy (RVCL-S) which rapidly progresses over 10-15 years in mid adulthood. We follow an observational RVCL-S cohort with sequential MRI and cognitive testing which may serve as an accelerated model of cSVD, allowing us to gain a greater understanding of imaging biomarkers of risk as well as imaging.

Ford et al. Neurology 2020. Top row shows fluid-attenuated inversion recovery (FLAIR) images; middle row shows diffusion-weighted imaging (DWI) images; bottom row shows T1 post-gadolinium images. (A) A 45-year-old woman with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) demonstrated a pseudotumor adjacent to the right frontal horn. The pseudotumor demonstrates an underlying ring-enhancing lesion on T1 postgadolinium with central hyperintensity on DWI and surrounding vasogenic edema on FLAIR. MRI scan a decade later demonstrates that the previous pseudotumor is inactive without central diffusion restriction, contrast enhancement, or significant vasogenic edema on FLAIR. Diffuse central > peripheral atrophy is prominent, and additional white matter lesions have developed a decade after the baseline MRI. (B) MRI scan of a 54-year-old woman with RVCL-S shows multiple subcortical and periventricular white matter lesions, several which are hyperintense on DWI and a few of which show nodular enhancement on T1 postgadolinium. Five years later, her MRI scan just before death demonstrates a relative decrease/regression in number and overall burden of white matter lesions on FLAIR, DWI, and T1 postgadolinium, with greater lesion burden near the ventricles and less within the subcortical white matter; however, substantial atrophy (central and peripheral) has progressed over the 5 years before death. Sequential neuroimaging on this patient never revealed any pseudotumors. (C) A 43- year-old woman with RVCL-S demonstrates periventricular and subcortical white matter lesions on FLAIR imaging, several, but not all, of which are bright on DWI and show nodular enhancement on T1 postgadolinium. Follow-up MRI scan 7 years later near the time of death shows substantial progression in FLAIR lesion burden with overall decrease in DWI hyperintense lesions. Furthermore, nodular enhancement of white matter lesions has diminished, but a ring-enhancing pseudotumor lesion has appeared adjacent to the right frontal horn. Notably, there is substantial progression of atrophy (central > peripheral) over the 7-year interval.
Ford et al. Neurology 2020: Top row shows fluid-attenuated inversion recovery (FLAIR) images; middle row shows diffusion-weighted imaging (DWI) images; bottom row shows T1 post-gadolinium images. (A) 45-year-old woman with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) (B) MRI scan of a 54-year-old woman with RVCL-S (C) 43-year-old woman with RVCL-S

Sporadic cerebral small vessel disease and vascular contributions to dementia

As the 2nd leading cause of dementia after Alzheimer’s Disease, the Ford lab, in collaboration with Hongyu An’s and Jin-Moo Lee’s Lab, prioritizes the investigation of vascular contributions to cognitive impairment and dementia, also known as VCID.   Shown is a MRI of brain showing how hypertension and other systemic vascular insults wreak havoc and structurally injure various brain regions, leading to fragile brain health and lowering the threshold for dementia.

Figure 7: Brain T1 MPRAGE demonstrates perivascular spaces (PVS) in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).
Brain T1 MPRAGE demonstrates perivascular spaces (PVS) in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).
Figure 6: Susceptibility weighted imaging demonstrates deep gray matter microbleeds in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).
Susceptibility weighted imaging demonstrates deep gray matter microbleeds in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).
Figure 8: FLAIR imaging demonstrating presence of white matter disease and silent lacunar infarction, in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).
FLAIR imaging demonstrating presence of white matter disease and silent lacunar infarction, in this patient with cerebral small vessel disease (CSVD) and vascular contributions to cognitive impairment and dementia (VCID).