Cluster B

Cluster B. Neurovascular & Neurodegenerative Diseases

Models of Cerebral Hemodynamics and their Use for Diagnosis of Alzheimer’s Disease and Mild Cognitive Impairment (MCI)

Collaborative Project B1
Rong Zhang, Ph.D (Project leader)
University of Texas, Southwestern Medical Center (Dallas, TX)
Vasilis Z. Marmarelis, Ph.D. (Primary BMSR Liaison)

The goal of this project is to advance our quantitative understanding of cerebral flow autoregulation and cerebral hemodynamics by extracting reliable models of this system from beat-to-beat hemodynamic data collected in adults under resting conditions. These models can be used to construct “functional biomarkers” that may improve clinical diagnosis of various cerebrovascular and neurodegenerative diseases, as well as assist in assessing the effects of treatments. Of particular interest is the development of model-based “functional biomarkers” for diagnosing early-stage Alzheimer’s patients, as well as examine the progress of patients with Mild Cognitive Impairment (MCI) with the intent of more accurate prognosis. We define the following Specific Aims:.

We define the following Specific Aims:

  • Closed-loop models of cerebral hemodynamics and comparison with open-loop models.
  • Closed/open-loop models of Alzheimer’s patients and comparison with control subjects.
  • Construct & test model-based “functional biomarkers” for Alzheimer’s disease diagnosis.
  • Examine functional biomarkers obtained from PDM-based models of MCI patients.


Model-based Functional Biomarkers for Diagnosis of Executive Dysfunction in Hypertensive Patients

Collaborative Project B2
Ihab Hajjar, MD (Project leader)
University of Southern California, Keck School of Medicine (Los Angeles, CA)
Vasilis Z. Marmarelis, Ph.D. (Primary BMSR Liaison)

The goal of this project is to advance our quantitative understanding of the impact of hypertension on cognitive function and cerebral flow autoregulation by extracting reliable models of this physiological system from beat-to-beat hemodynamic data of arterial blood pressure, cerebral blood flow velocity and CO2 tension that are collected in adult hypertensive subjects under resting conditions. These models can be used to construct “functional biomarkers” that may improve clinical diagnosis of executive dysfunction, commonly seen hypertension. These models can also be used to assess the effect of various antihypertensive medications on cerebral blood flow regulation, otherwise not possible using previously available methodologies. We define the following aims:

  • Obtain and interpret “functional biomarkers” from PDM-based models of cerebral hemodynamics in patients with hypertension and evidence of executive dysfunction.
  • Examine the sensitivity and specificity of these functional biomarkers in identifying hypertensive subjects with and without executive dysfunction.
  • Assess the effects of various antihypertensive medications on hypertensive subjects enrolled in a double-blind randomized clinical trial using these “functional biomarkers”.


Autonomic Correlates of Vaso-Occlusive Crisis and Pain in Sickle Cell Disease

Collaborative Project B3
Thomas Coates, MD, John Wood, MD, Ph.D., & Herbert Meiselman, Sc.D. (Project leaders)
Children’s Hospital Los Angeles & USC Keck School of Medicine (Los Angeles, CA)

Michael C.K. Khoo, Ph.D. (Primary BMSR Liaison)

The proposed project represents the continuation of a very productive collaboration that began with the start of the current funding cycle. Our studies to date have demonstrated that patients with sickle cell disease (SCD) exhibit abnormal autonomic nervous system (ANS) responses to a variety of stimuli. The long-term goal in the next funding cycle is to derive from these ANS responses accurate biophysical markers that can reliably predict the onset of pain and vaso-occlusive crises in patients with SCD. The specific aims are to determine how:

  • Biomarkers of parasympathetic withdrawal provoked by transient hypoxia, pulmonary stretch receptors (spontaneous sigh) and mental stress correlate with the clinical status of SCD subjects and their individual frequencies of vaso-occlusive crisis;
  • Biomarkers based on sympathetically-mediated sigh-vascoconstriction responses are related to the SCD subjects’ clinical status and history of vaso-occlusive crises;
  • To determine how biomarkers based on peripheral vasoconstriction responses are related to pain perceptions scores obtained from SCD and normal subjects during the application of calibrated heat/cold stimuli applied to the hand;


Model-based Biomarkers for Vascular Dementia & Vascular Cognitive Impairment

Collaborative Project B4
Helena C. Chui, MD (Project leader)
USC Keck School of Medicine (Los Angeles, CA)
Vasilis Z. Marmarelis, Ph.D. (Primary BMSR Liaison)

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