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EP-4741014-A2 - DIAGNOSIS OF DEMENTIA BY VASCULAR MAGNETIC RESONANCE IMAGING

EP4741014A2EP 4741014 A2EP4741014 A2EP 4741014A2EP-4741014-A2

Abstract

A method of diagnosing a likelihood of onset or progression of Alzheimer's disease and related dementias (ADRD) in a subject is provided. The method requires determining vascularization changes in different regions of the brain on the basis of a quantitative cerebral blood volume (qCBV) map of the subject's brain. The qCBV is obtained from one or more quantitative ultrashort time-to-echo contrast-enhanced (QUTE-CE) MRI images of the brain. A method of treating a subject for ADRD is provided. Diagnostic markers for onset and progression of Alzheimer's disease are also provided.

Inventors

  • GHARAGOUZLOO, CODI AMIR
  • FERRIS, CRAIG

Assignees

  • Northeastern University

Dates

Publication Date
20260513
Application Date
20190729

Claims (15)

  1. A method of determining a likelihood of onset or progression of a neurophysiological condition in a subject, the method comprising: generating a first representative quantitative cerebral blood volume (qCBV) for one or more regions of the brain of the subject using one or more first magnetic resonance imaging (MRI) images of the brain of the subject; generating a second representative qCBV for the one or more regions of the brain of the subject using one or more second MRI images of the brain of the subject generated during and/or following the subject undergoing a vascular challenge; determining one or more functional changes of the vasculature of the brain of the subject based on the first representative qCBV and the second representative qCBV; and detecting the likelihood of onset or progression of the neurophysiological condition in the subject based on the one or more functional changes of the vasculature of the brain of the subject.
  2. The method of claim 1, wherein the vascular challenge of the subject is a hypercapnic challenge of the subject.
  3. The method of claim 1, wherein the vascular challenge of the subject is a hypoxic challenge of the subject.
  4. The method of claim 1, wherein the one or more second MRI images of the brain of the subject were generated while the subject breathed CO 2 -enriched air.
  5. The method of claim 1, wherein the one or more second MRI images of the brain of the subject were generated after cessation of the subject breathing CO 2 -enriched air.
  6. The method of claim 1, wherein the one or more functional changes of the vasculature of the brain of the subject comprises a difference between an amount of cerebral blood volume in the one or more regions of the brain indicated by the first representative qCBV and an amount of cerebral blood volume in the one or more regions of the brain indicated by the second representative qCBV.
  7. A computing system comprising: one or more processors; and storage encoded with instructions that, when executed by the one or more processors, cause the one or more processors to perform a method comprising: generating a first representative quantitative cerebral blood volume (qCBV) for one or more regions of the brain of the subject using one or more first magnetic resonance imaging (MRI) images of the brain of the subject; generating a second representative qCBV for the one or more regions of the brain of the subject using one or more second MRI images of the brain of the subject generated during and/or following the subject undergoing a vascular challenge; determining one or more functional changes of the vasculature of the brain of the subject based on the first representative qCBV and the second representative qCBV; and detecting the likelihood of onset or progression of the neurophysiological condition in the subject based on the one or more functional changes of the vasculature of the brain of the subject.
  8. The computing system of claim 7, wherein the vascular challenge of the subject is a hypercapnic challenge of the subject.
  9. The computing system of claim 7, wherein the vascular challenge of the subject is a hypoxic challenge of the subject.
  10. The computing system of claim 7, wherein the one or more second MRI images of the brain of the subject were generated while the subject breathed CO2-enriched air or after cessation of the subject breathing CO 2 -enriched air.
  11. The computing system of claim 7, wherein the one or more functional changes of the vasculature of the brain of the subject comprises a difference between an amount of cerebral blood volume in the one or more regions of the brain indicated by the first representative qCBV and an amount of cerebral blood volume in the one or more regions of the brain indicated by the second representative qCBV.
  12. At least one non-transitory computer-readable storage medium having encoded thereon instructions that, when executed by at least one processor, cause the at least one processor to carry out a method comprising: generating a first representative quantitative cerebral blood volume (qCBV) for one or more regions of the brain of the subject using one or more first magnetic resonance imaging (MRI) images of the brain of the subject; generating a second representative qCBV for the one or more regions of the brain of the subject using one or more second MRI images of the brain of the subject generated during and/or following the subject undergoing a vascular challenge; determining one or more functional changes of the vasculature of the brain of the subject based on the first representative qCBV and the second representative qCBV; and detecting the likelihood of onset or progression of the neurophysiological condition in the subject based on the one or more functional changes of the vasculature of the brain of the subject.
  13. The at least one non-transitory computer-readable storage medium of claim 12, wherein the vascular challenge of the subject is a hypercapnic challenge or a hypoxic challenge of the subject.
  14. The at least one non-transitory computer-readable storage medium of claim 12, wherein the one or more second MRI images of the brain of the subject were generated while the subject breathed CO 2 -enriched air or after cessation of the subject breathing CO2-enriched air.
  15. The at least one non-transitory computer-readable storage medium of claim 12, wherein the one or more functional changes of the vasculature of the brain of the subject comprises a difference between an amount of cerebral blood volume in the one or more regions of the brain indicated by the first representative qCBV and an amount of cerebral blood volume in the one or more regions of the brain indicated by the second representative qCBV.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/711,251, filed on July 27, 2018, entitled "Diagnosis of Dementia by Vascular Magnetic Resonance Imaging," the disclosure of which is hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. EB013180 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Age related dementia is a global health problem affecting over 50 million people worldwide at an estimated cost of over $818 billion (WHO Fact Sheet, Dementia, 2017). Dementia affects more than 8 million seniors in the US alone at a total cost $277 billion (Alzheimer's Disease Facts and Figures, 2018). With aging comes the risk of Alzheimer's Disease (AD), a degenerative brain disorder that is rated as the number one cause of dementia (Wilson, R. S. et al., 2012; Barker, W. W. et al., 2002). Aging also carries the risk of cerebrovascular disease, traditionally considered to be the second leading cause of dementia (Banerjee, G et al., 2015; Roman, G. C. et al., 2004). However, there is accumulating evidence that cerebrovascular disease plays a key role in the neurodegeneration and dementia of AD (Schneider, J. A. et al., 2007; Wharton, S. B. et al. 2011) and may be the most common form of dementia in the elderly (Gorelick, P. B. et al., 2011; Roman, G. C. et al. 2001). This distinction is important, because cerebrovascular disease may be a key factor in the pathophysiology of AD (Kalaria, R. N. & Ballard, C., 1999). Hence, early detection and treatment of cerebrovascular disease may reduce the risk of AD with aging. Early biomarkers of dementia and AD could save the current US population as much as $12.72 to $92.56 billion per year from 2025 to 2050 (Alzheimer's Disease Facts and Figures, 2018). The exact biochemical mechanisms underpinning AD are as yet unsolved. Thus, there exists a compelling need to develop quantitative and reliable physiological biomarkers for diagnostics, prognosis, and treatment of AD and related forms of dementia. SUMMARY Provided herein is a method of diagnosing a likelihood of onset or progression of Alzheimer's Disease and Related Dementia (ADRD) in a subject. The method employs a measurement technique to quantify vascularity throughout the entire brain using magnetic resonance imaging (MRI) ultra-short time-to-echo (UTE) pulse sequences and an intravascular contrast agent. The technique allows measurement of blood volume per unit volume of an anatomical region of the brain. This, in turn allows a determination of whether a given anatomical region of the brain is hypervascularized or hypovascularized. According to an aspect of the technology presented herein, a greater number of hypervascularization regions relative to hypovascularization regions indicate an increased likelihood of onset of ADRD. A greater number of hypovascularization regions relative to hypervascularization regions indicate an increased likelihood of progression of ADRD. In another aspect of the present technology, a greater volume of hypervascularized regions of the brain than hypovascularized regions indicates an increased likelihood of onset of ADRD, while a greater volume of hypovascularized regions than hypervascularized regions indicates an increased likelihood of progression of ADRD. In yet other aspects, an increased ratio of hypervascularized regions to hypovascularized regions indicates increased likelihood of onset of ADRD, while a decrease in this ratio indicates an increased likelihood of progression of ADRD. Similarly, in other aspects of the technology, an increase of hypervascularization compared to a normal subject indicates an increased likelihood of onset of ADRD, while an increase of hypovascularization compared to a normal subject indicates an increased likelihood of progression of ADRD. In addition, dynamic measurements using this technique can be performed either by utilizing shorter time scales to observe normal oscillations in physiological blood volume modulation for the purposes of determining the connectivity of brain regions, or by providing a measurement of blood volume after neurofunctional modulation, e.g., hypoxia, whereby the vascular reserve can be obtained to assess cerebrovascular reactivity (CVR). Also provided herein are diagnostic markers for onset and for progression of ADRD. Using this measurement technique, a hypervascular trend was observed in an APOE4 preclinical rat model of ADRD before disease onset (7 m of age). This trend is related primarily to the microvasculature, suggesting that an increased capillary, or small vessel, density may be a coping mechanism for metabolic dysfunction in dementia. A trend towards hypovascularization was observed (rats 2 y of age) in the APOE4 preclinical rat model of ADRD both in terms of small