IP Library › Granted Patent US 12,642,433
Granted Patent B2
US 12,642,433 · App. 17/425,123 · Granted Jun 2, 2026

Quantitative measurement of the perivascular space for CNS and brain disorders

Inventors: Craig Ferris (Holden, MA); Ju Qiao (Boston, MA); Praveen Kulkarni (East Walpole, MA); Codi Gharagouzloo (Medford, MA)
Assignee: Northeastern University
A61B5/0042A61B5/055A61K49/06G01R33/5601G01R33/5617
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Quick Facts
Patent No.
US 12,642,433
App. No.
17/425,123
Granted
Jun 2, 2026
Kind
B2
Abstract

Disclosed are methods for quantification of a perivascular space in a subject's central nervous system. The methods include administering contrast agent into cerebrospinal fluid of the subject; performing quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI) on a region of interest of the subject's brain; and determining presence of the contrast agent in the perivascular space within the region of interest.

Claims (51)

1 . A method for evaluation of a perivascular space in a subject, the method comprising:

determining at least one kinetic value of flow of perivascular space in a region of interest, the determining comprising:

analyzing magnetic resonance imaging (MRI) data of the region of interest, the MRI data of the region of interest comprising first MRI data captured at a first time point and second MRI data captured at a second time point, one or more of the first time point or the second time point being after (a) a paramagnetic or superparamagnetic blood pool contrast agent was introduced into cerebrospinal fluid of the region of interest of the subject and (b) an occurrence of at least partial mixing of the cerebrospinal fluid with interstitial fluid, the analyzing the MRI data comprising identifying a first signal intensity for the first time point and a second signal intensity for the second time point, wherein each of the first signal intensity and the second signal intensity is obtained via an MRI device configured with a repetition time (TR) less than 10 ms and a time to echo (TE) less than 300 μs;

calculating a longitudinal rate of a change in signal intensity in the region of interest, the longitudinal rate of change in signal intensity comprising a difference in signal intensity obtained from the paramagnetic or superparamagnetic blood pool contrast agent in at least a perivascular space of the region of interest based on a spatial volume of each of the first signal intensity and the second signal intensity; and

evaluating the longitudinal rate of change in signal intensity to determine the at least one kinetic value of flow of the perivascular space within the region of interest.

2 . The method of claim 1 , wherein the region of interest is at least a portion of the subject's brain and the spatial volume is a volume of perivascular spaces of the at least the portion of the subject's brain.

3 . The method of claim 1 , wherein each of the first signal intensity and the second signal intensity is obtained at least in part by:

applying a magnetic field to the region of interest;

applying a radio frequency pulse sequence with a selected repetition time (TR) and a selected flip angle (FA) to excite protons in the region of interest, wherein the repetition time is less than about 10 ms, and the flip angle ranges from about 10° to about 30°;

measuring a response signal during relaxation of the protons at a selected time to echo (TE) with magnetic field gradients activated to provide a T 1 -weighted signal from the region of interest, wherein the time-to-echo is an ultra-short time-to-echo, or Zero TE (ZTE), less than about 300 μs; and

generating an image of the region of interest.

4 . The method of claim 3 , wherein each of the first signal intensity and the second signal intensity is representative of a concentration of the paramagnetic or superparamagnetic blood pool contrast agent in the region of interest.

5 . The method of claim 3 , further comprising setting the time to echo (TE) to less than about 30 μs.

6 . The method of claim 3 , further comprising setting the repetition time to a value from about 2 to about 10 ms.

7 . The method of claim 3 , further comprising setting the flip angle to a value from about 10° to about 25°.

8 . The method of claim 1 , wherein the MRI data is captured by performing quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), and wherein OUTE-CE MTI is performed before presence of the paramagnetic or superparamagnetic blood pool contrast agent in the perivascular space

and is subsequently performed after the paramagnetic or superparamagnetic blood pool contrast agent is present in the perivascular space.

9 . The method of claim 8 , wherein the paramagnetic or superparamagnetic blood pool contrast agent comprises ferumoxytol and QUTE-CE MRI is performed before administration of the ferumoxytol.

10 . The method of claim 8 , comprising determining the presence of contrast agent in the perivascular space at a plurality of times based on respective quantitative signal intensity obtained by the QUTE-CE MRI at said times in the perivascular space.

11 . The method of claim 8 , wherein determining the at least one kinetic value of flow comprises determining a spatial volume of the perivascular space when respective quantitative signal intensity obtained by QUTE-CE MRI for the perivascular space is near or at maximum value.

12 . The method of claim 1 , wherein the contrast agent is ferumoxytol.

13 . The method of claim 12 , wherein ferumoxytol is administered at a dose of about 2 to about 14 mgFe/kg body weight.

14 . The method of claim 1 , wherein administering of the paramagnetic or superparamagnetic blood pool contrast agent is intrathecal.

15 . 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:

determining at least one kinetic value of flow of tissue adjacent to vascular tissue in a region of interest of a subject, the determining comprising:

analyzing magnetic resonance imaging (MRI) data of the region of interest, the MRI data of the region of interest comprising first MRI data captured at a first time point and second MRI data captured at a second time point, one or more of the first time point or the second time point being after (a) a paramagnetic or superparamagnetic blood pool contrast agent was introduced into cerebrospinal fluid of the region of interest of the subject and (b) an occurrence of at least partial mixing of the cerebrospinal fluid with interstitial fluid, the analyzing the MRI data comprising identifying a first signal intensity for the first time point and a second signal intensity for the second time point, wherein each of the first signal intensity and the second signal intensity is obtained via an MRI device configured with a repetition time (TR) less than 10 ms and a time to echo (TE) less than 300 μs;

calculating a longitudinal rate of a change in signal intensity in the region of interest, the longitudinal rate of change in signal intensity comprising a difference in signal intensity obtained from the paramagnetic or superparamagnetic blood pool contrast agent in at least the tissue adjacent to the vascular tissue of the region of interest based on a spatial volume of each of the first signal intensity and the second signal intensity; and

evaluating the longitudinal rate of change in signal intensity to determine the at least one kinetic value of flow of the tissue adjacent to the vascular tissue within the region of interest.

16 . 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:

determining at least one kinetic value of flow of perivascular space in a region of interest of a subject, the determining comprising:

analyzing magnetic resonance imaging (MRI) data of the region of interest, the MRI data of the region of interest comprising first MRI data captured at a first time point and second MRI data captured at a second time point, one or more of the first time point or the second time point being after (a) a paramagnetic or superparamagnetic blood pool contrast agent was introduced into cerebrospinal fluid of the region of interest of the subject and (b) an occurrence of at least partial mixing of the cerebrospinal fluid with interstitial fluid, the analyzing the MRI data comprising identifying a first signal intensity for the first time point and a second signal intensity for the second time point, wherein each of the first signal intensity and the second signal intensity is obtained via an MRI device configured with a repetition time (TR) less than 10 ms and a time to echo (TE) less than 300 μs;

calculating a longitudinal rate of a change in signal intensity in the region of interest, the longitudinal rate of change in signal intensity comprising a difference in signal intensity obtained from the paramagnetic or superparamagnetic blood pool contrast agent in at least a perivascular space of the region of interest based on a spatial volume of each of the first signal intensity and the second signal intensity; and

evaluating the longitudinal rate of change in signal intensity to determine the at least one kinetic value of flow of the perivascular space within the region of interest.

17 . The method of claim 1 , wherein evaluating the change in signal intensity is based on a time-course of the at least partial mixing of the cerebrospinal fluid with the interstitial fluid.

18 . The method of claim 1 , wherein the at least one kinetic value of flow comprises a rate of mixing of the paramagnetic or superparamagnetic blood pool contrast agent in the perivascular space within the region of interest.

19 . The method of claim 18 , wherein the evaluating further comprises, once a mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, quantifying a volume of the perivascular space within the region of interest.

20 . The method of claim 19 , wherein the evaluating further comprises, once the mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, determining a clearance of the paramagnetic or superparamagnetic blood pool contrast agent from the cerebrospinal fluid into a soft palate of the subject.

21 . The method of claim 1 , wherein the at least one kinetic value of flow of the perivascular space within the region of interest comprises a difference in an amount of the paramagnetic or superparamagnetic blood pool contrast agent in each of the perivascular space within the region of interest and a soft palate of the subject at a predetermined time point during a time-course of glymphatic mixing.

22 . The method of claim 1 , wherein determining the at least one kinetic value of flow of the perivascular space within the region of interest comprises determining the at least one kinetic value of flow into or out of the perivascular space within the region of interest.

23 . The computing system of claim 15 , wherein the at least one kinetic value of flow comprises a rate of mixing of the paramagnetic or superparamagnetic blood pool contrast agent in the tissue adjacent to vascular tissue within the region of interest.

24 . The computing system of claim 23 , wherein the evaluating further comprises, once a mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, quantifying a volume of the tissue adjacent to vascular tissue within the region of interest.

25 . The computing system of claim 24 , wherein the evaluating further comprises, once the mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, determining a clearance of the paramagnetic or superparamagnetic blood pool contrast agent from the cerebrospinal fluid into a soft palate of the subject.

26 . The computing system of claim 15 , wherein the at least one kinetic value of flow of the tissue adjacent to vascular tissue within the region of interest comprises a difference in an amount of the paramagnetic or superparamagnetic blood pool contrast agent in each of the tissue adjacent to vascular tissue within the region of interest and a soft palate of the subject at a predetermined time point during a time-course of glymphatic mixing.

27 . The computing system of claim 15 , wherein determining the at least one kinetic value of flow of the tissue adjacent to vascular tissue within the region of interest comprises determining the at least one kinetic value of flow into or out of the tissue adjacent to vascular tissue within the region of interest.

28 . The computer-readable storage medium of claim 16 , wherein the at least one kinetic value of flow comprises a rate of mixing of the paramagnetic or superparamagnetic blood pool contrast agent in the perivascular space within the region of interest.

29 . The computer-readable storage medium of claim 28 , wherein the evaluating further comprises, once a mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, quantifying a volume of the perivascular space within the region of interest.

30 . The computer-readable storage medium of claim 29 , wherein the evaluating further comprises, once the mixing of the paramagnetic or superparamagnetic blood pool contrast agent has reached steady state, determining a clearance of the paramagnetic or superparamagnetic blood pool contrast agent from the cerebrospinal fluid into a soft palate of the subject.

31 . The computer-readable storage medium of claim 16 , wherein the at least one kinetic value of flow of the perivascular space within the region of interest comprises a difference in an amount of the paramagnetic or superparamagnetic blood pool contrast agent in each of the perivascular space within the region of interest and a soft palate of the subject at a predetermined time point during a time-course of glymphatic mixing.

32 . The computer-readable storage medium of claim 16 , wherein determining the at least one kinetic value of flow of the perivascular space within the region of interest comprises determining the at least one kinetic value of flow into or out of the perivascular space within the region of interest.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 19, 2022
From: FERRIS, CRAIG; QIAO, JU; KULKARNI, PRAVEEN; GHARAGOUZLOO, CODI
To: NORTHEASTERN UNIVERSITY
Reel/Frame 058694/0511 →
Continuity (2)
Provisional Application 62796925 · Jan 25, 2019
Related Publication 20220110524A1 · Apr 14, 2022
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