WO2017223092A1 - Système et procédé de détection in vivo de fuite du liquide cérébrospinal - Google Patents

Système et procédé de détection in vivo de fuite du liquide cérébrospinal Download PDF

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WO2017223092A1
WO2017223092A1 PCT/US2017/038342 US2017038342W WO2017223092A1 WO 2017223092 A1 WO2017223092 A1 WO 2017223092A1 US 2017038342 W US2017038342 W US 2017038342W WO 2017223092 A1 WO2017223092 A1 WO 2017223092A1
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tracer
patient
csf
brain
data
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Mony J. De Leon
Henry Rusinek
Yi Li
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New York University NYU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2576/00—Medical imaging apparatus involving image processing or analysis
    • A61B2576/02—Medical imaging apparatus involving image processing or analysis specially adapted for a particular organ or body part
    • A61B2576/026—Medical imaging apparatus involving image processing or analysis specially adapted for a particular organ or body part for the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A61B5/0263—Measuring blood flow using NMR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/03—Measuring fluid pressure within the body other than blood pressure, e.g. cerebral pressure ; Measuring pressure in body tissues or organs
    • A61B5/031—Intracranial pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A61B5/4088—Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • A61B5/4875—Hydration status, fluid retention of the body
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H30/00—ICT specially adapted for the handling or processing of medical images
    • G16H30/40—ICT specially adapted for the handling or processing of medical images for processing medical images, e.g. editing

Definitions

  • CSF cerebrospinal fluid
  • ISF interstitial fluid
  • one embodiment of the present invention provides a method for in vivo detection of cerebrospinal fluid (CSF) egress in a patient, particularly in a human.
  • the method comprises a first step of intravenously administering a tracer capable of being taken up by brain tissue of the patient and subsequently clearing the brain tissue of the patient.
  • the tracer may include, for example, tracers that are capable of binding to at least one of neurofibrillary tangles, neuropil threads, and beta-amyloid plaques in the brain tissue.
  • tracers that do not bind to brain or extracranial sites are useful as they enable clearance estimates to be made without having to account for tracer binding.
  • the tracer may be a Positron Emission Tomography (PET) radiotracer, such as, for example, 1 8 F- THK5517, " C- ⁇ , u C-Cocaine, 18 F-THK5351 , AV1451 , MK6240, n C-Butanol, etc.
  • PET Positron Emission Tomography
  • M I magnetic resonance imaging
  • the method may comprise a step for continuously detecting the tracer in the patient's head and nasal region and/or at least a portion of the patient's brain for a predetermined amount of time to obtain tracer data.
  • the tracer data may be obtained using a PET imaging device, in particular dynamic PET imaging.
  • the tracer data may also be obtained using MPJ imaging device.
  • the tracer data may include any suitable type of data and may comprise at least one of time activity curves (TAC), areas under the curves (AUC), and standardized uptake value (SUV) images of the tracer over at least a portion of the predetermined amount of time.
  • the method may further comprise the step of correlating the tracer data to a three-dimensional anatomical image of the patient's head, including nasal turbinate region, and other extracranial sites allowing the passage of CSF to the blood and the lymphatic system.
  • the three-dimensional anatomical image may be a three-dimensional magnetic resonance imaging (MRI) image of the patient's head and nasal region.
  • MRI magnetic resonance imaging
  • the method may further include a step for estimating a rate or a volume of CSF egress from a brain through a spinal fluid clearance pathway of the patient based the tracer data.
  • the spinal fluid clearance pathway may comprise at least one of a cerebral ventricular system, a subarachnoid CSF compartment, a nasal turbinate, olfactory, optic or other cranial nerve.
  • the tracer may be a non-binding tracer to brain tissue and estimates of CSF egress may be obtained directly from the brain.
  • the method may include a step for diagnosing a patient with a neurological, inflammatory or cardiovascular disorder based on the rate of CSF egress through the spinal fluid clearance system of the patient.
  • the disorder may include, for example, Alzheimer's disease, traumatic brain injury, sleep disturbances, stroke and vascular disease, and brain conditions that cause an inflammatory response.
  • an alternative method for in vivo detection of cerebrospinal fluid (CSF) egress in a patient comprises a first step of intravenously administering a tracer capable of being taken up by brain tissue of the patient and subsequently clearing the brain tissue of the patient.
  • the tracer may include, for example, tracers that are capable of binding to at least one of neurofibrillary tangles, neuropil threads, and beta-amyloid plaques in the brain tissue, or tracers that do not bind to brain or other tissues.
  • the tracer may be a Positron Emission Tomography (PET) radiotracer, such as, for example, 18 F-THK5517, " C- PiB, n C-Cocaine, I8 F-THK5351 , 18 F-MK6240, n C-Butanol, etc.
  • the tracer may be a magnetic resonance imaging (MRI) contrast agent.
  • the method may comprise a step for continuously detecting the tracer in the patient's brain and extracranial head including the nasal region for a predetermined amount of time to obtain tracer data.
  • the tracer data may be obtained using a PET imaging device, in particular dynamic PET imaging.
  • the tracer data may also be obtained using MRI imaging device.
  • the tracer data may include any suitable type of data and may comprise at least one of time activity curves (TAC), areas under the curves (AUC), and standardized uptake value (SUV) images of the tracer over at least a portion of the predetermined amount of time.
  • the method may further comprise the step of identifying one or more voxels within an extra-cranial shell region of interest (ROI) of the patient, wherein the shell ROI is outside the brain and the subarachnoid space, and includes bone and soft tissue.
  • the shell ROI may include at least one of dura, muscle, nasal turbinate and orbits.
  • the tracer data for each of the voxels are normalized by corresponding data for a cerebellar hemisphere gray matter of the patient.
  • the method may further include a step for estimating a rate of CSF egress through at least one of the voxels within the shell ROI based on the tracer data.
  • a first portion of the tracer data for the one or more voxels are temporally correlated to a second portion of the tracer data for lateral ventricles of the patient.
  • a first portion of the tracer data for the one or more voxels is above a predetermined threshold value compared to the tracer data.
  • a first portion of the tracer data for the one or more voxels is correlated to an amount of tracer present in the patient's blood.
  • the method may include a step for diagnosing a patient with a neurological, inflammatory or cardiovascular disorder based on the rate of CSF egress through the spinal fluid clearance system of the patient.
  • the disorder may include, for example, Alzheimer's disease, traumatic brain injury, sleep disturbances, stroke and vascular disease, and brain conditions that cause an inflammatory response or are associated with misfolded proteins. This procedure may also be used to establish risk in unaffected individuals such as elderly at risk for degenerative brain diseases.
  • a system may include an imaging device continuously gathering tracer data corresponding to uptake and clearance, within a brain of a patient, of a tracer intravenously administered to the patient, and a computing device comprising one or more processors and a set of instructions executing on the one or more processors.
  • the set of instructions are operable to: receive the tracer data from the imaging device, correlate the tracer data to a three-dimensional anatomical image of the patient's head, nasal region and/or brain, and estimating a rate or a volume of CSF egress from a brain through a spinal fluid clearance pathway of the patient based the tracer data.
  • an alternative system may include an imaging device continuously gathering tracer data corresponding to uptake and clearance, within a brain of a patient, of a tracer intravenously administered to the patient, and a computing device comprising one or more processors and a set of instructions executing on the one or more processors.
  • the set of instructions are operable to: receive the tracer data from the imaging device, identify one or more voxels within a shell region of interest (ROI) of the patient, wherein the shell ROI is outside the brain and the subarachnoid space, and includes bone and soft tissue, and estimating a rate of CSF egress through at least one of the voxels within the shell ROI based on the tracer data.
  • ROI shell region of interest
  • Fig. 1 shows an exemplary computer system for performing method for in vivo detection of cerebrospinal fluid (CSF) egress.
  • CSF cerebrospinal fluid
  • Fig. 2 shows an exemplary embodiment of a method for in vivo detection of cerebrospinal fluid (CSF) egress.
  • CSF cerebrospinal fluid
  • Fig. 3 shows another exemplary embodiment of a method for in vivo detection of cerebrospinal fluid (CSF) egress.
  • CSF cerebrospinal fluid
  • FIG. 4 shows experimental data for percentage of voxels significantly correlated with ventricular CSF for subjects according to Example I.
  • FIG. 5 shows experimental normalized counts over a period of time for AUG for the correlated superior turbinate, arterial and venous blood, and brain according to Example I.
  • Fig. 6 shows experimental raw counts over a period of time for AUC for the correlated superior turbinate, arterial and venous blood, and brain according to Example I.
  • Fig. 7 shows experimental time activity curves (TAC) and AUC for the ventricular CSF and superior nasal turbinate in AD and control subjects according to Example I.
  • FIG. 8 shows experimental data in scattergrams for AD and control subjects for amyloid gray matter binding according to Example I.
  • FIG. 9 shows experimental data corresponding to tissue activity curves for F over a period of time according to Example I.
  • Fig. 10 shows experimental data corresponding to distribution of AUC for F over a period of time according to Example I.
  • Fig. 1 1 shows a table for a timing schedule for reconstructed PET image frames according to Example II.
  • Fig. 12 shows experimental data corresponding to a reference TAC for CSF and TAC for two sample shell voxels over a period of time according to Example II.
  • Fig. 13 shows experimental data correspond to percentage distribution of shell and nasal cavity voxels whose tau PET derived TAC are correlated with the ventricular CSF TAC according to Example II.
  • Fig. 14 shows experimental data corresponding to average tau tracer counts for subjects over a period of time according to Example II.
  • FIG. 15 shows experimental data corresponding to AUC of ventricle CSF clearance in patients with AD according to Example II.
  • FIG. 16 shows experimental data corresponding to rate of ventricle CSF clearance in patients with AD according to Example II.
  • FIG. 17 shows experimental data corresponding to positive superior turbinate voxels in patients with AD according to Example II.
  • Fig. 18 shows experimental data corresponding to ventricular tracer AUC over a period of time according to Example II
  • Fig. 19 shows experimental data corresponding to rate of ventricular tracer clearance over a period of time according to Example II.
  • Fig. 20 shows experimental data corresponding to ventricular tracer AUC over a period of time normalized to cerebral lar gray matter according to Example II.
  • Fig. 21 shows experimental data corresponding to ventricular tracer AUC over a period of time normalized to total brain parenchyma according to Example II.
  • a brain-wide paravascular CSF-ISF exchange mechanism has been shown in animal models to facilitate the clearance of waste products including soluble amyloid- ⁇ ( ⁇ ) and tau protein.
  • Studies in non-human species show a drainage pathway for subarachnoid CSF via olfactory nerves as they traverse the cribiform plate exchanging CSF at the nasal mucosa with lymphatic vessels for drainage via cervical lymph nodes. Drainage via the cribiform plate is rapid as radio labeled albumin Indian ink and paramagnetic contrast injected into the CSF reach the middle turbinates of the rodent nose within minutes.
  • Other routes of CSF drainage have been identified along cranial and spinal nerves and most recently in the mouse via dural lymphatics.
  • CSF can efflux directly back into blood via well-developed arachnoid granulations in the venous sinuses of brain and spinal cord which are not prominent in the rodent brain, however, the overall significance of this exit pathway is poorly characterized. While a CSF drainage pathway via the cribiform plate has been suggested in one human post mortem study, and hypothesized to be impaired in Alzheimer's Disease (AD) due to paravascular ⁇ deposition, there had not previously been any in vivo evidence for a human cribiform drainage pathway. Using dynamic PET imaging with l 8 F-THK5117, a tracer for tau pathology, the present application describes a CSF drainage pathway at the nasal turbinates in the human.
  • AD Alzheimer's Disease
  • AD Alzheimer's disease
  • CSF is primarily cleared along olfactory nerves that traverse the cribriform plate, draining into lymphatic vessels in the nasal mucosa.
  • Rodent CSF clearance is rapid as radio- labeled albumin, Indian ink and paramagnetic contrast injected into the CSF reach the turbinates within minutes. Much less is known about the human CSF clearance anatomy. Arachnoid granulations, arguably considered important human CSF egress sites, are not found in the rodent. The only evidence for a human nasal turbinate efflux pathway comes from post mortem studies.
  • ventricular CSF time activity curves may be used to identify temporally correlated extracranial sites clearing CSF.
  • PET Positron Emission Tomography
  • TAC time activity curves
  • Region of interest sampling demonstrated anatomical specificity for the superior turbinate and ventricle tracer clearance for distinguishing between normal elderly and Alzheimer subjects. Further it was observed that the reduced CSF clearance in Alzheimer's disease is associated with an increased accumulation of amyloid using PET PIB imaging. These results suggest a functional CSF egress pathway through the human nasal turbinates, that may have value in neurological diseases with suspected impaired CSF clearance.
  • an imaging device for detecting a tracer capable of being taken up by brain tissue of the patient and subsequent clearing the brain tissue of the patient may be provided.
  • the tracer may be a tracer that binds to the brain tissue.
  • the tracer may be a tracer that does not bind to the brain tissue.
  • the imaging device may be any suitable imaging device for providing continuous imaging of a patient over any suitable predetermined period of time, e.g. , over a period of 40 mins, 50 mins, 80 mins, etc., in which CSF clearance and/or egress is to be observed.
  • the imaging device may include, for example, Positron Emission Tomography (PET) imaging devices, in particular dynamic PET imaging devices, magnetic resonance image (MRI) imaging devices, etc.
  • PET Positron Emission Tomography
  • MRI magnetic resonance image
  • the imaging device may include any suitable imaging device that is capable of providing continuous and/or real-time imaging of CSF through brain tissue.
  • the imaging device may further include, be operably connected to, or be in communication with any suitable processing arrangement for analyzing the tracer data.
  • the exemplary embodiments described herein may be implemented in any number of manners, including as a separate software module, as a combination of hardware and software, etc.
  • the exemplary analysis methods may be embodiment in one or more programs stored in a non-transitory storage medium and containing lines of code that, when compiled, may be executed by at least one of the plurality of processor cores or a separate processor.
  • a system comprising a plurality of processor cores and a set of instructions executing on the plurality of processor cores may be provided. The set of instructions may be operable to perform the exemplary methods discussed below.
  • the exemplary analysis methods may be embodied in an exemplary system 100 as shown in Fig. 1.
  • an exemplary method described herein may be performed entirely or in part by a processing arrangement 1 1 0.
  • Such processing/computing arrangement 1 10 may be, e.g. , entirely or a part of, or include, but not limited to, a computer/processor that can include, e.g. , one or more microprocessors, and use instructions stored on a computer-accessible medium (e.g. , RAM, ROM, hard drive, or other storage device).
  • a computer-accessible medium 120 e.g.
  • a storage device such as a hard disk, floppy disk, memory stick, CD-ROM, RAM, ROM, etc., or a collection thereof
  • the computer-accessible medium 120 may be a non-transitory computer-accessible medium.
  • the computer-accessible medium 120 can contain executable instructions 130 thereon.
  • a storage arrangement 140 can be provided separately from the computer-accessible medium 120, which can provide the instructions to the processing arrangement 1 10 so as to configure the processing arrangement to execute certain exemplary procedures, processes and methods, as described herein, for example.
  • System 100 may also include a display or output device, an input device such as a keyboard, mouse, touch screen or other input device, and may be connected to additional systems via a logical network.
  • Logical connections may include a local area network (LAN) and a wide area network (WAN) that are presented here by way of example and not limitation.
  • LAN local area network
  • WAN wide area network
  • Such networking environments are commonplace in office-wide or enterprise-wide computer networks, intranets and the Internet and may use a wide variety of different communication protocols.
  • network computing environments can typically encompass many types of computer system configurations, including personal computers, hand-held devices, multiprocessor systems, microprocessor-based or programmable consumer electronics, network PCs, minicomputers, mainframe computers, and the like.
  • Embodiments of the invention may also be practiced in distributed computing environments where tasks are performed by local and remote processing devices that are linked (either by hardwired links, wireless links, or by a combination of hardwired or wireless links) through a communications network.
  • program modules may be located in both local and remote memory storage devices.
  • Fig. 2 illustrates an exemplary method 200 for in vivo detection of cerebrospinal fluid (CSF) egress in a patient.
  • a subject for the analysis in particular a human patient may ⁇ be administered with a tracer for imaging analysis.
  • the tracer may be administered to the patient by any suitable method, for example, by intravenous injection.
  • the tracer may be any suitable radiotracer or contrast agent that is capable of being taken up by brain tissue of the patient and subsequently clearing the brain tissue of the patient.
  • the tracer may be any suitable tracer that is suitable for crossing the blood-brain barrier.
  • the tracer may be capable of being taken up and cleared by brain tissue without substantial binding of the tracer to the brain tissue.
  • the tracer may be capable of binding to at least one of neurofibrillary tangles, neuropil threads, and beta-amyloid plaques in the brain tissue.
  • the tracer may be capable of binding to a tau protein in the brain tissue.
  • the tracer may be capable of binding to an amyloid in the brain tissue.
  • the tracer may be any suitable radiotracer, such as those suitable to be detected by- Positron Emission Tomography (PET), such as, tau and amyloid tracers, such as, for example, 18 F- THK5517, "C-PiB. 18 F-THK5351 , etc.
  • PET tracer may be n C-Cocainc and/or n C-Butanol.
  • the tracer may be a magnetic resonance imaging (MRI) contrast agent.
  • MRI magnetic resonance imaging
  • tracer data may be obtained by detecting the migration of the tracer through the patient body, in particular, the patient's head and nasal region, and/or portions of or the entirety of the patient's brain.
  • the tracer data may be detected by an imaging device in a continuous manner for any suitable predetermined period of time, e.g. , over a period of 40 mins, 50 mins, 80 mins, etc., in which CSF clearance and/or egress is to be observed.
  • the imaging device may include, for example, Positron Emission Tomography (PET) imaging devices, in particular, dynamic PET imaging devices, magnetic resonance image (MRI) imaging devices, etc.
  • PET Positron Emission Tomography
  • MRI magnetic resonance image
  • the tracer data may be obtained by PET imaging, and more particularly by dynamic PET imaging.
  • the tracer data may also be obtained using MRI imaging device.
  • the tracer data may include any suitable type of data and may comprise at least one of time activity curves (TAG), areas under the curves (AUC), and standardized uptake value (SUV) images of the tracer over at least a portion of the predetermined amount of time.
  • TAG time activity curves
  • AUC areas under the curves
  • SUV standardized uptake value
  • the tracer data may be correlated to a three-dimensional anatomical image of the patient's head and nasal region, and/or the portion of or the entirety of the patient's brain.
  • the three-dimensional anatomical image may be a three-dimensional magnetic resonance imaging (MRI) image of the patient's head and nasal region, and/or a portion of or the entirety of the patient's brain.
  • the extracranial tracer data may be correlated to a three- dimensional anatomical image of an extracranial region of the patient's head and nasal region, while the tracer data for at least a portion of brain tissue may be correlated to a separate three- dimensional anatomical image of the corresponding portion of the brain.
  • the tracer data for the entirety of the patient's brain may be correlated to a three- dimensional anatomical image of the entirety of the patient's brain.
  • the method may further include a step for estimating a rate or a volume of CSF egress from a brain through a spinal fluid clearance pathway of the patient based the tracer data.
  • the spinal fluid clearance pathway may include any portion of the patient's spinal fluid clearance system where CSF is permitted to exit brain tissue of the patient.
  • spinal fluid clearance system may include a cerebral ventricular system, a subarachnoid CSF compartment, and/or a nasal turbinate (in particular, the superior nasal turbinate).
  • the CSF egress pathway may also traverse the cribriform plate to the superior turbinate and to nasal cavity lymphatics.
  • the estimated rates and/or volumes of CSF egress from the brain through the spinal fluid clearance system may be used to diagnose a patient with a neurological, inflammatory or cardiovascular disorder based on the rate of CSF egress through the spinal fluid clearance system of the patient.
  • patients having a reduced rate or volume of CSF egress may be indicative of a neurological, inflammatory or cardiovascular disorder.
  • the disorder may be a disease with abnormal protein deposits (e.g. , misfolded brain proteins) such as, for example, Parkinson's disease, progressive supranuclear palsy, and Alzheimer's disease.
  • Other disorders may include, traumatic brain injury, sleep disturbances, stroke and vascular disease, brain conditions that cause an inflammatory response, etc.
  • the rate and/or volume of CSF egress may also be indicative of intra-laminar tau distributions in lesion progression.
  • a physician may provide treatment to improve the rate and/or volume of CSF egress in a patient, such as, for example, modification of sleep of the patient, etc.
  • Such treatments to modify the rate and/or volume of CSF egress in a patient may impact (e.g. , reduce) the brain' s burden of accumulated misfolded proteins, such as, for example, tau and amyloid proteins.
  • Fig. 3 illustrates another exemplary method 300 for in vivo detection of cerebrospinal fluid (CSF) egress in a patient.
  • Steps 310 and 320 are substantially similar to step 210 and 220 as discussed above.
  • the tracer data for each of the voxels may be normalized by at least a portion or an entirety of the patient's brain.
  • the portion may include one or more of the lateral ventricle, neocortical gray and white matter, and cerebellar hemisphere gray matter of the patient.
  • the tracer data for each of the voxels are normalized by corresponding data for a cerebellar hemisphere gray matter of the patient.
  • one or more voxels within a shell region of interest (ROI) of the patient may be identified for further analysis.
  • the shell ROI is an area outside the brain and the subarachnoid space of the patient, and includes the bone and soft tissue.
  • the shell ROI may include at least one of dura, muscle, nasal turbinate and orbits.
  • the one or more voxels may be identified via any suitable way for identifying those voxels in which substantial amounts of the tracers pass through, or those voxels that temporally correspond to flow of CSF out of brain tissue.
  • the one or more voxels may be identified by any suitable quantitative model for clearance of the tracer into the CSF compartment (system).
  • the one or more voxels may be identified using a kinetic model of CSF tau clearance.
  • the one or more voxels may be identified based on the rate of incorporation of tracer into the brain.
  • the one or more voxels may be identified based on the rate of removal of tracer from the brain, for example, dynamic PET imaging may be correlated to data obtained from periodic blood sampling.
  • the blood sampling may be obtained from, for example, an internal carotid artery, or may be venous blood sampled at the junction of the superior sagittal and transverse sinus.
  • a first portion of the tracer data for the one or more voxels may be temporally correlated to a second portion of the tracer data for lateral ventricles of the patient.
  • a first portion of the tracer data for the one or more voxels is above a predetermined threshold value compared to the tracer data.
  • a first portion of the tracer data for the one or more voxels is correlated to an amount of tracer present in the patient's blood.
  • an estimate may be obtained for a rate or volume of CSF egress through at least one of the voxels within the shell ROI based on the tracer data.
  • the estimated rates and/or volumes of CSF egress from the brain through the one or more voxels may be used to diagnose a patient with a neurological, inflammatory or cardiovascular disorder based on the rate of CSF egress through the spinal fluid clearance system of the patient.
  • patients having a reduced rate or volume of CSF egress may be indicative of a neurological, inflammatory or cardiovascular disorder, such as, for example, Alzheimer's disease, traumatic brain injury, sleep disturbances, stroke and vascular disease, and brain conditions that cause an inflammatory response.
  • the rate and/or volume of CSF egress may also be indicative of intra-laminar tau distributions in lesion progression. Based on the estimated rates and/or volumes of CSF egress from the brain through the one or more voxels, a physician may provide treatment to improve the rate and/or volume of CSF egress in a patient, such as, for example, modification of sleep of the patient, etc.
  • AD patients were recruited from the memory clinic of Tohoku University Hospital. An ethics committee approved written informed consent was obtained from all participants or the legal care takers. All 15 subjects underwent two dynamic acquisition PET exams ( 18 F-THK51 17 and " C-PiB) except for 2 controls that did not complete 1 1 C-PiB PET imaging.
  • PET acquisitions The PET radiotracers were administered in two imaging sessions within 2 weeks.
  • the radiotracer (18)F-labeled arylquinoline derivative 6-[(3- l 8F-fluoro-2- hydroxy)propoxy]-2-(4-methylaminophenyl)quinoline or THK-51 17, was developed and validated for binding to neurofibrillary tangles and neuropil threads.
  • the second radiotracer Pittsburgh compound B ( n C-PiB), an analog of thioflavin T is validated biomarker for beta- amyloid plaques in brain tissue.
  • Both tracers were prepared at the Cyclotron and Radioisotope Center of Tohoku University, and both have low molecular weight ( ⁇ 5KD) and both show rapid brain uptake and clearance.
  • 185 mBq of 1 8 F-THK51 17 and 296 mBq of 1 1 C-PiB were administered by IV bolus injection.
  • PET data were acquired axially along the cantho-meatal plane in list mode continuously for 90 min. using an Eminence STARGATE PET scanner (Shimadzu, Kyoto, Japan).
  • Another suitable PET imaging device may be the Eminence SET-3000GCT-X (Shimadzu Corp.. Kyoto, Japan) scanner for measuring regional brain radioactivity.
  • This scanner provides 99 sections with an axial field of view (FOV) of 2(5.0 cm.
  • the spatial resolution was 3.45 mm i n- plane and 3.72 mm full-width at half-maximum (FWHM) axially.
  • the superior- inferior field of view for the PET scans encompassed the skull superiorly and inferiorly the foramen magnum and maxilla.
  • MRI acquisition Each subject received a 3-D volumetric MR l study using a high- resolution Tl -weighted SPGR gradient echo sequence that produced 1 10 gapless axial sections with 2.0mm voxel size (echo time/repetition time, 2.4/50 ms; flip angle 45°; acquisition matrix 256x256; 1 excitation; axial field of view 22 cm, with 1 10 slices with a thickness, 2.0 mm, (SIGNA 1 .5 T magnet, General Electric, Milwaukee, WI).
  • the MRI field of view (FOV) covered the PET FOV. The MRI was used for regional tissue segmentation and to correct the PET for partial volume effects.
  • PET Image Workflow The data for both tracers was decay corrected and standardized uptake value (SUV) images created by normalizing by injected dose and body weight.
  • the SUV images were displayed with a 2.6 mm slice thickness and a 2x2 mm in plane voxel size.
  • SPM 1 2 default procedures using affine transformations were used for realignment of the dynamic PET frames and for coregistration of the Tl weighted MRI with the original PET data (www.fil.ion.ucl.ac.uk/spm).
  • the partial volume correction for the higher brain count contamination of lower count CSF signals was examined with a modified one tissue model. All results reported remained significant after the correction and the corrected results are presented in the appendix.
  • a shell region of interest was defined on MRI which included bone, and soft tissue (e.g. dura, muscle, nasal turbinates, and orbits) and excluded brain, subarachnoid CSF, and air.
  • Hypothesis testing was done using anatomical ROIs drawn on MRI scans resliced to a standard plane and reformatted back to the coregistered PET scans to sample the PET in the original space.
  • FIG. 4 depicts for all subjects the percentage +/- SEM of voxels significantly correlated with ventricular CSF (r range .90-1.00) for the combined superior and middle turbinates and the total shell.
  • shell voxels whose signals correlated with CSF at r >.95 were mapped to the MRI.
  • the correlation between TAC does not reflect the absolute tracer concentration
  • the AUC for the correlated superior turbinate voxels were compared with the AUC from blood, CSF and brain and the other ROIs.
  • Figures 5 and 6 demonstrate over the 35- 80min the normalize counts (Fig. 5 and the raw count TAC in Fig. 6). Specifically, the AUC of the superior turbinates and ventricular CSF do not differ, nor do the arterial and venous blood AUG differ from each other. However, the blood AUCs are significantly lower than either the CSF or the superior turbinates. The brain has a consistently greater AUC due to specific and non-specific tracer binding.
  • the superior turbinate ROI is 0.2% of the shell volume and contains 1 .0% of the total shell correlations with CSF. Combined superior and middle turbinates account for 5% of the positive shell voxels. The data show that nearly 80% of the remaining counts are in the CSF structures including the subarachnoid space.
  • AUC cerebral blood flow
  • Fig. 9 shows the tissue activity curves for F varying in the range 35-60 ml/l OOg/min.
  • Fig. 10 shows the corresponding distribution of AUC for the time period 10-35 min after injection, demonstrating negligible effect of F.
  • Example I The method of Example I is designed to evaluate CSF egress out of the brain by examining the time course and concentration of tracer counts following an IV injection of a PET radioligand.
  • the method involves three steps, first for each subject a shell region, outside of the brain and subarachnoid space, containing bone and soft tissue is created. Second, possible CSF sites are identified by identifying in the shell, voxels with a high temporal correlation with the ventricular counts. It was observed that all subjects demonstrated positive superior turbinate voxels. Third, to further characterize the positive voxels as CSF-like anatomical regions of interest were created and the positive voxels within these regions were tested. The tests were designed to compare the positive voxels with respect to "pure" CSF, blood, and brain.
  • Example I demonstrates that using PET of a CSF egress to the nasal turbinates and ventricle that is reduced in AD is of potential clinical interest.
  • the AD related defects detected in CSF clearance at the ventricle and superior turbinate rely on the performance of a small PET based radiotracer where the kinetics of brain penetration, binding and exit remain poorly characterized and may contribute to magnitude estimation errors.
  • membrane permeability could affect the timing of brain delivery of tracer to ventricle and non-brain regions which formed the basis of our detection of non-brain CSF signals. While these effects do not invalidate detection of CSF shown in Example I, it does potentially impact on the interpretation of the magnitude of CSF removed.
  • the brain CSF volumes were directly measured and it was demonstrated that after adjustment the estimated reduced tracer clearance from the CSF remained reduced in AD. However, it did not control for the large fraction of CSF in the spinal column, even though this is not known to be a principal site for absorption or affected by AD. In healthy adults, the CSF is replaced every 8 hours whereas in AD this has not been estimated and consequently the overall effects remain unknown.
  • Example I shows that a reduced tracer efflux at the turbinates and ventricle are associated with an increased brain ⁇ binding as determined using 1 l C-PiB PET.
  • the method of Example I does not directly measure tau or ⁇ clearance, CSF ⁇ clearance may be reduced in AD in vivo while the production of ⁇ appears unaffected. As such, it is believed that once the ⁇ is transported to the ISF (after possible delay at the brain CSF barrier), the rate of clearance afterwards is highly dependent on the CSF bulk flow our method estimates.
  • the data of Example I support a mechanism where reduced solute clearance in AD is related to elevated brain ⁇ levels.
  • prior human ⁇ clearance observations directly measure the whole body turnover of ⁇ , but do not image the brain. Consequently, the relationship of ⁇ clearance pathology to CSF drainage remains unknown.
  • the method of Example I estimates CSF drainage but does not directly measure ⁇ clearance.
  • Example I manages the distance of the nasal turbinate OI from brain, and uses partial volume corrected data to provide some measure of control over potential errors. The results of Example I show that the nasal turbinate signal over the last 35 minutes of the study are more closely related to ventricular CSF than to either blood or brain.
  • Example I demonstrates a potentially complimentary view to other methods examining the efflux of solutes from brain ISF and CSF. As such this method may be of useful in neurodegenerative and possibly other brain diseases where inflammation or metabolic alterations may affect the bulk CSF flow. This method may have some early advantages as IV PET tracer administration is less invasive than intrathecal MR contrast administration, but has the disadvantages of radiation exposure and long study durations.
  • Example I shows in human evidence for the bulk flow of CSF from the brain to the superior nasal turbinates. Analysis of the tracer counts showed the counts in the nasal turbinates were most similar to ventricular CSF as compared with either blood or brain. Based on a comparison between Alzheimer patients and controls and it is observed that: 1. the tracer (CSF) clearance is reduced in AD; and 2. the CSF clearance reduction in AD is related to the extent of ⁇ deposition in the brain. Overall, these data point to the potential for a novel site for the non-invasive biomarker for human CSF clearance.
  • AD Alzheimer's disease
  • Both tracers were prepared at the Cyclotron and Radioisotope Center of Tohoku University, both have low molecular weight ( ⁇ 5KD) and both freely cross the blood- brain barrier.
  • 185 mBq of 1 8 F-THK51 17 and 296 mBq of ! l C-PiB were administered by IV bo!us injection.
  • PET data were acquired axially along the cantho-meatal plane in list mode continuously for 90 min using a SET-3000 G/X PET scanner (Shimadzu, Kyoto, Japan).
  • Fig. 1 1 lists the timing of the reconstructed PET image frames.
  • the scanner is equipped with high energy resolution germanium oxyorthosilicate (GSO) scintillators that provide 4.5 mm (transverse) and 5.4 mm (axial) spatial resolutions (full width at half maximum, at 10 cm off axis) and sensitivity of 21 cps/kBq. Attenuation correction was based on transmission image from a rotating 137-Cs point source.
  • GSO germanium oxyorthosilicate
  • MR I acquisition Each subject received a high-resolution MRl on a GE SIGNA 1 .5 T magnet (General Electric, Milwaukee, WI, USA).
  • the protocol included a Tl -weighted SPGR gradient echo axial sequence with parameters: echo time/repetition time, 2.4/ 22 ms; flip angle 20°; acquisition matrix 256x256x1 10; 1 excitation; axial field of view 22 cm, bandwidth 122Hz/px, 0.86 x 0.86 x 1 .0 voxel size.
  • the MRl field of view (FOV) covered the PET FOV.
  • MRl reformatted to the native PET space was used for regional tissue segmentation and PET partial volume correction.
  • PET Image Workflow The images from both PET tracers were reconstructed to a 128 x 128 x 79 matrix of 2 x 2 x 2.6 mm voxels. After decay correction, standardized uptake value (SUV) images were created by normalizing radioactivity by injected dose and body weight. Each dynamic PET frame was coregistered with the corresponding Tl weighted MRl using Statistical Parametric Mapping (SPM 12) software (u-ww.fH.ion.ucl.ac.uk/spm), PET images were sampled in their original space and partial volume corrected using a modified one tissue model.
  • SPM 12 Statistical Parametric Mapping
  • MRl Regional Segmentation To test for the hypothesized nasal turbinate egress portal, using SPM12, an extra-cranial shell region of interest (ROI) was defined on MRl.
  • the shell included scalp, bone and soft tissues (muscle, nasal turbinates, and globes of the eye) and extended inferiorly to the foramen magnum and maxilla. It excluded brain, subarachnoid CSF, and air.
  • the extra-cranial shell region (A-D) is shown at the exterior of the patient's head in light grey. The following subregions were examined: A. the superior and middle turbinates; B. pterygoid muscle; C. globes of the eye and superior turbinate; and D. the ventricular CSF.
  • the following shell ROIs were drawn on the MRl blind to the PET data for specificity testing: 1.
  • the superior nasal turbinates were sampled at a distance 5.2mm (2 voxels) inferior to the frontal lobe in order to minimize partial volume effects from brain.
  • the anterior boundary was at the crista galli.
  • the dimensions of the region were 18 mm anterior-posterior (A-P), 14mm left- right (L-R), and 10mm cranio-caudal (C-C).
  • the middle nasal turbinates were sampled inferior to the superior turbinate.
  • the dimensions of this ROI were: 34mm A-P, 16mm L-R and 18mm C-C.
  • the globes of the eyes and lateral pterygoid muscle were sampled bilaterally and both ROIs were 12mm A-P, 12 L-R, and 6mm C-C.
  • the MRI brain was segmented into: lateral ventricle, neocortical gray and white matter. and cerebellar hemisphere gray matter using Free-Surfer (V. 5.1 , The ventricular CSF ROI was modified by shrinking the outer ependymal margin by 2 voxels (4mm) to minimize partial volume contamination from brain tissue.
  • Image-derived arterial blood tracer concentrations were sampled from the internal carotid artery and venous blood sampled at the junction of the superior sagittal and transverse sinus.
  • mapping CSF clearance in the shell To identify and anatomically map CSF positive signals in the shell for each subject, we applied a "seeding" procedure similar to one used to identify neural networks in resting fMRI analyses. Using SUV data, the time activity curve (TAG) of every shell voxel from 3-80min, was correlated (Pearson Product r) with the 3-80min TAC from the ventricular CSF.
  • TAG time activity curve
  • a time activity curve (TAC) was correlated (Pearson Product r) with the TAC from the ventricular CSF.
  • TAC time activity curve
  • the correlations were derived from 14 time points spanning a 3-80 min interval.
  • ti , t 2 , . . .. t n time points in a dynamic PET acquisition
  • y, v(ti) is the time activity curve of a shell voxel
  • x x CSF(tj) the time activity curve from CSF
  • x and y bar indicate the average value:
  • Fig. 12 illustrates this concept on two sample time activity curves.
  • Shell voxels correlated with ventricular CSF with r>.95 were considered CSF positive.
  • the correlations were based on the 3-80min time frames.
  • Non-parametric tests were used to test the major hypotheses. Correlations were examined with Spearman tests and partial correlations using Quade's "index of matched correlation”. Between group contrasts were made with the Mann-Whitney U. Within subject anatomical specificity tests were examined with the related samples Wilcoxon Signed Rank Tests. The Holm-Bonferroni method for multiple comparisons was used for p value adjustment. All tests were two-sided and statistical significance was set at p ⁇ 05 when not adjusted for multiple comparisons.
  • Fig. 14 shows the averaged tau tracer counts (SUV) +/- SEM for all study subjects plotted over 35-80min. Tracer concentrations from CSF positive superior turbinate and ventricular CSF do not differ from each other, but both are significantly different than blood and brain (p's ⁇ .05). The average tracer concentration over 35 to 80min from the CSF positive superior turbinate voxels (1.27+/- 0.25), did not differ from the ventricular CSF ( 1 .27 +/- 0.34. p>.05.
  • Figures 15- 17 show ventricle and superior turbinate CSF clearance in AD. As compared with NL, AD subjects show: reduced magnitude of ventricular tracer (AUC35- 80min)(see Fig. 15), reduced rate of ventricular tracer clearance (see Fig. 16), and a lower number of CSF positive superior turbinate voxels (see Fig. 17).
  • FIG. 18 shows the relationship, for 8 PiB positive subjects, between the amyloid binding SUVR.
  • Figure 18 shows the ventricular tracer AUC 3 5-80min and
  • Figure 19 shows the rate of ventricular tracer clearance.
  • the superior turbinate data did not reach significance in the correlation with the amyloid binding.
  • the superior turbinates have two unique properties: the highest regional density of CSF correlated voxels whose tracer concentration is consistent with the ventricular CSF, but different from brain, muscle, and blood. Other extracranial sites including the middle turbinates, globe of the eye, and pterygoid muscle did not share these characteristics. These results are anatomically consistent with in vivo rodent and post mortem cisterna magna dye injections in large mammals including humans that identified a CSF egress pathway traversing the cribriform plate to the superior turbinates and to nasal cavity lymphatics. Other human evidence for a nasal CSF pathway comes from demonstrations of rapid intranasal delivery of macromolecules to the CSF.
  • Spatial resolution limitations may have accounted for the turbinates to show tracer concentrations consistent with ventricular CSF across all subjects, but owing to decreased numbers of AD related turbinate egress portals and small sample size, to show only trend reductions in AD. Spatial resolution limitations also limited measurement of CSF clearance from the subarachnoid space. On the other hand, the larger lateral ventricle provides good CSF tracer concentration estimates and was a better CSF clearance biomarker. The ventricular measures showed both high diagnostic accuracy and excellent correlation with amyloid binding.
  • PET has advantages as intravenous radiotracer administration is minimally invasive while offering a conventional diagnostic uptake measure.
  • the PET approach is complimentary to the more invasive methods used in animal experiments in aging, sleep pathology, and neurodegeneration models examining the efflux of solutes to and from brain to CSF and blood.
  • the disadvantages include radiation exposure, the less direct delivery from blood, and longer study durations.

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Abstract

La présente invention concerne une fuite de liquide cérébrospinal (CSF) chez un patient pouvant être détectée in vivo par une première administration intraveineuse d'un traceur pouvant être prélevé par le tissu cérébral du patient et par l'élimination ultérieure du tissu cérébral. Le traceur peut être détecté en utilisant n'importe quel dispositif approprié dans les régions de tête, nasale, et/ou optique du patient, et/ou une partie ou l'intégralité du cerveau sur une durée prédéterminée pour obtenir les données concernant le traceur. Les données concernant le traceur peuvent être utilisées pour estimer un débit ou un volume de fuite de CSF depuis le cerveau à travers une voie de clairance du liquide spinal du patient. Le débit ou le volume estimé de fuite de CSF peut être utile pour fournir au patient un diagnostic de trouble neurologique, inflammatoire ou cardiovasculaire, par exemple, la maladie d'Alzheimer, la lésion cérébrale traumatique, les troubles du sommeil, l'accident vasculaire cérébral et les maladies vasculaires, et les états cérébraux qui provoquent une réponse inflammatoire.
PCT/US2017/038342 2016-06-21 2017-06-20 Système et procédé de détection in vivo de fuite du liquide cérébrospinal Ceased WO2017223092A1 (fr)

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CN110599472A (zh) * 2019-09-03 2019-12-20 佛山原子医疗设备有限公司 计算spect定量断层图像中suv归一化系数的方法及系统

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Publication number Priority date Publication date Assignee Title
WO2018174721A3 (fr) * 2017-03-23 2018-12-06 Brainwidesolutions As Fluides indicateurs, systèmes et procédés pour évaluer le mouvement de substances dans, vers ou depuis un compartiment de liquide céphalorachidien, de cerveau ou de moelle épinière d'une cavité cranio-spinale d'un être humain
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