Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1999-04-07
2001-11-20
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S420000, C324S307000, C324S309000, C324S312000, C424S009362
Reexamination Certificate
active
06321105
ABSTRACT:
BACKGROUND OF THE INVENTION
A large number of psychiatric (i.e. schizophrenia), neurological (i.e. Parkinson's disease), and neurodegenerative (i.e. Huntington's chorea) pathologies involve changes of mental states or conditions based upon changes in neurotransmitter and receptor balances. Detection of such changes may allow for diagnosis well ahead of manifestation of severe clinical symptoms, and knowledge of the nature and the extent of such changes is of paramount importance for the determination of therapy. For instance, in Parkinson's disease the chronic use of L-DOPA therapy leads to a progressive diminution in its efficacy. Thus, one would like to be able to monitor the progression of the disease more closely to effect possible changes in dosing. Similar problems present for many of the currently used dopaminergic ligands in schizophrenia. Determination of the effects of these therapies upon the brain is very difficult at the present time.
Two methodologies have been widely used for the determination of changes in neurotransmitter and receptor dynamics in vivo. These two techniques (Positron Emission Tomography and Single Photon Emission Computed Tomography, PET and SPECT) involve the use of radioactivity. Positron Emission Tomography is a very versatile technique which has been used successfully for the mapping of Cerebral Blood Flow (CBF), cerebral glucose metabolism (using
18
F-fluorodeoxyglucose, FDG) or receptor activity (using radioactive pharmacological ligands), while SPECT is more limited to the detection of nonspecific processes. Unfortunately, both techniques suffer from severe limitations in spatial and temporal resolution, and cannot be proposed for repeated applications. Moreover, PET is characterized by limited availability and high costs, which are partly due to the short half-life of many of the radiopharmaceuticals which have to be administered.
A third alternative has recently been developed and is called pharmacological Magnetic Resonance Imaging (phMRI) and is based upon changes in Blood Oxygen Level Dependent (BOLD) contrast. The method rests on the spatially and temporally resolved visualization of the hemodynamic response evoked by neuronal activation following application of a specific pharmacological stimulus. Briefly: neuronal activation results in an increased local metabolic activity, increased oxygen consumption and increased local concentration of paramagnetic deoxyhemoglobin. Since the latter is compartmentalized in the vasculature, its higher magnetic susceptibility leads to a decreased Signal Intensity (SI) of brain tissue in T
2
*-weighted MR images. This effect is however quickly overcompensated by increased relative Cerebral Blood Flow (rCBF), with consequent inflow of fresh blood with lower content in deoxyhemoglobin, leading finally to increased SI on T
2
*-weighted images in the area of neuronal activation.
While phMRI offers the needed high spatial and temporal resolution as well as the non-invasiveness of MRI, it suffers from the lack of sensitivity of the BOLD effect, which amounts to an increase in SI of only 2-3% at clinical field strengths. This is by far not enough for the establishment of a robust clinical procedure. This problem has been dealt with, with better results, for the analogous technique called functional MRI (fMRI), which differs from phMRI by the nature of the stimulus which is sensorial or motor rather than pharmacological. In fMRI, the low intensity of the BOLD effect is compensated by repeated acquisition of alternating data blocks at rest and under stimulation and using statistical approaches like Multivariate Analysis of Covariance (ManCova) to generate Statistical Parameter Maps (SPM) which represent the statistical significance—on a pixel-by-pixel basis—of any differences in SI between scans taken at rest and during stimulation. However, this solution is not applicable to phMRI due to the long duration (typically 1 hour) of the response to pharmacological stimulation, as opposed to the short duration (seconds) to sensorial or motor stimulation.
While two reports have described the use of contrast agents to increase the sensitivity of phMRI (1, 2), none of them recognized, nor even suggested, the diagnostic potential of the technique and none of them tested its applicability on animal models of disease. On the contrary, the present application acknowledges the lack of methods to visualize brain disorders by imaging the underlying imbalances in neurotransmitters and neuroreceptors using specific pharmacological stimuli and non-invasive imaging techniques with high spatial resolution and gives a solution to said medical need.
SUMMARY OF THE INVENTION
In its most important aspect, the present invention is a method to detect, diagnose and stage neurological disorders by taking T
2
- or T
2
*-weighted images of the brain after i.v. administration of a susceptibility contrast agent with extended half life (so-called negative blood-pool contrast agents). Baseline images are taken at the equilibrium distribution of the agent. For any given MR sequence and for any given concentration of a given agent in blood, a drop in SI of brain tissue will be observed which shows a positive correlation with relative Cerebral Blood Volume (rCBV). Appropriate mathematical treatment of the signal intensity loss yields &Dgr;R
2
or &Dgr;R
2
* (depending on the use of T
2
- or T
2
*-weighted sequences, respectively), which can be taken to be proportional to the changes in rCBV. Therefore, one can obtain rCBV maps from baseline scans after contrast administration.
The patient, human being or animal, is then subjected to a pharmacological diagnostic challenge by administration of a stress agent, the nature of which depends closely on the nature of the suspected disease (if a diagnosis is attempted) or of the already diagnosed disease (if choice of therapy or assessment of success of therapy are the aims of the procedure). Basically, all known neurotransmitters, their agonists and antagonists (at both the release and receptor level) can be administered as stress agents for diagnostic challenge.
The metabolic response associated with neuronal activation following diagnostic challenge results in a substantial increase in rCBV and hence a decrease in SI (or increase in &Dgr;R
2
and &Dgr;R
2
*) in the area of activation, thus allowing a mapping of neurotransmitter activity and specifically the detection of imbalances in neurotransmitter and receptor activity. In a preferred embodiment, this method can be used to assess the performance of therapeutic drugs by comparing the response to the stimulus in the naive patient to the response in the patient treated with various doses of the same drug or with different drugs, greatly facilitating the establishment of therapy which otherwise would have to rely solely on the observation of clinical symptoms, usually over an extended period of time.
Thus, our invention provides the capability to detect, diagnose and grade neurological, neurodegenerative and psychiatric disorders by monitoring rCBV changes following diagnostic challenge in T
2
- or T
2
*-weighted MR images taken at the equilibrium distribution of a susceptibility contrast blood pool agent.
REFERENCES:
patent: 5352979 (1994-10-01), Conturo
patent: 5357959 (1994-10-01), Fishman
patent: 5376667 (1994-12-01), Somers et al.
patent: 5459400 (1995-10-01), Moonen
patent: 5494655 (1996-02-01), Rocklage et al.
patent: 5685305 (1997-11-01), Moonen et al.
patent: 5833947 (1998-11-01), Rocklage et al.
patent: 5902815 (1999-05-01), Olney et al.
patent: 5914097 (1999-06-01), White
Marota et al Proceedings of International Society for Magnetic Resonance in Medicine 5thScientific 1997, vol. 2, p. 731 “Activation of Rat Brain by Cocaine: Functional Imaging with Bold etc.” XP-00211551.
Cuenod et al Proceedings of Society of Magnetic Resonance in Medicine 12thScientific vol. 3, 8/93 vol. 3, p. 1387 “Local Brain response etc.” XP002110552.
Graham et al. Proceedings of Society of Magnetic Resonance in Medicine 2ndmeeting Comparison of G
Cavagna Friedrich M.
Jenkins Bruce G.
Mandeville Joe B.
Bracco S.p.A.
Lateef Marvin M.
Lin Jeoyuh
Nixon & Vanderhye
LandOfFree
Method for diagnosing neurological, neurodegenerative and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for diagnosing neurological, neurodegenerative and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for diagnosing neurological, neurodegenerative and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2593033