Method for diagnosing neurological, neurodegenerative and psychiatric diseases by magnetic resonance imaging using contrast agents with high magnetic susceptibility and extended plasma half life

• US 6,321,105 B1
• Filed: 04/07/1999
• Issued: 11/20/2001
• Est. Priority Date: 04/08/1998
• Status: Expired due to Fees

• Current Assignee: Bracco SPA, General Hospital Corporation
• Original Assignee: Bracco SPA
• Inventors: Jenkins, Bruce G., Mandeville, Joe B., Cavagna, Friedrich M.
• Primary Examiner(s): Lateef, Marvin M.
• Assistant Examiner(s): Lin, Jeoyuh
• Application Number:
  US09/287,268
• Time in Patent Office: 958 Days
• Field of Search: 600/420, 600/407, 324/307, 324/309, 324/312, 424/9
• US Class Current: 600/407
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: G01R 33/281 Means for the use of in vitro contrast agents G01R33/282 takes precedence; involving use of a contrast agent in MR imaging G01R33/5601; in vivo contrast agents A61K49/0002
• CPC Class Codes: G01R 33/4804 Spatially selective measurement of temperature or pH
• CPC Class Codes: G01R 33/50 based on the determination of relaxation times , e.g. T1 measurement by IR sequences; T2 measurement by multiple-echo sequences
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

A method for Magnetic Resonance Imaging (MRI) of changes in neurotransmitter and neuroreceptor activity as a metabolic response to diagnostic challenge or therapeutic treatment in a patient with suspected or already diagnosed mental illnesses of psychiatric, neurodegnerative or neurological nature, by (a) administering to a patient a drug eliciting an MRI detectable hemodynamic response; (b) administering to the patient an MRI contrast agent with high magnetic susceptibility, and then (c) measuring, in a spatially and temporally resolved manner, relative Cerebral Blood Volume (rCBV) changes associated to neuronal activation using T₂- or T₂*-weighted MRI scans at the equilibrium distribution of said contrast agent.

Claims

1. A method for magnetic resonance imaging (MRI) of changes in neurotransmitter and neuroreceptor activity as a metabolic response to diagnostic challenge or therapeutic treatment in a patient with suspected or already diagnosed mental illnesses of psychiatric, neurodegenerative or neurological nature, comprising the steps of:

(a) administering to said patient a drug eliciticiting an MRI detectable hemodynamic response;

(b) administering to said patient an MRI ferromagnetic, antiferromagnetic or superparamagnetic contrast agent with high magnetic susceptibility and

(c) measuring, in a spatially and temporally resolved manner, relative Cerebral Blood Volume (rCBV) changes associated to neuronal activating using T₂- or T₂*-weighted MRI scans at the equilibrium distribution of said contrast agent.

2. A method as claimed in claim 1 in which said contrast agent has plasma half life sufficient to allow for constant or sufficiently stable concentration in blood over a period of time necessary to elicit the full amplitude of the metabolic response to a drug administered for diagnostic or therapeutic purposes.

3. A method as in claim 2 where the contrast agent has plasma kinetics allowing for a time window of 2 at least two hours (2 h) during which plasma clearance assessed as {R₂*(t₂)−

R₂*(t₁)}/R₂*(t₁) where R₂* is the transversal relaxation rate and t₁ and t₂ are any two time points after administration of said drug with t₂=t₁+2 h amounting to less than a value of 0.4.

4. A method as in claim 2 where the contrast agent has plasma kinetics allowing for a time window of 2 at least two hours (2 h) during which plasma clearance assessed as {R₂(t₂)−

R₂(t₁)}/R₂(t₁) where R₂ is the transversal relaxation rate and t₁ and t₂ are any two time points after administration of said drug with t₂=t₁+2 h amounting to less than a value of 0.4.

5. The method of claim 1 applied to diagnosis or guidance of therapy in schizophrenia.

6. The method of claim 5 applied to the assessment of success and guidance of therapy of schizophrenia by assessing the effect of administration of neuroleptics and/or antipsychotics.

7. The method of claim 6 in which the neuroleptic or the antipsychotic agent is selected from the group consisting of haloperidol, olanzapine, respirdol, and sertindone.

8. A method as claimed in claim 6 applied to determine a co-medication to minimize adverse effects of antipsychotic drugs.

9. The method of claim 1 to detect or diagnose Alzheimer'"'"'s disease.

10. The method as described in claim 9 wherein said contrast agents are used for guidance and assessment of success of therapy by assessing the effect of cholinesterase inhibitors, acetylcholine agonists or of other anti AD medications.

11. The method of claim 1 applied to detcction, diagnosis and staging of Parkinson'"'"'s disease.

12. The method as claimed in claim 11 applied to assessment of success and guidance of therapy of Parkinson'"'"'s Disease, by comparing the effects of the administration of anti-PD drugs.

13. The method of claim 11 carried out by detecting rCBV changes associated with hyperactivity of postsynaptic dopamine receptors.

14. The method as claimed in claim 12 in which the anti PD-drug is selected from the group consisting of L-DOPA, pergolide, bromocryptine, cabegoline, promipexole and ropinirole.

15. A method for measuring or depicting in a spatially and timely resolved manner the changes in regional Cerebral blood Volume (rCBV mapping) associated with changes in neurotransmitter activity exploiting the susceptibility contract effect, employing the compartmentalization of susceptibility contrast agents in the vasculature and of the constant or nearly constant concentration in blood over time comprising the steps of:

(a) administering to said patient a drug eliciticiting an MRI detectable hemodynamic response;

(b) administering to said patient an MRI ferromagnetic, antiferromagnetic or superparamagnetic contrast agent with high magnetic susceptibility and

(c) measuring, in a spatially and temporally resolved manner, relative Cerebral Blood Volume (rCBV) changes associated to neuronal activating using T₂- or T₂*weighted MRI scans at the equilibrium distribution of said contrast agent, and relating the changes in signal intensity (SI) in T=₂*- or T₂-weighted MR images to changes of rCBV.

16. A method as claimed in claim 15 where a neuronal activation map is obtained by computing and mapping statistical parameters which represent the statistical significance of the observed changes in rCBV following administration of said drug.

17. A method for mapping rCBV changes associated with neurotransmittcr activity using T₂- or T₌₂*-weighted sequences using a ferromagnetic, antiferromagnetic or superparamagnetic susceptibility contrast agents to determine transversal apparent relaxation rates R₂ and R₂*, wherein T₂ and T₂* are monoexponential time constants and R₂ and R₂* are transversal relaxation rates of brain tissue, apparent relaxivity meaning the time constant for the decay of transversal magnetization obtained assuming monoexponential decay after excitation by radiofrequency, using the relation Δ

RR₂*=−

(InS_t/S₀)/TE, where Δ

R₂* is the change in relaxation rate S_t is the signal intensity at time t after contrast administration, S₀ is the precontrast signal intensity baseline and TE is the Echo Time, and relating the approximately linear relationship between Δ

R₂* and agent concentration in tissue to determine relative changes in blood volume, as(−

V_t)/V₀=(Δ

R₂*_(t)/Δ

RR₂*₍₀₎)−

1, where V₀ is the value for rCBV at rest and V_t is the value for rCBV at time t after contrast administration.

18. A method for assessing changes in neurotransmitter and neuroreceptor activity as a metabolic response to diagnostic challenge or therapeutic treatment in a patient with suspected or already diagnosed mental illness of psychiatric, neurodegenerative or neurological nature, said method comprising the steps of

(a) inducing neuronal activation in the patient by administering a neuronal activator eliciting a hemodynamic response,

(b) MR Imaging said patient to assess changes in the patient'"'"'s regional cerebral blood volume using a negative blood and contrast agent, and thereafter

(c) relating to the changes to the patient'"'"'s condition.