U.S. patent application number 14/053382 was filed with the patent office on 2014-02-13 for radiopharmaceutical imaging of neurodegenerative diseases.
This patent application is currently assigned to Avid Radiopharmaceuticals, Inc.. The applicant listed for this patent is Avid Radiopharmaceuticals, Inc.. Invention is credited to Alan P. Carpenter, Franz F. Hefti, Daniel M. Skovronsky.
Application Number | 20140044642 14/053382 |
Document ID | / |
Family ID | 40874716 |
Filed Date | 2014-02-13 |
United States Patent
Application |
20140044642 |
Kind Code |
A1 |
Hefti; Franz F. ; et
al. |
February 13, 2014 |
RADIOPHARMACEUTICAL IMAGING OF NEURODEGENERATIVE DISEASES
Abstract
Methods for simultaneously detecting dementia or cognitive
impairment, such as Alzheimer's Disease (AD), Parkinson's Disease
(PD), Lewy Body Dementia (LBD) and Vascular Dementia (VaD) in a
patient using dual or multiple radiopharmaceutical probes are
provided herein.
Inventors: |
Hefti; Franz F.;
(Bernardsville, NJ) ; Skovronsky; Daniel M.; (Glen
Mills, PA) ; Carpenter; Alan P.; (Carlisle,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Avid Radiopharmaceuticals, Inc. |
Philadelphia |
PA |
US |
|
|
Assignee: |
Avid Radiopharmaceuticals,
Inc.
Philadelphia
PA
|
Family ID: |
40874716 |
Appl. No.: |
14/053382 |
Filed: |
October 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12418177 |
Apr 3, 2009 |
8557222 |
|
|
14053382 |
|
|
|
|
61042480 |
Apr 4, 2008 |
|
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Current U.S.
Class: |
424/1.73 |
Current CPC
Class: |
A61B 6/037 20130101;
A61K 51/0455 20130101; A61B 6/508 20130101; A61K 51/0491
20130101 |
Class at
Publication: |
424/1.73 |
International
Class: |
A61K 51/04 20060101
A61K051/04 |
Claims
1. A method for detecting or ruling out multiple neurodegenerative
diseased states or pathologic processes in a patient comprising:
administering an effective amount of .sup.18F-AV-45 to a patient;
acquiring an image to detect the presence or absence of the
.beta.-amyloid plaque in the cortical regions of the brain of the
patient; administering an effective amount of .sup.18FDG; acquiring
an image to detect metabolic activity of the brain of the patient;
detecting the presence or absence of .beta.-amyloid plaque in the
brain of the patient; and detecting the presence or absence of the
metabolic activity in the brain of the patient.
2. The method of claim 1, wherein the effective amount of
.sup.18F-AV-45 comprises from about 0.1 to about 20 mCi.
3. The method of claim 1, wherein the effective amount of
.sup.18F-AV-45 comprises about 10 mCi.
4. The method of claim 1, wherein the .beta.-amyloid plaque is
associated with at least one of dementia, cognitive impairment,
Alzheimer's Disease (AD), Parkinson's Disease (PD), Dementia with
Lewy Bodies (DLB), Vascular Dementia (VaD), and combinations
thereof.
5. The method of claim 1, wherein the metabolic activity is
associated with at least one of dementia, cognitive impairment,
Alzheimer's Disease (AD), Parkinson's Disease (PD), Dementia with
Lewy Bodies (DLB), Vascular Dementia (VaD), and combinations
thereof.
6. The method of claim 1, wherein the step of administering
.sup.18F-AV-45 and the step of administering the .sup.18FDG are
performed concurrently.
7. The method of claim 1, wherein the step of acquiring an image to
detect the presence or absence of the .beta.-amyloid plaque in the
cortical regions of the brain of the patient and the step of
acquiring an image to detect metabolic activity of the brain of the
patient are performed concurrently.
8. The method of claim 1, wherein the step of acquiring an image to
detect the presence or absence of the .beta.-amyloid plaque in the
cortical regions of the brain of the patient and the step of
acquiring an image to detect metabolic activity of the brain of the
patient are performed sequentially.
9. The method of claim 1, wherein the steps of acquiring images
comprise positron emission tomography (PET) imaging, single photon
emission computed tomography (SPECT) imaging, PET with concurrent
computed tomography imaging (PET/CT), PET with concurrent magnetic
resonance imaging (PET/MRI), SPECT with concurrent CT imaging
(SPECT/CT), or a combination thereof.
10. The method of claim 1, further comprising the step of
normalizing the image intensity of the acquired images to the
cerebellum of the brain of the patient.
11. The method of claim 1, wherein the steps of detecting the first
diseased state or pathologic process and detecting the second
diseased state or pathologic process are performed
sequentially.
12. The method of claim 1, wherein the steps of detecting the first
diseased state or pathologic process and detecting the second
diseased state or pathologic process are performed concurrently.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/418,177 filed Apr. 3, 2009 entitled
"Radiopharmaceutical Imaging of Neurodegenerative Diseases," which
claims priority to U.S. Provisional Patent Application Ser. No.
61/042,480, filed Apr. 4, 2008, the disclosures of which are
incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] The invention presented herein relates generally to
monitoring neurodegenerative diseases in the human brain by means
of radiopharmaceutical imaging by positron emission tomography or
single photon emission computed tomography. More specifically, the
present invention relates to the differential detection of
neurodegenerative processes in the brains of patients with
cognitive impairment or movement disorders using two or more
different brain imaging radiopharmaceuticals.
BACKGROUND
[0003] Alzheimer's Disease (AD) is a progressive neurodegenerative
disorder characterized by cognitive decline, irreversible memory
loss, disorientation and language impairment. It is the most common
cause of dementia in the United States. AD can strike persons as
young as 40-50 years of age, but because the presence of the
disease is difficult to detect without histopathological
examination of brain tissue, the time of onset in living subjects
is unknown. The prevalence of AD increases with age, with estimates
of the affected population as high as 40% by ages 85-90.
[0004] AD is only definitively diagnosed through postmortem
examination of brain tissue, when pathologists examine the brain
tissue for the presence of abundant senile plaques (SPs) composed
of amyloid-.beta. (A.beta.) peptide aggregates and neurofibrillary
tangles (NFTs) formed by filaments of highly phosphorylated tau
proteins. An amyloid deposit is formed by the aggregation of
amyloid peptides, followed by the further combination of aggregates
and/or amyloid peptides. The fibrillar aggregates of amyloid
peptides, A.beta.1-40 and A.beta.1-42, are major metabolic peptides
derived from amyloid precursor protein that are found in senile
plaques and cerebrovascular amyloid deposits in AD patients.
[0005] Parkinson's Disease (PD), another common neurodegenerative
disease, is a progressive disorder characterized by resting
tremors, bradykinesia, muscular rigidity, and postural instability.
PD affects men and women without distinction, regardless of social,
ethnic, economic or geographic backgrounds. PD usually develops
after the age of 60, though 15% of those diagnosed are under the
age of 50. Family history of PD is an etiological factor for 5-10%
of patients diagnosed with the disease, yet only 1% of cases have
been shown to be clearly familial. It is estimated that 1.5 million
Americans are currently living with Parkinson's Disease.
[0006] Dementia with Lewy Bodies (DLB) is a progressive
neurodegenerative disorder characterized by symptoms that fluctuate
between various degrees of manifestation. Such symptoms include
progressive dementia, Parkinsonian movement difficulties,
hallucinations, and increased sensitivity to neuroleptic drugs. As
with AD, advanced age is considered to be a risk factor for DLB,
with average onset typically between the ages of 50-85. 20% of all
dementia cases are caused by DLB and over 50% of PD patients
develop Parkinson's Disease Dementia (PDD), a type of DLB. DLB may
occur alone or in conjunction with other brain abnormalities,
including those involved in AD and PD, as mentioned above.
Currently, conclusive diagnosis of DLB is made during postmortem
autopsy.
[0007] PD and DLB share an etiology of dopamine deficiency, which
is correlated with the death of dopaminergic neurons in the
substantia nigra. Dopamine is a neurotransmitter that allows for
smooth, coordinated function of the body's muscles and movement.
The cause of dopaminergic neuronal death in PD is unknown, but it
is recognized that in DLB, abnormal protein deposits called Lewy
body proteins or "Lewy bodies" are instrumental in the death of
dopaminergic neurons. Lewy bodies occur mostly in the substantia
nigra and locus ceruleus sections of the brain stem and also, to a
lesser extent, in the subcortical and cortical regions of the
brain. Because of this specific localization in the brain, Lewy
bodies also interfere with the production of acetylcholine, causing
disruption in perception, thinking and behavior. Lewy bodies are
also typically considered to be a type of SP, as Lewy bodies are
made up of aggregated .alpha.-synuclein protein deposits.
[0008] An additional etiology of neurodegeneration can be a mixture
of pathologies that involves a component of microvascular, or
perfusion, deficits in the brain. Commonly referred to as "mixed
dementia", this type of neurodegeneration often involves both
perfusion deficits as well as amyloid plaque pathology. Different
meanings have been associated with the term mixed dementia. One
definition of mixed dementia encompasses a combination of AD and
other pathologies such as hypothyroidism, or vitamin B-12
deficiency. However, mixed dementia is most commonly refers to the
coexistence of AD and vascular dementia (VaD). Mixed dementia is
clinically important because the combination of AD and VaD may have
a greater impact on the brain than either by itself. Mixed dementia
is traditionally difficult to diagnose, although symptoms are
generally similar to those of AD or VaD or a combination of the
two.
[0009] Because of the central role of the presence of A.beta.
plaques in AD and death of dopaminergic neurons in PD and DLB,
there has been a wide interest in developing radiolabeled ligands
that bind to and allow imaging of such abnormalities. Several
radioisotopically-labeled A.beta.-aggregate-specific ligands have
been reported for the imaging of amyloid plaque in the living
subject using positron emission tomography (PET) or single photon
emission computed tomography (SPECT). These ligands are mainly
targeted to nigrostriatal neurons and D2/D3 receptors in the brain.
Examples of such radioisotopically-labeled
A.beta.-aggregate-specific ligands include [(99m)Tc]TRODAT-1 and
[(123)I]IBZM, among many others. In addition, several
radiopharmaceuticals have been used for PET or SPECT imaging of
regional cerebral perfusion. PET radiopharmaceuticals such as
.sup.15O-labeled water (H.sub.2.sup.15O) and .sup.13N-ammonia
(.sup.13NH.sub.3) have been employed for perfusion imaging. SPECT
radiopharmaceuticals such as Tc-99m HMPAO and Tc-99m Bicisate are
also used as cerebral perfusion agents.
[0010] Dual-isotope imaging techniques have been employed in trials
including parathyroid studies to detect the existence of an adenoma
on the thyroid and in myocardial imaging studies of perfusion and
myocardial tissue viability. Additionally, in the brain, a
simultaneous .sup.18F-FDG and .sup.99mTc-HMPAO SPECT imaging
technique has been utilized to image selected areas in the
neuroanatomy of anxiety and depression such as the hippocampus,
basal ganglia and gyri temporales superiores. There have also been
studies employing a dual SPECT imaging technique with
[.sup.99mTc]TRODAT-1 and [.sup.123I]IBZM to image nigrostriatal
neurons and D2/D3 receptors.
SUMMARY
[0011] Embodiments of the present invention provide a method for
differentially detecting multiple pathologies or diseased states of
the brain, including administering a first radiopharmaceutical for
detecting a structure associated with a first diseased state to a
patient, administering a second radiopharmaceutical for detecting a
structure associated with a second diseased state to the patient,
imaging a portion of a brain of the patient comprising a region of
the brain wherein the structures associated with the first diseased
state and the second diseased state are expected to be positioned,
and detecting the first diseased state, the second diseased state
or both the first diseased state and the second diseased state in
sequential or simultaneous nuclear imaging procedures. In some
embodiments, the steps of administering the first
radiopharmaceutical and administering the second
radiopharmaceutical are performed concurrently.
[0012] In some aspects of the present invention, the first diseased
state includes at least one of dementia, cognitive impairment,
Alzheimer's Disease (AD), Parkinson's Disease (PD), Dementia with
Lewy Bodies (DLB), Vascular Dementia (VaD), and combinations
thereof. In other aspects, the second diseased state includes at
least one of dementia, cognitive impairment, Alzheimer's Disease
(AD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB),
Vascular Dementia (VaD), and combinations thereof.
[0013] In certain embodiments, the step of imaging includes
positron emission tomography (PET) imaging, single photon emission
computed tomography (SPECT) imaging, PET with concurrent computed
tomography imaging (PET/CT), PET with concurrent magnetic resonance
imaging (PET/MRI), SPECT with concurrent CT imaging (SPECT/CT), or
a combination thereof.
[0014] The method for detecting multiple diseased states of certain
embodiments further includes the step of waiting for a period of
time following administration of the first radiopharmaceutical. In
other embodiments, the method for detecting multiple diseased
states includes waiting for a period of time following
administration of the second radiopharmaceutical. In yet other
embodiments, the method further includes the step of administering
a third radiopharmaceutical.
[0015] Other embodiments of the present invention are directed to a
method for detecting multiple diseased states or pathologic
processes in a patient including administering an effective amount
of a radiopharmaceutical targeted to .beta.-amyloid plaque to a
patient, wherein the .beta.-amyloid plaque is associated with a
first diseased state or pathologic process, acquiring an image to
detect the presence or absence of the .beta.-amyloid plaque in the
cortical regions of the brain of the patient, administering an
effective amount of a metabolic imaging radiopharmaceutical,
wherein the metabolic imaging radiopharmaceutical corresponds to
glucose utilization in the brain of the patient and wherein a
decrease in the metabolic imaging radiopharmaceutical signal is
associated with a second diseased state or pathologic process,
acquiring an image to detect metabolic activity of the brain of the
patient, detecting the presence or absence of the first diseased
state or pathologic process, and detecting the presence or absence
of the second diseased state or pathologic process. The metabolic
imaging radiopharmaceutical of certain embodiments comprises
[.sup.18F]fluorodeoxyglucose .sup.18FDG. The radiopharmaceutical
targeted to .beta.-amyloid plaque of certain embodiments comprises
((E)-4-(2-(6-(2-(2-(2-[.sup.18F]
fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methylbenzenamine))
.sup.18F-AV-45. In some aspects of the invention, the effective
amount of .sup.18F-AV-45 includes from about 0.1 to about 20 mCi.
In certain aspects, the effective amount of .sup.18F-AV-45 includes
about 10 mCi. In additional aspects of the invention, an effective
amount of .sup.18FDG, between 0.1 to about 20 mCi, may be
administered to a human subject followed by imaging either prior
to, concurrently with, or following the administration and another
PET brain imaging radiopharmaceutical, such as AV-45 for imaging
the .beta.-amyloid plaques or AV-133 for imaging VMAT2 as a marker
of dopaminergic neuronal integrity.
[0016] In some embodiments, the step of administering the
radiopharmaceutical targeted to .beta.-amyloid plaque and the step
of administering the metabolic imaging radiopharmaceutical are
performed concurrently. In other embodiments, the step of acquiring
an image to detect the presence or absence of the .beta.-amyloid
plaque in the cortical regions of the brain of the patient and the
step of acquiring an image to detect metabolic activity of the
brain of the patient are performed concurrently. In some
embodiments, the method for detecting multiple diseased states in a
patient further includes normalizing the image intensity of the
acquired images to a reference region, such as the cerebellum of
the brain of the patient. In certain embodiments, the steps of
detecting the first diseased state or pathologic process and
detecting the second diseased state or pathologic process are
performed sequentially. In other embodiments, these steps are
performed concurrently.
[0017] Other embodiments of the present invention are directed to a
method for detecting multiple diseased states or pathologic
processes in a patient including administering an effective amount
of a radiopharmaceutical targeted to .beta.-amyloid plaque to a
patient, wherein the .beta.-amyloid plaque is associated with a
first diseased state or pathologic process, acquiring an image to
detect the presence or absence of the .beta.-amyloid plaque in the
cortical regions of the brain of the patient, administering an
effective amount of a radiopharmaceutical targeted to nigrostriatal
neurons of the patient, wherein the dopaminergic degeneration of
nigrostriatal neurons is associated with a second diseased state or
pathologic process, acquiring an image to detect the dopaminergic
degeneration of nigrostriatal neurons in the striatal regions of
the brain of the patient, detecting the presence or absence of the
first diseased state or pathologic process, and detecting the
presence or absence of the second diseased state or pathologic
process. The radiopharmaceutical targeted to nigrostriatal neurons
of some embodiments comprises
((2R,3R,11bR)-9-(3-[18F]fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11-
b-hexahydro-1H pyrido[2,1a]isoquinolin-2-ol) (.sup.18F-AV-133). In
certain aspects of the invention, the effective amount of
.sup.18F-AV-133 includes from about 0.1 to about 20 mCi. In other
aspects, the effective amount of .sup.18F-AV-133 includes about 10
mCi.
[0018] In some embodiments, the step of administering the
radiopharmaceutical targeted to .beta.-amyloid plaque and the step
of administering the radiopharmaceutical targeted to nigrostriatal
neurons are performed concurrently. In other embodiments, the step
of acquiring an image to detect the presence or absence of the
.beta.-amyloid plaque in the cortical regions of the brain of the
patient and the step of acquiring an image to detect the
dopaminergic degeneration of nigrostriatal neurons in the striatal
regions of the brain of the patient are performed concurrently. In
yet other embodiments, the steps of detecting the first diseased
state or pathologic process and detecting the second diseased state
or pathologic process are performed sequentially. In still other
embodiments, the steps of detecting the first diseased state or
pathologic process and detecting the second diseased state or
pathologic process are performed concurrently.
[0019] Embodiments of the present invention are further directed to
a method for detecting Alzheimer's Disease (AD) and Vascular
Dementia (VaD) in a patient comprising administering an effective
amount of a radiopharmaceutical targeted to .beta.-amyloid plaque
to a patient, wherein the .beta.-amyloid plaque is associated with
Alzheimer's Disease (AD), acquiring an image to detect the presence
or absence of the .beta.-amyloid plaque in the cortical regions of
the brain of the patient, administering an effective amount of a
perfusion imaging radiopharmaceutical, wherein the perfusion
imaging radiopharmaceutical indicates blood flow in the brain of
the patient and wherein a decrease in the perfusion imaging
radiopharmaceutical signal is associated with Vascular Dementia
(VaD), acquiring an image to detect perfusion of the brain of the
patient, detecting the presence or absence of Alzheimer's Disease
(AD) in the patient, and detecting the presence or absence of
Vascular Dementia (VaD) in the patient. The perfusion imaging
radiopharmaceutical of certain aspects of the present invention
comprises H.sub.2.sup.15O. In other aspects, the perfusion imaging
radiopharmaceutical comprises .sup.13NH.sub.3.
[0020] In certain embodiments, the step of administering the
radiopharmaceutical targeted to .beta.-amyloid plaque and the step
of administering the perfusion imaging radiopharmaceutical are
performed concurrently. In other embodiments, the step of acquiring
an image to detect the presence or absence of the .beta.-amyloid
plaque in the cortical regions of the brain of the patient and the
step of acquiring an image to detect perfusion of the brain of the
patient are performed concurrently. In certain embodiments, the
steps of detecting Alzheimer's Disease (AD) and detecting Vascular
Dementia (VaD) are performed sequentially. In other embodiments,
the steps of detecting Alzheimer's Disease (AD) and detecting
Vascular Dementia (VaD) are performed concurrently.
DESCRIPTION OF THE DRAWINGS
[0021] For a fuller understanding of the nature and advantages of
the present invention, reference should be made to the following
detailed description taken in connection with the accompanying
drawings, in which:
[0022] FIGS. 1-12 are simulated images of the brain created by the
fusion of two separate image data sets in order to demonstrate the
imaging of two or more targeted radiopharmaceuticals in the
brain;
[0023] FIG. 1 is a simulated image of the brain of a healthy
individual with no observable amyloid plaques and normal
dopaminergic neurons;
[0024] FIG. 2 shows simulated activity curves for cortical regions
of the brain of a healthy individual;
[0025] FIG. 3 shows simulated activity curves for striatal regions
of the brain of a healthy individual;
[0026] FIG. 4 is a simulated image of the brain of an individual
exhibiting the symptoms of Alzheimer's Disease;
[0027] FIG. 5 shows simulated activity curves for cortical regions
of the brain of an individual exhibiting the symptoms of
Alzheimer's Disease;
[0028] FIG. 6 shows simulated activity curves for striatal regions
of the brain of an individual exhibiting the symptoms of
Alzheimer's Disease;
[0029] FIG. 7 is a simulated image of the brain of an individual
exhibiting the symptoms of Parkinson's Disease;
[0030] FIG. 8 shows simulated activity curves for cortical regions
of the brain of an individual exhibiting the symptoms of
Parkinson's Disease;
[0031] FIG. 9 shows simulated activity curves for striatal regions
of the brain of an individual exhibiting the symptoms of
Parkinson's Disease;
[0032] FIG. 10 is a simulated image of the brain of an individual
with both Alzheimer's Disease and Parkinson's Disease;
[0033] FIG. 11 shows simulated activity curves for cortical regions
of the brain of an individual with Alzheimer's Disease and
Parkinson's Disease; and
[0034] FIG. 12 shows simulated activity curves for striatal regions
of the brain of an individual with Alzheimer's Disease and
Parkinson's Disease.
DETAILED DESCRIPTION
[0035] It is to be understood that this invention is not limited to
the particular processes, compositions, or methodologies described,
as these may vary. It is also to be understood that the terminology
used in the description is for the purpose of describing the
particular versions or embodiments only and is not intended to
limit the scope of the present invention. Unless defined otherwise,
all technical and scientific terms used herein have the same
meanings as commonly understood by one of ordinary skill in the
art. In case of conflict, the patent specification, including
definitions, will prevail.
[0036] As used herein, the singular forms "a", "an" and "the"
include plural reference, unless the context clearly dictates
otherwise.
[0037] As used herein, the terms "A.beta.-binding
radiopharmaceutical" and "A.beta.-aggregate binding
radiopharmaceutical" refer to a compound, or pharmaceutically
acceptable salt thereof that binds to amyloid-.beta. peptide
aggregates or amyloid plaques and that is radiolabeled with an
isotope.
[0038] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0039] "Administering", as used herein in conjunction with a
diagnostic agent, such as, for example, a radiopharmaceutical,
means to administer directly into or onto a target tissue or to
administer the diagnostic agent systemically to a patient whereby
the diagnostic agent is used to image the tissue or a pathology
associated with the tissue to which it is targeted. "Administering"
a composition may be accomplished by injection, infusion, or by
either method in combination with other known techniques. Such
combination techniques include, but are not limited to, heating,
radiation and ultrasound.
[0040] As used herein, the term "healthy individual", "normal
individual" or "normal healthy individual" refers to an individual
who is not suspected to suffer from any cognitive disorder such as,
but not limited to, dementia or Alzheimer's Disease and/or an
individual who is not suspected to have .beta.-amyloid peptide
aggregates in the cortex of the brain such as, but not limited to,
someone who is less than 50 years of age.
[0041] The term "individual", as used herein, refers to a living
creature.
[0042] An "isotopically-labeled", "radiolabeled", "labeled",
"detectable" or "detectable amyloid binding" compound,
"radioligand" or "radiolabeled pharmaceutical", as used herein,
refers to a compound of the present invention where one or more
atoms are replaced or substituted by an atom having an atomic mass
or mass number different from the atomic mass or mass number
typically found in nature (i.e., naturally occurring). Suitable
radionuclides (i.e., "detectable isotopes") that may be
incorporated in the compounds of the present invention include, but
are not limited to, .sup.11C, .sup.13N, .sup.15O, .sup.18F,
.sup.75Br, .sup.76Br, .sup.77Br, .sup.82Br, .sup.99mTc, .sup.123I,
.sup.124I, .sup.125I, and .sup.131I. An isotopically labeled
compound need only be enriched with a detectable isotope to a
degree that permits detection with a technique suitable for the
particular application.
[0043] "Optional" or "optionally", as used herein, may be taken to
mean that a subsequently described structure, event or circumstance
may or may not occur and that the description of the invention
includes instances where the event occurs and instances where it
does not.
[0044] The term "pathology" herein refers to an altered endogenous
biological process that may be associated with the aberrant
production of proteins, peptides, RNA and other substances
associated with the disease process.
[0045] The term "patient" generally refers to any living organism
to which the compounds described herein are administered and may
include, but is not limited to, any non-human mammal, primate or
human. Such "patients" may or may not be exhibiting the signs,
symptoms or pathology of one or more particular diseased
states.
[0046] A "therapeutically effective amount" or "effective amount"
of a composition, as used herein, is a predetermined amount
calculated to achieve the desired effect.
[0047] The term "tissue", as used herein, refers to any aggregation
of similarly specialized cells united in the performance of a
particular function.
[0048] Embodiments hereof provide a method for imaging structures
in the brain of a patient relating to dementia or cognitive
impairment, such as Alzheimer's Disease (AD), Parkinson's Disease
(PD), Dementia with Lewy Bodies (DLB) and Vascular Dementia (VaD)
using two or more different radiopharmaceuticals.
[0049] Various embodiments are directed to detection and
discrimination between neurological disorders, and in particular
embodiments, detection and discrimination between various
neurological disorders that are each manifested in the symptoms of
dementia. Certain aspects of the invention are directed to the
detection and differential diagnosis of Alzheimer's Disease (AD),
Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB).
[0050] In numerous embodiments of the present invention, a method
of imaging is provided including a method of .beta.-amyloid
radiopharmaceutical imaging together with nigrostriatal neuronal
imaging or metabolic imaging or perfusion imaging of the brain. In
some embodiments, a first radiopharmaceutical such as, for example,
a .beta.-amyloid specific radiopharmaceutical, may be administered
for imaging the presence of cortical pathology associated with AD
and a second radiopharmaceutical such as, for example, a dopamine
transporter (DAT) specific radiopharmaceutical or a vesicular
monoamine transporter (VMAT) specific radiopharmaceutical for
detecting PD or DLB, may be administered simultaneously or after a
short period of time following administration of the first
radiopharmaceutical for imaging the integrity of dopaminergic
neurons in the striatal region of the brain. In another embodiment,
a .beta.-amyloid imaging radiopharmaceutical may be administered
simultaneously with or within a short period of time, prior to or
following, the administration of a cerebral perfusion imaging
radiopharmaceutical. Such a combination of radiopharmaceuticals may
allow the imaging of both amyloid plaque pathology (i.e.
Alzheimer's Disease) and Vascular Dementia (VaD) in the same
patient. PET and/or SPECT may be used to image the brain of the
patient and detect the radiopharmaceuticals in embodiments of the
present invention over a time period conducive to the
pharmacokinetics of each radiopharmaceutical in the brain. In other
embodiments, a combination of radiopharmaceuticals, such as, for
example, .sup.18F-AV-45 and .sup.18FDG, provides for the imaging of
both amyloid plaque pathology and brain metabolic activity in the
same patient, thereby allowing for the assessment of the spatial
correlation between plaque pathology and decreased metabolic
utilization of glucose in the brain. Such methods may allow
physicians to make a more accurate diagnosis of the presence or
absence of AD, PD, DLB or VaD in a given subject in a shorter
period of time than what is currently possible. Additionally, the
methods of such embodiments may allow for the differential
diagnosis of the underlying cause of, for example, memory
impairment in patients with cognitive defects, or may allow for a
better understanding of the relationship between certain brain
pathologies and brain function in these neurodegenerative
diseases.
[0051] Embodiments of the invention described herein provide a
method that involves diagnostic imaging with two or more
radiopharmaceuticals in the same dementia patient, where the
radiopharmaceuticals target different underlying pathological,
functional or perfusion processes in the brain, with at least one
such radiopharmaceutical being an amyloid plaque imaging agent.
This dual or multiple radiopharmaceutical imaging method for the
brain will allow a physician or other medical professional to more
accurately characterize a given dementia patient for the presence
or absence of amyloid plaque (the most common cause of dementia),
the presence or absence of dopaminergic degeneration caused by Lewy
bodies (PD and DLB) and the presence or absence of cerebral
perfusion defects (VaD). Various aspects of this method of imaging
are directed to combining an amyloid plaque imaging
radiopharmaceutical with at least one other imaging method (e.g.
radiopharmaceutical) for evaluation of the underlying causes of
dementia.
[0052] The method of various embodiments allows for the
differential diagnosis of AD, PD, DLB and VaD and may be described
in the following exemplary steps: administering a first
radiopharmaceutical for detecting a first disease or target in the
brain of a patient; administering a second radiopharmaceutical for
detecting a second disease or target in the brain of the patient;
waiting for a period of time adequate to allow uptake and binding
of the administered radiopharmaceuticals in the appropriate regions
of the brain of the patient; imaging one or more aspects of the
brain of the patient; and reviewing the image(s) to make a
diagnosis or other assessment (e.g. determine severity, prognosis,
staging or response to treatment) of the patient. Depending on the
radiopharmaceuticals used, the order of the foregoing steps may be
varied. For example, in one embodiment, a single imaging session
may provide a concurrent image of two or more radiopharmaceuticals
in the brain. In other embodiments, imaging may be performed after
both the first radiopharmaceutical injection as well as following
the injection of the second radiopharmaceutical. The
neurodegenerative disease processes may vary among embodiments and
can be any individual disease or combination of diseases for which
radiopharmaceutical imaging probes have been designed. For example,
in particular embodiments, a first disease may be AD and a second
(concurrent) disease may be PD, DLB or VaD. In certain embodiments
of the present invention, methods are provided for imaging
.beta.-amyloid plaque (i.e. Alzheimer's disease) and a second
neurodegenerative disease process, such as PD or DLB or VaD in the
same subject in a single imaging session.
[0053] The first and second radiopharmaceuticals may be any
radiopharmaceuticals known in the art that have been developed to
detect different types of dementia. For example, methods of the
invention may utilize any molecule with a high affinity for
.beta.-amyloid plaque together with a nigrostriatal imaging
compound, such as a DAT or VMAT2 specific radiopharmaceutical. The
radiopharmaceutical embodiments may also include any molecule with
an affinity for a moiety associated with a central nervous system
(CNS) disorder. Certain radiopharmaceutical embodiments may include
a radiolabeled antibody, protein, peptide, nucleic acid, organic
molecule, small molecule, polymer or a combination of these.
However, it is to be noted that radiopharmaceuticals that are small
molecules are generally preferred for this multiple
radiopharmaceutical imaging procedure, due to their greater degree
of diffusability in order to cross the blood-brain barrier,
relative to proteins or polymeric materials.
[0054] Radiopharmaceuticals useful for the detection of
.beta.-amyloid, which could be used in this multiple
radiopharmaceutical imaging methodology, include, but are not
limited to, those described in WO 2006/014381, US 2003/0236391, US
2005/0043523, WO 2007/047204, WO 2007/086800, WO 2006/057323, EP
1815872, WO 2005/016888, EP 1655287, U.S. Pat. No. 6,696,039, U.S.
Pat. No. 6,946,116, U.S. Pat. No. 7,250,525, WO 2006/078384, WO
2006/066104, WO 2007/126733, US 2006/269473, US 2006/269474,
US2005/0271584, US 2007/0031328, Mathis et al., J. Med. Chem. 2003,
46: 2740-2754, Small et al., N Engl. J. Med. 2006, 355: 2652-2663,
Zhang et al., Nucl. Med. Biol. 2005, 32: 799-809, Ono et al., Nucl.
Med. Biol. 2002, 29:633-642, Ono et al., Nucl. Med. Biol. 2005, 32:
329-335, Qu et al., Bioinorg. Med. Chem. Lett. 2007, 17: 3581-3584,
Kemppainen et al., Neurology 2007, 68: 1603-1606, Pike et al.,
Brain 2007, 130; 2837-2844, Klunk et al., Ann. Neurol. 2004; 55,
306-319, Verhoeff et al., Am J. Geriatr. Psychiatry 2004, 12,
584-595, and Newberg et al., J. Nucl. Med. 2006; 47, 748-754, each
of which is hereby incorporated by reference in its entirety.
[0055] The nigrostriatal imaging radiopharmaceuticals useful in
embodiments of the present invention for combination imaging with
A.beta. specific radiopharmaceuticals can be, for example, D2/D3
receptor imaging compounds or DAT or VMAT2 imaging
radiopharmaceuticals. These types of radiopharmaceuticals have been
described previously and are well known to one skilled in the art.
Specific examples include, but are not limited to, [.sup.123I-IBZM,
.sup.99mTc]TRODAT-1, an iodinated cocaine derivative such as
.sup.123I-FP-CIT, .sup.123I-.beta.-CIT, and radiopharmaceutical
derivatives of tetrabenazine such as C-dihydrotetrabenazine, and
.sup.18F-fluoropropyl dihydrotetrabenazine as described in Kung et
al., Semin. Nucl. Med. 2003, 33(1), 2-13, Kung et al. Nucl. Med.
Biol. 2007, 34, 239-246, and Kilbourn et al., Nucl. Med. Biol.
2007, 34, 233-237, each of which is hereby incorporated by
reference in its entirety.
[0056] The radiopharmaceuticals of various embodiments of the
present invention may be labeled with any radioisotopes that can be
imaged with a PET or SPECT camera. For example,
radiopharmaceuticals of various embodiments may be radiolabeled
with radiosotopes such as, but not limited to, .sup.76Br,
.sup.123I, .sup.125I, .sup.131I, .sup.99mTc, .sup.11C, .sup.18F, or
other gamma- or positron-emitting radionuclides. In other
embodiments, the radiopharmaceutical may be radiolabeled with a
combination of radioisotopes.
[0057] The radioactive half-life of the radiopharmaceutical of
embodiments of the present invention may vary depending on which
radioisotope is utilized. Accordingly, in some embodiments, the
radiopharmaceutical has a radioactive half-life of about 24 hours
or less. In other embodiments, the radioactive half-life of the
radiopharmaceutical may be about 12 hours or less, in still others,
about 6 hours or less, and in some, about 2 hours to about 1 hour
or less. In addition, the amount of radioactivity emitted by the
radiopharmaceutical may vary among embodiments, and may depend upon
various aspects of the procedure such as, for example, the period
of time between administration and imaging or the physiology of the
patient. For example, in some embodiments, 0.1 to 20 mCi (3.7 to
740 MBq) each of two different radiopharmaceuticals may be
administered to an individual. Hence, an effective amount of each
of the radiopharmaceutical may be from about 0.1 to about 20 mCi.
In other embodiments, an effective amount of each
radiopharmaceutical may be from about 0.1 to about 10 mCi. In still
other embodiments, an effective amount of each radiopharmaceutical
may be from about 0.1 to about 2 mCi. In further embodiments, lower
effective amounts of radiolabeled compound may be possible.
However, the precision of measurements and the quality of PET or
SPECT images taken when a low dose of radiopharmaceutical is
administered may deteriorate, and the time required for imaging the
radiopharmaceutical may increase at lower injected doses.
[0058] In certain embodiments of the present invention, the first
and second radiopharmaceuticals may be labeled with radioisotopes
having different emission energies. For example, in one embodiment,
a first radiopharmaceutical may be labeled with .sup.18F and a
second radiopharmaceutical may be labeled with .sup.123I. The gamma
energies of .sup.18F and .sup.123I (511 KeV and 159 KeV,
respectively) may be separated at least in part with SPECT cameras
using energy discrimination techniques well known to those in the
art such as, for example, those described in Sandler et al., J. Am.
Coll. Cardiol., 1995, 26: 870-878 and U.S. Pat. No. 3,904,530, both
of which are hereby incorporated by reference in their
entireties.
[0059] In some embodiments, the first and second
radiopharmaceuticals may be administered individually in, for
example, separate injections. In other embodiments, the first and
second radiopharmaceuticals may be administered concurrently in,
for example, a single injection. When administered individually,
administration of the second radiopharmaceutical may occur
following administration of a first radiopharmaceutical after an
appropriate period of time of from seconds to several hours. For
example, in some embodiments, the second radiopharmaceutical may be
administered about 15 seconds to about 2 hours following
administration of the first radiopharmaceutical. In certain
embodiments, following separate administrations, the
radiopharmaceuticals may be imaged sequentially or concurrently, as
long as the total procedure time is of reasonable duration for the
patient. In some embodiments, the dual radiopharmaceutical imaging
method may be completed within less than approximately 4 hours and
preferentially within 2 hours or less. In various embodiments, the
second radiopharmaceutical may be administered about 30 seconds to
about 1 hour or about 1 minute to about 30 minutes or about 5 to
about 15 minutes following administration of the first
radiopharmaceutical.
[0060] The radiopharmaceuticals of embodiments of the present
invention may be administered by any procedure known in the art
including, but not limited to, parenterally by, for example,
intravenous injection, intramuscular injection or subcutaneous
injection, intraperitoneally, or via buccal or nasal spray. In
certain embodiments, the radiopharmaceuticals may be administered
by bolus injection or infusion. The first and second
radiopharmaceuticals may be individually administered systemically
or locally. For example, in some embodiments, the first and/or
second radiopharmaceutical may be administered systemically by, for
example, intravenous injection, and in other embodiments, the first
and/or second radiopharmaceuticals may be administered directly by,
for example, injection into the brain or the carotid artery. In
some embodiments, the first and second radiopharmaceuticals may be
administered by the same procedure, and in other embodiments, the
radiopharmaceuticals may be administered by different
administration procedures. For example, in one embodiment, a first
radiopharmaceutical may be administered systemically by intravenous
bolus injection, and the second radiopharmaceutical may be
administered by local bolus injection directly into the carotid
artery of the patient.
[0061] In some embodiments of the multiple radiopharmaceuticals
imaging method, the steps of administering the first and second
radiopharmaceuticals may be followed by a step of waiting for a
period of time. The waiting period may vary among embodiments of
the invention and is generally a period sufficient for the
radiopharmaceuticals being utilized. For example, the waiting
period may be a time period sufficient for at least a portion of a
systemically administered radiopharmaceutical to be deposited into
the target tissue, such as, for example, the brain, and bind to the
substrate of the radiopharmaceutical composition, such as, for
example, A.beta. plaque, DAT or VMAT2. Additionally, the waiting
period may vary among embodiments as a result of, for example,
manner, location, and amount of radiopharmaceutical administered,
affinity of the radiopharmaceutical for target tissue, and the
health of the individual. Embodiments of the invention are not
limited by the waiting time, which may generally be from, for
example, about 15 minutes to about 4 hours. In other embodiments,
the waiting period may be from about 15 minutes to about 3 hours or
about 30 minutes and about 2 hours or about 30 minutes and about
1.5 hours or about 45 minutes and about 1 hour. In additional
embodiments of the present invention, a waiting step follows the
administration of a first radiopharmaceutical followed by acquiring
a PET or SPECT scan, administering a second radiopharmaceutical,
waiting a period of time and then acquiring a PET or SPECT
scan.
[0062] The step of imaging may be carried out by any procedure
known in the art that may allow the imaging of the
radiopharmaceuticals administered. For example, in some
embodiments, imaging may be carried out by PET or SPECT imaging. In
other embodiments, the imaging may be carried out by both PET and
SPECT or by combined imaging methods such as PET/CT (PET with
concurrent computed tomography imaging) or PET/MRI (PET with
concurrent magnetic resonance imaging). The imaging procedure may
result in one or more images of the region of observation of the
patient, and in embodiments in which imaging results in more than
one image, these multiple images may be combined, overlaid, added,
subtracted, color coded or otherwise fused and mathematically
manipulated by any method known in the art. The first and second
radiopharmaceuticals may be imaged individually or concurrently. In
some embodiments in which the radiopharmaceuticals are imaged
individually, the order in which the radiopharmaceutical imaging
procedure is performed is not crucial and may depend on the
half-life of the radioisotope, the dose of the radiopharmaceutical
administered as well as the pharmacokinetics of each
radiopharmaceutical in the region of observation. In certain
embodiments, each imaging procedure may be performed within the
same 24 hour period and in particular embodiments, within a 1-4
hour time period or within less than a 2 hour time period. The
image produced may be a digital or analog image that may be
displayed as a "hard" image on, for example, printer paper,
photographic paper or film, or as an image on a screen, such as for
example, a video or LCD screen.
[0063] The images produced using the imaging procedure embodied in
the present invention may be analyzed by any method known in the
art. For example, in one embodiment, the image may be analyzed by a
physician or another medical professional who visually observes the
derived images and grades the disease state based on the observable
presence of the first and/or second radiopharmaceutical in the
images produced. In another embodiment, the images may be analyzed
by a processor or processor system. For example, in one embodiment,
image data derived from a PET or SPECT scan can be inputted into a
processor that identifies individual pixels or groups of pixels
whose brightness is greater than a predetermined threshold or an
average background, and identified pixels may be characterized as
indicating the presence of a radiopharmaceutical. In another
embodiment, the image data may be derived from images scanned and
inputted into a processor. In such embodiments, a similar process
that identifies bright spots on the image may be used to locate the
radiopharmaceuticals in the image. In certain embodiments, the
analysis of the image may further include determining the
intensity, concentration, strength or combination thereof of the
output brightness, which may be correlated to the amount of
radiopharmaceutical in the image, an area or region of the image,
or a particular spot on the image. Without wishing to be bound by
theory, an area or spot on an image having a greater intensity than
other areas or spots may hold a higher concentration of
radiopharmaceutical targeted to, for example, .beta.-amyloid, DAT
or VMAT and, thus, may have a higher concentration of the
radioisotope attached to the region where the radiopharmaceutical
localizes in the brain. Images may also be analyzed by the spatial
location of regions of interest to which the administered
radiopharmaceuticals are targeted. In other embodiments, analysis
of the pharmacokinetics of the administered radiopharmaceuticals
may provide information on the appropriate timing of injection of
each radiopharmaceutical, which is yet another way to differentiate
between the two administered radiopharmaceuticals in the acquired
images.
[0064] By identifying areas, regions or spots on an image that
correlate to the presence of a radiopharmaceutical, the presence or
absence of a diseased state may be determined. For example, in
embodiments in which a first radiopharmaceutical for detecting
.beta.-amyloid is used and a second radiopharmaceutical for
detecting DAT or VMAT is used, each image may be used to diagnose
the presence or absence of AD, PD and DLB individually in each
image. In other embodiments, the images may be used to diagnose AD
and/or PD and/or DLB individually from two or more images taken at
different time points, and in still other embodiments, the images
may be used to concurrently diagnose AD, PD and DLB in each of two
or more images taken at different time points.
[0065] In particular embodiments, a radiopharmaceutical for
detecting AD by imaging .beta.-amyloid or a metabolic tracer (e.g.,
.sup.18F-FDG) may be administered first to a patient and images of
the patient may be acquired followed by administration of a
nigrostriatal imaging compound and imaging of the patient for
detecting PD and DLB. In other embodiments, the same
radiopharmaceuticals may be administered and the patient may be
imaged in reverse order to provide similar diagnostic
information.
[0066] Alternatively, in still other embodiments, both
radiopharmaceuticals may be administered to the patient within
minutes of each other followed by PET or SPECT imaging for both
compounds simultaneously. In such embodiments, radiopharmaceuticals
and diseased states may be selected for the detection of structures
in separate regions of the brain of a patient. For example, the AD
diagnostic radiopharmaceutical binds primarily to .beta.-amyloid in
the cortical region of the brain, which is spatially separated from
the DAT or VMAT2 radiopharmaceutical, which binds to dopaminergic
neurons in the striatum of the brain. Therefore, a single image
acquired of a patient who has been administered both .beta.-amyloid
and DAT or VMAT2 detecting radiopharmaceuticals may be analyzed
separately for AD and PD and/or DLB concurrently because the
spatial separation of the two radiopharmaceutical signals in the
brain allows the physician to observe both signals. The amount of
spatial separation may vary among embodiments, and may depend on
factors, such as, for example, the distribution of disease
associated structures, the sensitivity and spatial resolution of
the imaging device, the radiopharmaceuticals used and the skill of
the practitioner, among other factors. In some embodiments, spatial
separation between disease-associated structures may be at least
about 5 mm apart, at least about 10 mm apart, or at least about 50
mm apart. In other embodiments, the spatial separation may be
smaller. In yet further embodiments, physical attributes associated
with the disease-associated structures such as, for example,
concentration of disease-associated structures and size of the
structures or the characteristics of the radiopharmaceutical
utilized such as, for example, the type of radioisotope associated
with the radiopharmaceutical or ability to spectrally separate
different radioisotopes may provide evidence of one
disease-associated structure versus another. For example, spatially
overlapping structures may be separately imaged if the energies of
the radioisotopes attached to the radiopharmaceuticals are
resolvable by energy discrimination methods available on many SPECT
cameras. In some embodiments, PET radiopharmaceuticals labeled with
different radioisotopes may be separated in a PET brain image based
on different rates of decay for the radioisotopes employed (e.g. by
imaging the short-lived radioisotope prior to imaging the
longer-lived radioisotope).
[0067] The imaging methods described in embodiments of the
invention may provide a larger amount of diagnostic information in
a relatively shorter period of time, compared to images separately
created on a different imaging day for each radiopharmaceutical
utilized. As such, using embodiments of methods of the invention, a
physician or other medical professional may determine the presence
or absence of, for example, .beta.-amyloid plaque, decreases in DAT
or VMAT transporters, and/or decreases in cerebral perfusion more
quickly thereby diagnosing or monitoring AD, PD and/or DLB and/or
VaD more quickly than currently possible by imaging individual
radiopharmaceuticals over several imaging sessions.
EXAMPLES
[0068] In order that the invention disclosed herein may be more
efficiently understood, the following example is provided. The
following example is for illustrative purposes only and is not to
be construed as limiting the invention in any manner.
Example 1
Dual Radiopharmaceutical Imaging of .beta.-Amyloid and
Nigrostriatal Neurons
[0069] Data was generated from the radiopharmaceutical imaging of
.beta.-amyloid plaque and nigrostriatal dopaminergic degeneration
utilizing dual radiopharmaceuticals. The radiopharmaceuticals
utilized included .sup.18F-AV-45, which targets .beta.-amyloid
plaque and .sup.18F-AV-133, which targets nigrostriatal neurons.
The radiopharmaceuticals were administered via intravenous
injection to subjects who were clinically diagnosed with
Parkinson's Disease (PD) or Alzheimer's Disease (AD).
[0070] Data was analyzed for PD patients (PD_AV133) and Healthy
Controls (HC_AV133) as well as for AD patients (AD_AV45) and
Healthy Controls (HC_AV45). Data and images derived from subjects
in each category were analyzed individually. Data and images from
an average of 4 subjects in each respective category was also
analyzed and used as the basis of this protocol. The optimal
imaging protocol was judged based on the following criteria:
clarity of images/data in the cortical, grey, and white volumes of
interest (VOIs) of the brain (relating to diagnosis of AD) and the
striatal VOIs of the brain (relating to diagnosis of PD/DLB); ease
and level of certainty of the individual diagnoses of the presence
or absence of AD, PD, and DLB; minimum level of radiation injected
into a patient; and minimum protocol completion time.
[0071] Simulated (i.e. fused) images of the brains of a healthy
individual, an individual exhibiting symptoms of AD, an individual
exhibiting symptoms of PD, and an individual exhibiting symptoms of
both AD and PD are illustrated in FIGS. 1, 4, 7 and 10,
respectively. FIGS. 1, 4, 7 and 10 were created by the fusion of
two separate image data sets, one from a PET scan of an .sup.18F
amyloid plaque-binding radiopharmaceutical (.sup.18F-AV-45) and one
from a PET scan of an .sup.18F VMAT2 targeted radiopharmaceutical
(.sup.18F-AV-133). FIG. 1 is a simulated image of the brain of a
healthy individual with no observable amyloid plaques and normal
dopaminergic neurons (imaged between 70 and 80 minutes). As can be
seen, the fused image shows no appreciable cortical brain signal
from .sup.18F-AV-45, which is indicative of the lack of amyloid
plaque deposits. In addition, FIG. 1 shows a strong signal in the
nigrostriatal region from the VMAT2 imaging compound
.sup.18F-AV-133, which is typical for someone without signs or
symptoms of PD or DLB. FIG. 4 shows a simulated image of the brain
of an individual with clinical signs of AD. Amyloid plaque deposits
are visible in the frontal region of the brain (orange) (imaged
between 70 and 80 minutes) from the .sup.18F-AV-45
radiopharmaceutical signal. This figure also shows a normal uptake
of the .sup.18F-AV-133 radiopharmaceutical in the nigrostriatal
region of the brain. This image pattern is consistent with a pure
AD diagnosis, with no evidence of loss of striatal neurons (which
would be observed if PD or DLB were also present). FIG. 7 is a
simulated image of the brain of an individual exhibiting the
symptoms of PD. As shown in FIG. 7, lack of intensity in the
striatal regions of the .sup.18F-AV-133 radiopharmaceutical is
indicative of dopaminergic degeneration and is visible (imaged
between 70 and 80 minutes). In addition, this image does not show
evidence of amyloid signal in the cortical brain regions from
.sup.18F-AV-45. This image pattern is consistent with a pure PD
diagnosis, without evidence of AD amyloid plaque pathology. FIG. 10
shows a simulated fused image of the brain of an individual with
both AD and PD. Amyloid plaques (green) (from .sup.18F-AV-45
retention in cortical brain) and lack of intensity in the striatal
regions (due to diminished uptake of AV-133 from losses of strial
neurons in PD) are both visible (imaged between 70 and 80
minutes).
[0072] The Statistical Parametric Mapping (SPM2) application in
MATLAB.RTM. (Version 7.3 R2006b, MathWorks, Inc.) was used to align
the raw images and create a mean image from the image set. The mean
image was normalized to a SPECT template, although in other
experiments, other templates were used. Using the image viewer
application in MRICro, the normalized mean image was compared with
the template image to confirm that the two images align. Using
SPM2, the realigned images from an image set were normalized to the
normalized mean image for that set. In MATLAB.RTM., volume of
interest (VOI) images were overlaid on the normalized images, and
the radioactive counts per voxel per minute for specific brain
regions were extracted into a Microsoft Office Excel spreadsheet.
(voxel size was 8 mm.sup.3). Specific brain regions included left
and right caudate, left and right anterior putamen, left and right
posterior putamen, precuneus, posterior cingulate, cerebellum
(grey), frontal lobe, occipital lobe, parietal lobe and temporal
lobe. Standardized uptake values (SUVs) were calculated from the
counts extracted from the images. The dose administered to each
subject was then normalized to 10, and the resulting number was
multiplied with the counts for each brain region. New SUVs were in
turn recalculated from the new values. The SUVs from four subjects
in each category were averaged together, and four separate disease
state possibilities were identified: (1) AD_AV45 & HC_AV133,
(2) PD_AV133 & HC_AV45, (3) AD_AV45 & PD_AV133, and (4)
HC_AV45 & HC_AV133.
[0073] For each case shown in FIGS. 1, 4, 7 and 10, the SUVs from
the frontal, precuneus and cerebellum regions (cortical regions)
for the subjects were plotted simultaneously with time and separate
plots were created for the SUVs from the striatal regions (i.e.,
left and right posterior putamen and cerebellum) of the subjects
simultaneously with time, as illustrated in FIGS. 2, 3, 5, 6, 8, 9,
11 and 12. The cortical regions are where amyloid plaques are found
in the brain using the .sup.18F-AV-45 radiopharmaceutical, while
the striatal regions contain dopaminergic neurons detected with the
.sup.18F-AV-133 radiopharmaceutical. In particular, FIG. 2 shows
simulated activity curves for cortical regions of the brain of a
healthy individual and FIG. 3 shows simulated activity curves for
striatal regions of the brain of the healthy individual. FIGS. 5
and 6 show simulated activity curves for cortical and striatal
regions of the brain, respectively, for an individual with AD.
FIGS. 8 and 9 show simulated activity curves for cortical and
striatal regions of the brain, respectively, of an individual with
PD while FIGS. 11 and 12 show simulated activity curves for
cortical and striatal regions of the brain, respectively, of an
individual with AD and PD. These plots demonstrated the
pharmacokinetics of each administered radiopharmaceutical, and such
information was utilized in considering dissimilar injection times,
and dose normalization. Whenever the two radiopharmaceuticals were
considered as being simultaneously present in the brain, the SUVs
from both radiopharmaceuticals for each region were summed
together, and the summed SUVs were plotted. This allowed for the
simulation/prediction of the interaction and possible interference
of activity of one radiopharmaceutical with the other when both are
present in the brain during the imaging of the subject.
[0074] Images from these subjects were further analyzed. The
calculations performed on the radioactive counts (i.e., dose
normalization, summation of activity) were also performed on the
images, producing a prospective image for the visual inspection by
physicians or other medical professionals.
[0075] Through analyzing and experimenting with the plots and
images described above, a protocol for the simultaneous imaging of
AD plaques and dopaminergic neuronal degeneration was created. This
protocol included the following: administering 10 mCi of
.sup.18F-AV-45 to a subject; waiting a period of 30 minutes; 10
minute imaging acquisition period to detect the presence or absence
of amyloid plaques in the cortical regions of the brain; then
administering 10 mCi of .sup.18F-AV-133 to the same subject (about
50 minutes after the start of protocol); waiting a period of 30
minutes; 10 minute imaging acquisition period to detect the
presence or absence of dopaminergic neuronal degeneration in the
striatal regions of the brain (.sup.18F-AV-45 washout and
radioactive decay is essentially complete at this point, thus
minimally interfering with .sup.18F-AV-133 activity). The total
protocol time was about 80 to 90 minutes. When analyzing the images
gleaned from the two imaging acquisition periods, the image
intensity was visually normalized to the cerebellum to enable a
clear and easy diagnosis of the presence or absence of AD, PD or
DLB.
[0076] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
* * * * *