METHODS AND TOOLS FOR DETECTING, DIAGNOSING, PREDICTING, PROGNOSTICATING, OR TREATING A NEUROBEHAVIORAL PHENOTYPE IN A SUBJECT
The present tools and methods for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject. These tools and methods relates to a genotype and neurophenotype topography-based approach for analyzing brain neuroimaging and gene expression maps to identify drug targets associated with neurobehavioral phenotypes and, conversely, neurobehavioral phenotypes associated with potential drug targets, to develop rational design and application of pharmacological therapeutics for brain disorders, and to provide methods and tools for treatment of subjects in need of neurological therapy.
1 . A method of detecting a neurobehavioral phenotype in a subject, said method comprising:
a. obtaining or having obtained a sample of neurobehavioral phenotype mapping data from the subject;
b. defining a genotype topography of a first brain area for a gene based on gene expression mapping data;
c. defining a neurophenotype topography of a second brain area for the neurobehavioral phenotype based on neurobehavioral phenotype mapping data;
d. contacting the genotype topography of the first brain area and the neurophenotype topography of the second brain area to establish an alignment;
e. detecting whether the neurobehavioral phenotype is present in the sample by contacting the sample with the aligned genotype topography and neurophenotype topography.
2 . The method of claim 1 , wherein the neurobehavioral phenotype is at least one of: an affective disorder, a personality disorder, an attention deficit hyperactivity disorder, a neurodegenerative disease, a neurodevelopmental disorder, a cognitive change associated with chemotherapy; a psychiatric symptom associated with neurodegenerative diseases, a sex difference in brain function in health and disease, a traumatic brain injury, and a measurable neural feature.
3 . A method of diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, said method comprising:
a. obtaining or having obtained a sample of neurobehavioral phenotype mapping data from the subject;
b. defining a genotype topography of a first brain area for a gene based on gene expression mapping data;
c. defining a neurophenotype topography of a second brain area for the neurobehavioral phenotype based on neurobehavioral phenotype mapping data;
d. contacting the genotype topography of the first brain area and the neurophenotype topography of the second brain area to establish an alignment;
e. detecting whether the neurobehavioral phenotype is present in the sample by contacting the sample with the aligned genotype topography and neurophenotype topography; and
f. diagnosing, predicting, prognosticating, or treating the subject when the neurobehavioral phenotype is detected.
4 . The method of claim 3 , further comprising administering a therapeutic agent to the subject.
5 . The method of claim 4 , further comprising identifying one or more therapeutic agents suitable for treatment of the detected neurobehavioral phenotype.
6 . The method of claim 5 , wherein the one or more therapeutic agents are selected based on a gene associated with the detected neurobehavioral phenotype.
7 . The method of claim 6 , wherein the gene is one of more of PDYN, OXTR, OPRK1, PNOC, OXT, AVP, OPRL1, APOE, GRIN2C, GABRA2, HTR2A, HTR3A, HRTR2C, HTR6, MAOA, CHRM1, CHRM3, CCR5, CXCR4, CXCR7, HRH3, ADRB2, DRD2, SNCA, GBA, GPR88, GPR139, and LRRK2.
8 . The method of claim 5 , further comprising identifying gene expression targets associated with the detected neurobehavioral phenotype.
9 . The method of claim 5 , further comprising combining one or more therapeutic agents indicated to be suitable for treatment of the detected neurobehavioral phenotype.
10 . The method of claim 5 , further comprising dosing of one or more therapeutic agents in amounts indicated to be effective for treatment of the detected neurobehavioral phenotype.
11 . The method of claim 5 , further comprising selecting a therapeutic agent indicated to be most suitable for treatment of the detected neurobehavioral phenotype.
12 . The method of claim 5 , further comprising not administering one or more therapeutic agents to the subject indicated to not be suitable for treatment of the detected neurobehavioral phenotype.
13 . The method of claim 12 , wherein the one or more therapeutic agents is shown to have activity in a brain area outside the alignment of the first brain area and the second brain area.
14 . The method of claim 4 , wherein the one or more of steps of claim 3 are repeated after the subject has been diagnosed, prognosticated to be at risk for, or treated for the detected neurobehavioral phenotype.
15 . The method of claim 14 , further comprising altering a therapeutic regimen for the subject based on changes in the detected neurobehavioral phenotype.
16 . The method of claim 3 , further comprising selecting the subject for inclusion in a clinical study.
17 . The method of claim 16 , further comprising forming a patient population suitable for inclusion in the clinical study.
18 . The method of claim 3 , wherein the neurobehavioral phenotype is one of:
a. an affective disorder such as obsessive compulsive disorder, bipolar disorder, unipolar depression, dysthymia and cyclothymia, generalized anxiety disorder, panic disorder, phobias, and post-traumatic stress disorder;
b. a personality disorder such as schizophrenia, paranoid personality disorder; schizoid personality disorder; schizotypal personality disorder; antisocial personality disorder; borderline personality disorder; histrionic personality disorder; narcissistic personality disorder; avoidant (or anxious) personality disorder; dependent personality disorder; and obsessive compulsive personality disorder;
c. an attention deficit hyperactivity disorder such as inattentive type, hyperactive-impulsive type, and combination type;
d. a neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease; amyotrophic lateral sclerosis; Friedreich's ataxia; Huntington's disease; Lewy body disease; and spinal muscular atrophy;
e. a neurodevelopmental disorders such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD) and learning disorders; cognitive changes associated with chemotherapy;
f. a psychiatric symptom associated with neurodegenerative diseases such as feeling sad or down, confused thinking or reduced ability to concentrate, excessive fears or worries, or extreme feelings of guilt, extreme mood changes of highs and lows, withdrawal from friends and activities, significant tiredness, low energy or problems sleeping, detachment from reality (delusions), paranoia or hallucinations, inability to cope with daily problems or stress, trouble understanding and relating to situations and to people, alcohol or drug abuse, major changes in eating habits, sex drive changes, excessive anger, hostility or violence, and suicidal thinking;
g. a sex differences in brain function in health and disease;
h. a traumatic brain injury; and
i. any measurable neural feature.
19 . The method of claim 3 , wherein the subject does not undergo invasive pharmacoimaging.
20 . A method for treating a subject with a neurobehavioral phenotype, the method comprising the steps of:
determining whether the subject has neurobehavioral phenotype mapping data indicative of the neurobehavioral phenotype by:
obtaining or having obtained a sample of neurobehavioral phenotype mapping data from the subject;
defining a genotype topography of a first brain area for a gene based on gene expression mapping data;
defining a neurophenotype topography of a second brain area for the neurobehavioral phenotype based on neurobehavioral phenotype mapping data;
contacting the genotype topography of the first brain area and the neurophenotype topography of the second brain area to establish an alignment;
performing or having performed a comparison of the sample with the aligned genotype topography and neurophenotype topography to determine if the subject has the neurobehavioral phenotype; and
if the subject has the neurobehavioral phenotype as determined by comparison of the sample with the aligned genotype topography and neurophenotype topography, then administering a therapeutic agent targeted to one or more genes associated with the aligned genotype topography and neurophenotype topography, or
if the subject has the neurobehavioral phenotype as determined by comparison of the sample with the aligned genotype topography and neurophenotype topography, then administering a therapeutic agent targeted to one or more neurobehavioral phenotypes associated with the aligned genotype topography and neurophenotype topography.
21 . The method of claim 20 , further comprising increasing the likelihood that the treatment for the subject will be effective for treatment of the neurobehavioral phenotype.
22 . A method of detecting a neurobehavioral phenotype in subjects of a patient population, said method comprising:
a. obtaining or having obtained a sample of neurobehavioral phenotype mapping data from each subject in the patient population;
b. defining a neurophenotype topography of a second brain area for the neurobehavioral phenotype based on neurobehavioral phenotype mapping data;
c. contacting the genotype topography of the first brain area and the neurophenotype topography of the second brain area to establish an alignment;
d. detecting whether the neurobehavioral phenotype is present in the sample by contacting the sample with the aligned genotype topography and neurophenotype topography.