Predictive neurodiagnostic methods

Abstract

Disclosed are methods of predicting the risk of developing a neurological disorder in a mammalian subject and methods of use of this profile for providing neuroanalytical services for an end user. Also disclosed is a system comprising a processor and a memory having a neurodiagnostic algorithm and plurality of data sets, the processor being capable of reading the data sets, executing the neurodiagnostic algorithm, and deriving a risk profile therefrom.

1 . A method of predicting the risk of developing a neurological disorder in a first mammalian subject, comprising the steps of:
 screening for the presence of one or more biomarkers;   performing diagnostic imaging of the subject;   performing behavioral tests indicative of the neurological disorder;   measuring the subject's exposure to an environmental factor;   measuring/identifying a physical characteristic of the subject;   determining the presence of the neurological disorder in a family member of the first subject;   combining the results from the steps above; and   comparing the combined results with combined results obtained from a second mammalian subject diagnosed with the neurological disorder,   a high correlation between the combined results from the second subject and the combined results obtained from the first subject being indicative of a heightened risk of the first subject developing the neurological disorder.   
     
     
         2 . The method of  claim 1 , wherein the screening step comprises screening for a biomarker which is a nucleic acid, polypeptide, prion, virus, brain plaque, CNS plaque, fibril, intranuclear neuronal inclusions, and/or brain structure abnormality. 
     
     
         3 . The method of  claim 2 , wherein the nucleic acid is a gene or coding portion thereof, SNP, mRNA, miRNA, pri-miRNA, or prepri-miRNA. 
     
     
         4 . The method of  claim 3 , wherein the nucleic acid is over-expressed miR-196a, miR-29a, or miR-330. 
     
     
         5 . The method of  claim 3 , wherein the nucleic acid is under-expressed miR-133b, miR-205, miR-34b/c, miR-9, miR-9*, or miR-132. 
     
     
         6 . . The method of  claim 3 , wherein the nucleic acid is a mutation in the Cu/Zn superoxide dismutase 1 (SOD1) gene, an unstable microsatellite repeat (insertion mutation) in a gene, HTT gene, androgen receptor on the X chromosome, ATXN1, ATXN2, ATXN3, ATXN7, TBP, CACNA1A, mutation in C9orf72 (on chromosome 9), FMR1 (on the X-chromosome), AFF2 (on the X-chromosome), FMR2 (on the X-chromosome), FXN or X25, (frataxin—reduced expression), DMPK, OSCA or SCA8, PPP2R2B or SCA12, α-synuclein, leucine-rich repeat kinase 2 (LRRK-2), glucocerebrosidase (GBA), ABHD12, SNCA, or LRRK2. 
     
     
         7 . The method of  claim 2 , wherein the polypeptide is a surface marker, tau protein, beta amyloid, polyglutamate (peptide), alpha-synuclein, non-Abeta component (NAC), polyQ expansion, TDP-43 protein aggregate, FUS protein aggregate, or mutant Huntingtin aggregate. 
     
     
         8 . The method of  claim 2 , wherein the biomarker is a Lewy body fibril, neurofibrillary tangle, or alpha-synuclein fibril. 
     
     
         9 . The method of  claim 2 , wherein the biomarker is an amyloid plaque or a senile plaque. 
     
     
         10 . The method of  claim 2 , wherein the biomarker is Herpes simplex virus-1(HSV-1 type HHV-1), roseolovirus (type HHV-6), Epstein Barr virus (EBV type HHV-4), Varicella zoster virus (VZV type HHV3), H1N1 Influenza a viruses, HIV, and/or HTLV-II . 
     
     
         11 . The method of  claim 1 , wherein the screening step is performed by obtaining a sample of a body fluid or tissue and screening for the biomarker in the sample. 
     
     
         12 . The method of  claim 11 , wherein the body fluid is blood, cerebral spinal fluid, serum, lymph, saliva, lacrimal secretion, sweat, mucous, vaginal secretion, lymph, urine, or seminal fluid. 
     
     
         13 . The method of  claim 1 , wherein the diagnostic imaging performed is an x-ray, a computerized axial tomographic (CAT) scan, magnetic resonance imaging (MRI) scan, functional MRI (fMRI), single photon emission computed tomography (SPECT) perfusion image, computed tomography (CT) scan, proton MR spectroscopy scan, positron emission tomographic (PET) scan, and/or [F-18] fluoro-2-deoxy-D-glucose-positron emission tomographic (18F-FDG PET) scan, DaTSCAN, and/or ultrasound. 
     
     
         14 . The method of  claim 1 , wherein the behavioral test performed measures sensory abilities, motor functions, body weight, body temperature, and/or pain threshold, learning abilities, memory, and symptoms of anxiety, depression, schizophrenia, and/or drug addiction. 
     
     
         15 . The method of  claim 14 , wherein the behavioral test performed measures acoustic startle, eye blink, pupil constriction, visual cliff, auditory threshold, and/or olfactory acuity. 
     
     
         16 . The method of  claim 1 , wherein the subject's exposure to pesticides, herbicides, fungicides, solvents, other toxic chemicals, tobacco smoke, heavy metals, electromagnetic fields, ultraviolet radiation, and/or diet (malnutrition, vitamin deficiency), and/or alcohol consumption is measured. 
     
     
         17 . The method of  claim 16 , wherein the subject's exposure to iMPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), rotenone, paraquat, maneb, Agent orange, manganese, lead, iron, methylmercury, copper, zinc, selenium, polychlorinated biphenyls, and/or a reactive oxygen species (ROS) is measured. 
     
     
         18 . The method of  claim 1 , wherein exposure of the subject to the environmental factor causes apoptosis, oxidative stress, perturbed calcium homeostasis (loss of intracellular Ca +2 ), excitotoxicity, mitochondrial dysfunction, and/or activation of caspases. 
     
     
         19 . The method of  claim 1 , wherein the physical factor measured is age, gender, ethnicity, heart rate, REM, cardioelectrical signals, and/or the presence of genetic polymorphisms, endocrine conditions, oxidative stress, inflammation, stroke, traumatic brain injury, hypertension, diabetes, head/CNS trauma, depression, infection, cancer, vitamin deficiency, and/or immune and/or metabolic conditions. 
     
     
         20 . The method of  claim 1 , wherein the neurological disorder is a neurodegenerative disorder, a neurotrauma disorder, and/or a neuropsychological disorder. 
     
     
         21 . The method of  claim 20 , wherein the neurodegenerative disorder is a polyglutamine (PolyQ) disease, non-polyglutamine disease, Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, trinucleotide repeat disorder, dementia, multiple system atrophy, HIV-associated neurocognitive disorders (HAND), or polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC), Parkinson's disease, essential tremor, cerebellar tremor, dystonic tremor, orthostatic tremor, Parkinsonian tremor, rubral tremor, or psychogenic tremor. 
     
     
         22 . The method of  claim 21 , wherein the polyglutamine disease is Spinocerebellar ataxia type 1 (SCA1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA17 (Spinocerebellar ataxia Type 17), DRPLA (Dentatorubropallidoluysian atrophy), HD (Huntington's disease), SBMA (Spinobulbar muscular atrophy or Kennedy disease), dentatorubral atrophy, or pallidoluysian atrophy. 
     
     
         23 . The method of  claim 20 , wherein the neurodegenerative disorder is a non-polyglutamine disease. 
     
     
         24 . The method of  claim 23 , wherein the non-polyglutamine disease is FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor/ataxia syndrome), FRAXE (Fragile XE mental retardation), FRDA (Friedreich's ataxia), DM (Myotonic dystrophy), SCA8 (Spinocerebellar ataxia Type 8), or SCA12 (Spinocerebellar ataxia Type 12. 
     
     
         25 . The method of  claim 20 , wherein the neurotrauma disorder results from a traumatic brain injury, concussion, or stroke. 
     
     
         26 . The method of  claim 1 , wherein the subject is asymptomatic. 
     
     
         27 . The method of  claim 1 , wherein the combination steps comprise generating a risk score, and wherein if the risk score of the first subject is similar to the risk score of the second subject, the first subject has a heightened risk of developing the neurological disorder. 
     
     
         28 . The method of  claim 1 , further comprising developing and implementing a treatment plan to the first subject, the treatment plan comprising administering a therapeutically effective composition to the first subject. 
     
     
         29 . A system comprising: a processor and a memory, the memory having a neurodiagnostic algorithm and a plurality of data sets, the data sets including:
 a) biomarker screening data;   b) diagnostic imaging data;   c) behavioral test data;   d) exposure to environmental risk factors;   e) subject health data; and   f) family medical history data,   
       the processor being capable of reading the data sets, executing the neurodiagnostic algorithm, and deriving a risk score or profile therefrom. 
     
     
         30 . The system of  claim 29 , further comprising a display means for visualizing the risk score or profile. 
     
     
         31 . The system of  claim 29 , wherein the system memory is at locations distant from the processor. 
     
     
         32 . A data subscription service accessing the data sets of  claim 29 , wherein the neurodiagnostic algorithm predicts treatment outcomes from the risk profile. 
     
     
         33 . The system of  claim 29 , wherein the subject health data is obtained from an individual asymptomatic for neurological disorders. 
     
     
         34 . A relational database comprising a plurality of subject-independent neurodiagnostic data sets comprising:
 a) biomarker screening data;   b) diagnostic imaging data;   c) behavioral test data;   d) environmental risk factor data,   
       the one or more subject-dependent neurodiagnostic data sets further including subject medical history and subject family medical histories. 
     
     
         35 . A data subscription service accessing the database of  claim 34 . 
     
     
         36 . A method of providing neuroanalytical services, comprising:
 generating a patient profile for neurological risk, comprising analyzing subject-independent neuroanalytical data sets and subject-dependent neuroanalytical data sets; and   delivering the patient risk profile to an end user.   
     
     
         37 . The method of  claim 36 , wherein subject-independent neuroanalytical data sets include third-party data of neurological disease-relevant biomarkers, neural imaging data, environmental risk factors for neurological disorders; and wherein subject-dependent neuroanalytical data sets include subject and family medical environmental and behavioral data medical history data. 
     
     
         38 . The method of  claim 36 , wherein the patient risk profile comprises an aggregated risk of individual risk factors delineated or calculated from the subject-independent neuroanalytical data sets and subject-dependent neuroanalytical data sets. 
     
     
         39 . The method of  claim 38 , wherein an algorithm is biased to value risk higher from the subject-dependent neuroanalytical data as compared to subject-independent neuroanalytical data. 
     
     
         40 . The method of  claims 36 - 39 , wherein the risk profile is delivered to an end user using SaaS, PaaS, or laaS-based service models. 
     
     
         41 . The method of  claim 40 , wherein Private and Public Cloud architecture is employed. 
     
     
         42 . The method of  claim 41 , wherein the end user obtains the risk profile on a tablet, smartphone, or portable computing device. 
     
     
         43 . The method of  claim 42 , wherein the delivery is real-time or near real-time.