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(2) Patent Application Publication (10) Pub. No.: US 2013/0237454 A1 Schutzer (43) Pub US 20130237454A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2013/0237454 A1 Schutzer (43) Pub. Date: Sep. 12, 2013 (54) DIAGNOSTIC MARKERS FOR Publication Classification NEUROPSYCHIATRIC DISEASE (51) Int. Cl. (76) Inventor: Steven E. Schutzer, Water Mill, NY G0IN 33/68 (2006.01) (US) (52) U.S. CI. CPC .................................. G0IN33/6896 (2013.01) (21) Appl. No.: 13/697,417 USPC ..…. 506/12 (22) PCT Filed: May 12, 2011 (57) ABSTRACT Biomarkers for the diagnosis of neuropsychiatric diseases are (86) PCT No.: PCT/US11/00843 presented herein. In particular embodiments, biomarkers are § 371 (c)(1), identified that are useful for diagnosing multiple sclerosis, (2), (4) Date: May 23, 2013 chronic fatigue syndrome, or Neurologic Lyme disease. Also encompassed is a method for diagnosing a patient with a Related U.S. Application Data neuropsychiatric disease, such as multiple sclerosis, chronic e K_f e fatigue syndrome, or Neurologic Lyme disease, by analyzing (60) Provisional application No. 61/395,354, filed on May biological samples isolated from the patient or the patient as 12, 2010. a whole to assess levels of the biomarkers described herein. 1895 72% 63 735 8% 92% ; Patent Application Publication Sep. 12, 2013 US 2013/0237454 A1 Figure l US 2013/0237454 A1 Sep. 12, 2013 DLAGNOSTIC MARKERS FOR tiple sclerosis is more common in women than men and NEUROPSYCHIATRIC DISEASE generally begins between ages 20 and 40, but can develop at any age. Multiple sclerosis is generally viewed as an autoim FIELD OF THE INVENTION mune syndrome directed against unidentified central nervous [0001] The present invention relates to identifying biologic tissue antigens. The determination of susceptibility to mul markers (biomarkers) that can be used for diagnosis of a tiple sclerosis development is complex and appears to be neuropsychiatric disease. As described herein, neuropsychi governed by both environmental and genetic factors. Some of atric disease may be used to refer to diseases having neuro the symptoms of multiple sclerosis are caused by damage to logic or psychiatric or combined neurologic and psychiatric the myelin sheath, the protective covering that surrounds features. Such neuropsychiatric diseases include, without nerve cells. When this nerve covering is damaged, nerve limitation, multiple sclerosis, chronic fatigue syndrome, and impulses are slowed down or stopped. Ultimately, damage to Neurologic Lyme disease. In particular embodiments, the the myelin sheath results in nerve damage. Multiple sclerosis present invention relates to identifying biomarkers for diag is, moreover, commonly a progressive disease that leads to nosis of multiple sclerosis, chronic fatigue syndrome (CFS: more severe neurologic dysfunction overtime. Nerve damage also referred to hereinas CF), or Neurologic Lyme disease. In may be caused by inflammation that occurs when the body’s a more particular aspect, the invention pertains to the identi immune cells attack the nervous system. Repeated episodes fication of a biomarker signature that is diagnostic for each of of inflammation can occur along any area of the brain and multiple sclerosis, chronic fatigue syndrome, Neurologic spinal cord, which is why the disease is often referred to as Lyme disease. Accordingly, the invention further relates to a one characterized by symptoms and signs over time and method for diagnosing a person or other mammal with a space. neuropsychiatric disease, such as multiple sclerosis, or at risk [0004] Multiple sclerosis is difficult to diagnose because of developing same. The biomarkers and diagnostic signa the progress, severity and specific symptoms of multiple scle tures described herein also identify metabolic/biochemical rosis are quite variable and unpredictable. There are no labo pathways as potential candidates for therapeutic targeting. ratory tests, symptoms or physical findings that can singly The invention further relates to guidance pertaining to appro determine if a person has multiple sclerosis. The differential priate treatment of the person or mammal diagnosed with a diagnosis of multiple sclerosis is quite varied and includes particular neuropsychiatric disease in accordance the meth metabolic, genetic, oncologic, immunologic, and infectious ods described herein. Accurate diagnosis of neuropsychiatric disease assessment. Other diseases that may need to be con disease, particularly with respect to diseases that are difficult sidered in the differential diagnoses, but should be considered to distinguish clinically, should reduce the duration and/or depending on the clinical presentation, include: Acute dis severity of the disease by ensuring that the patient is treated seminated encephalomyelitis, CNS vasculitis, Behçet dis using an appropriate therapeutic regimen. ease, Sjögren syndrome, Sarcoid, neoplasms, CADASIL (ce rebral autosomal dominant arteriopathy with subcortical BACKGROUND OF THE INVENTION infarcts and leukoencephalopathy), Migrainous ischemia, [0002] Knowledge of the entire protein content, the pro Cerebrovascular disease, Progressive multifocal leukoen teome, of normal human cerebrospinal fluid (CSF) would cephalopathy, Inherited white matter diseases, effects of provide a critical standard to allow meaningful comparisons radiation therapy or drugs, CNS lymphoma, Lyme disease, with and between neurologic and psychiatric disorders. CSF HTLV-1 infection, CNS lupus, Mitochondrial encephalopa contains both cellular and soluble components providing thies, Antiphospholipid antibody syndrome, cerebral emboli, insights into processes occurring in the central nervous sys Thrombocytopenic purpura, Progressive multifocal leukoen tem (CNS). As much as 30 to 40% of CSF is formed by the cephalopathy, Mycoplasma encephalopathy, Vitamin B12 extracellular fluid of the brain and spinal cord. CSF contains deficiency, Paraneoplastic syndromes, Psychiatric syn both normal and disease specific components, and provides dromes (Rolak LA, Fleming J O. The Neurologist 2007; 13: an accessible liquid window into the brain. In fact, recent data 57-72). Over the last twenty years, tests such as magnetic suggest CSF may provide more relevant evidence for initial or resonance imaging (MRI), examination of CSF, and evoked propagating pathology than the brain parenchyma itself in response testing have played an increasingly important role in certain neuropsychiatric diseases [Ransohoff (2009) Nature the diagnostic process. In 2005, revised McDonald criteria for 457: 155-156]. Comprehensive characterization of the nor multiple sclerosis were published (Polman et al. Diagnostic mal CSF proteome, furthermore, facilitates identification of Criteria for Multiple Sclerosis: 2005 Revisions to the disease-specific markers [Ekegren et al. (2008) J Mass Spec “McDonald” Criteria. Ann Neurol. (2005) 58:840–846 and trom 43:559–571]. Knowledge of which proteins are present, Polman et al. Ann Neurol (2011) 69:292-302). In addition to absent, or of changed concentrations may lead to diagnostic, the traditional diagnostic tools, the revised criteria provide prognostic, or disease-activity biomarkers as well as provide specific guidelines for using findings of MRI, cerebrospinal insights into disease etiology and pathogenesis. An advantage fluid analysis and visual evoked potentials to support a diag of a full proteome analysis is the ability to identify not just one nosis of multiple sclerosis. However, even with these revised but a multitude of proteins at a single instance. criteria, diagnosis of multiple sclerosis is still challenging and [0003] Multiple sclerosis, for example, is an excellent can frequently takes several months or even years. didate disease for such an approach because it is often a [0005] Rendering a conclusive diagnosis of multiple scle progressive debilitating disease that is difficult to diagnose rosis on an expedited basis would be of great benefit to definitively, especially during the early stages of the disease. patients in light of the potential for recurrence of attacks and Multiple sclerosis is a common demyelinating disease of the progression of the disease. Drugs for the treatment of multiple central nervous system (CNS) that affects up to 0.1% of the sclerosis are now available which slow or prevent progression Caucasian population of northern European descent. Mul of the disease in many patients, and an early diagnosis would, US 2013/0237454 A1 Sep. 12, 2013 therefore, allow early intervention and could significantly tification of at least one of the biomarkers in the biological improve the quality of life for many multiple sclerosis sample indicates a positive diagnosis or is indicative of mul patients. tiple sclerosis in the patient. In an embodiment thereof, the at [0006] It is therefore an object of the present invention to least one biomarker identified in the biological sample is provide an efficient diagnosis system for neuropsychiatric present in the biological sample and set forth in Table 1m, 3m, disease in general, a particular example of which is multiple or 4H-m, and the presence of the at least one biomarker sclerosis, so as to provide biomarkers with which a clinician indicates a positive diagnosis or is indicative of multiple can diagnose or exclude a particular disease in a patient or sclerosis. In another embodiment, the at least one biomarker other mammal. The same reasoning applies to Neurologic identified in the biological sample is absent from the biologi Lyme Disease and Chronic Fatigue syndrome. cal
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