US 2010.0041621A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0041621 A1 Renshaw et al. (43) Pub. Date: Feb. 18, 2010 (54) METHODS AND COMPOSITIONS FOR Related U.S. Application Data IMPROVING COGNITIVE PERFORMANCE (60) Provisional application No. 61/089.331, filed on Aug. 15, 2008. (76) Inventors: Perry Renshaw, Salt Lake City, UT (US); Deborah Yurgelun-Todd, Publication Classification Salt Lake City, UT (US) (51) Int. Cl. A63L/7068 (2006.01) Correspondence Address: A 6LX 3L/7072 (2006.01) CLARK & ELBNG LLP 101 FEDERAL STREET (52) U.S. Cl. ............................................. 514/51; 514/49 BOSTON, MA 02110 (US) (57) ABSTRACT The invention provides methods and compositions for (21) Appl. No.: 12/541.504 improving cognitive performance involving administration of a cytidine-containing or uridine-containing compound to a (22) Filed: Aug. 14, 2009 neuropsychologically healthy human. Patent Application Publication Feb. 18, 2010 Sheet 1 of 3 US 2010/0041621 A1 Figure 1. 8 Week Follow-Up Patent Application Publication Feb. 18, 2010 Sheet 2 of 3 US 2010/0041621 A1 Figure 2. Patent Application Publication Feb. 18, 2010 Sheet 3 of 3 US 2010/0041621 A1 ACC Spectrum Figure 3, PCr 5 O 5 - O - 15 Chemical Shift (ppm) Parieto-Occipital Spectrum PCir PME y-NTP a-NTP B-NTP 5 O 5 O 15 Chemical Shift (ppm) US 2010/0041621 A1 Feb. 18, 2010 METHODS AND COMPOSITIONS FOR 0010. In certain embodiments, the human does not have a IMPROVING COGNITIVE PERFORMANCE neurological, psychiatric, or cognitive disorder, including, e.g., mood disorders (e.g., unipolar depression, dysthymia, CROSS-REFERENCE TO RELATED cyclothymia, and bipolar disorder), attention-deficit hyperac APPLICATIONS tivity disorder (ADHD), anxiety disorders (e.g., panic disor 0001. This application claims benefit of U.S. Provisional der and generalized anxiety disorder), obsessive-compulsive Application No. 61/089,331, filed Aug. 15, 2008, which is disorder (OCD), post-traumatic stress disorder (PTSD), pho hereby incorporated by reference. bias, and psychotic disorders (e.g., Schizophrenia and Schizoaffective disorder); does not have a sleep disorder, e.g., insomnia, constructive or obstructive sleep apnea, restless leg BACKGROUND OF THE INVENTION syndrome, periodic limb movements, problem sleepiness, 0002. The invention relates to the fields of brain health and and narcolepsy; has a normal sleep-wake cycle; has not had a cognitive function. stroke or other traumatic injury to the brain; is not using, 0003 Cognition encompasses the high level intellectual abusing, withdrawing from, or dependent on a controlled functions carried out by the brain, including comprehension, Substance, e.g., alcohol, stimulants (e.g., amphetamines, speech, visual perception, calculation, attention, memory, methamphetamine, methylphenidate, and cocaine), mari problem-solving, and self-monitoring. The frontal brain huana, and opiate or opioid drugs; does not use or is not serves important executive functions in cognition, e.g., the dependent on tobacco or nicotine; or does not suffer from ability to Suppress unacceptable social responses. Within the cardiovascular disease, cancer, dysmenorrhea, infertility, frontal brain, the anteriorcingulate cortex (ACC) is thought to preeclampsia, postpartum depression, menopausal discom encode working memory, detect/evaluate errors, and direct fort, osteoporosis, thrombosis, inflammation, hyperlipi attention appropriately. Patients with neuropsychological demia, hypertension, rheumatoid arthritis, hyperglyceri diseases affecting the frontal brain are disadvantaged in edu demia, or gestational diabetes. cational, occupational, and Social situations. 0011. In other embodiments, the human is less than 30, 40, 0004 Several treatments exist for impaired cognitive 50, or 60 years old. function associated with pathological conditions and aging. 0012. By “neuropsychologically healthy human' is meant However, because cognitive performance fundamentally lim a person who does not have and has not been diagnosed with its achievement throughout life, it would be desirable for a neurological, cognitive, psychiatric, or sleep disorder, e.g., neuropsychologically health persons to improve cognitive one listed herein; who is not suffering from sleep deprivation, performance. disrupted sleep-wake cycles, head trauma, cerebral vasocon striction sequelae, stroke, or otherischemic event in the brain; SUMMARY OF THE INVENTION who does not have age-related dementia or cognitive decline; 0005. In one aspect, the invention features a method of who is not using, abusing, withdrawing from, or dependent on improving cognitive performance by administering a cyti a controlled Substance, e.g., alcohol, stimulants including dine-containing or uridine-containing compound to a neurop amphetamines, methamphetamine, methylphenidate, and sychologically healthy human. cocaine, marihuana, and opiate or opioid drugs; and who is 0006. In preferred embodiments, the improved cognitive not using or dependent on tobacco or nicotine. performance is increased attention or attentional control, 0013 By “improving cognitive performance' is meant accuracy under time pressure, working memory, or learning increasing in speed, accuracy, or effectiveness the perfor aptitude; the compound administered is CDP-choline, uri mance of a cognitive function. By “cognitive function' is dine, or triacetyluridine; the cytidine-containing or uridine meant mental processes involving manipulation of informa containing compound is provided in a nutraceutical compo tion and sensory input. sition, e.g., a drink or tablet, optionally containing one or 0014. By “increased' is meant detectably higher in ability more of vitamin B6, vitamin B12, niacin, folic acid, tyrosine, or capacity, as may be perceived by the human or evidenced phenylalanine, taurine, malic acid, glucuronolactone, and by, e.g., a neuropsychological test. The increase may be, e.g., caffeine; and the cytidine-containing or uridine-containing a 2%. 5%, 10%, or 50% increase in cognitive performance of compound is administered orally. a human relative to the cognitive performance of the human 0007. In another embodiment, the cytidine-containing or prior to treatment with the cytidine-containing or uridine uridine-containing compound is administered chronically, containing compound. e.g., for a period of 3, 5, 10,90, or 180 days or 1, 5, or 10 years. 0015. By “attention' is meant the cognitive process of 0008. In certain embodiments, the method may involve selectively focusing on one aspect of the environment while diagnosing a human as neuropsychologically healthy prior to ignoring other aspects. administration of the cytidine-containing or uridine-contain ing compound. 0016. By “attentional control' is meant the appropriate 0009. In another aspect, the invention features a nutraceu direction of attention to the most relevant aspect of the envi tical composition comprising an effective amount of a cyti rOnment. dine-containing or uridine-containing compound and option 0017. By “working memory” is meant the capacity for ally additional ingredients, e.g., vitamin B6, vitamin B12, retaining recently received or manipulated information in an niacin, folic acid, tyrosine, phenylalanine, taurine, malic acid, active, readily available state. glucuronolactone, and caffeine, for administration to a neu 0018. By “learning aptitude” is meant the relative ability ropsychologically healthy human to improve the cognitive to learn new information or concepts. Learning aptitude of a function of the human. Desirably, the cytidine-containing or person may be measured with respect to a previous measure uridine-containing compound is selected from CDP-choline, ment of aptitude for the same person or with respect to norms uridine, and triacetyluridine. of an appropriately matched population. US 2010/0041621 A1 Feb. 18, 2010 0019. By “verbal learning aptitude” is meant the ability to top of the corpus callosum. The portion of the MRSI grid learn the uses of words. encompassing the genu and splenium of the corpus callosum 0020. By “accuracy under time pressure' is meant the (left, Sagittal image, outer green box) was then shifted in the ability to complete a mental task without error when a limited X and y dimensions in the axial plane to align the MRSI grid amount of time is given to complete the mental task. (right, axial image, outer green box) with the longitudinal 0021. By "frontal brain' is meant the prefrontal cortex of fissure. Two 25 cm voxels (effective size) were placed in the brain. each of the two regions of interest, the anterior cingulate 0022. By “anterior cingulate cortex (ACC) is meant the cortex (ACC) and parietal/occipital cortex (POC) (right, axial structure within the prefrontal cortex that lies anterior to the image, Small green boxes). genu of the corpus callosum. 0034 FIG.3 depicts in vivo P spectra from the ACC and 0023. By “parieto-occipital cortex' (POC) is meant the POC of a subject. Sample in vivo 'P brain spectra from 25 region of the parietal and occipital cortex thought to be cm effective voxels in the ACC and the POC of a study involved in integration of sensory information, particularly participant at 4 Tesla. Raw data are displayed with the mod visuospatial and visuomotor activities. eled fit and residual; 15 Hz exponential filtering has been 0024. By “an effective amount” is meant an amount of a applied for display. PME, phosphomonoester, PE, phospho compound Sufficient to improve cognitive performance. ethanolamine: