CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from US Provisional Application No.

61/681,563 and No. 61/681,567, both filed on August 9, 2012, each of which is hereby incorporated by reference herein in its entirety.

FIELD

[0002] The invention relates to methods and compositions for treating

neuropsychiatric diseases. In particular, this invention relates compositions for preventing or slowing myelin deterioration or loss and methods of making and using the same in treating and preventing neuropsychiatric diseases. This invention also relates to compositions for myelin repair and methods of making and using the same in treating neurological diseases.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH

[0003] This invention was made with U.S. Government support by National

Institute of Health (NIH) grants (MH 0266029 and AG027342), the Risk Control Strategies Foundation, and the Research and Psychiatry Services of the Department of Veterans Affairs. Thus, the U.S. Government has certain rights in this invention.

BACKGROUND

[0004] Neuropsychiatric diseases are disorders of the brain, spinal cord and nerves throughout the body, which together control all the workings of the body. When something goes wrong with a part of the nervous system, one can have trouble moving, speaking, swallowing, breathing, behaving, or learning. One can also have problems with one's memory, thinking, senses, or mood.

[0005] Currently, there are more than 600 neuropsychiatric diseases. These disease have various and diverse causes. For example, Huntington's disease and muscular dystrophy diseases are caused by faulty genes. Spinal bifida is caused by problems with the way the nervous system develops. Parkinson's disease and Alzheimer's disease, including late onset Alzheimer's disease (LOAD), are degenerative diseases, where nerve cells are damaged or die. Epilepsy is one of uncontrolled electrical activity causing seizure disorders, multiple sclerosis is a disease of myelin causing various cognitive, motor, sensory, and psychiatric symptoms.

[0006] Stroke is caused by diseases of the blood vessels that supply the brain. In addition, there can also be injuries, infection and abnormal growth to the spinal cord and/or brain; exemplary diseases include meningitis, brain tumor and etc. There are also diseases usually referred to as psychiatric that manifest primarily with disturbed thinking, emotions, mood, and behavior such as schizophrenia, bipolar disorder, autism, etc.

[0007] Much is to be understood about the underlying mechanisms of these diseases and such discovery can lead to possible cures or therapeutics that target one or more common causes of these diseases.

SUMMARY

[0008] Provided herein are compositions and methods for treatment of populations suffering from myelin deterioration or loss as well as populations suffering from inadequate myelination or remyelination.

[0009] In one aspect of the present invention, it is provided a composition comprising a compound effective for preventing or slowing myelin deterioration or loss from any cause, thereby preventing or delaying the onset of any myelin-associated disorder as disclosed herein. For example, age-related myelin deterioration or loss and its associated cognitive decline can be slowed using existing medications that improve metabolic risk factors and myelin deterioration or loss in cognitively unaffected older individuals at risk for late onset Alzheimer's disease (LOAD). In vivo MRI methods to measure myelin health combined with cognitive measures focused on cognitive processing speed provide the opportunity to overturn the widely held acceptance of brain aging as an immutable process and demonstrate that available medications can provide primary prevention of LOAD.

[0010] In one aspect of the present invention, it is provided a composition, which composition comprising a compound effective for myelin repair/remyelination.

[0011] In another aspect, it is provided a method of fabricating a composition. The method comprises forming a composition according to any embodiments of invention composition disclosed herein.

[0012] In another aspect, it is provided method of treating, ameliorating, or preventing a disorder associated with myelin development, maintenance or repair, which method comprising applying to a subject (e.g., human patient) a composition according to any embodiments of invention composition disclosed herein. [0013] In another aspect, it is provided method of treating, ameliorating, or preventing a disorder associated with myelin dysfunction or remyelination, which method comprising applying to a subject (e.g., human patient) a composition according to any embodiments of invention composition disclosed herein.

[0014] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the compound is effective to treat, ameliorate or prevent a disorder associated with myelin deterioration or loss.

[0015] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the compound is effective to treat, ameliorate or prevent a disorder associated with myelin breakdown and/or loss.

[0016] In some embodiments the composition provided herein comprises one or more medications that down regulate the renin angiotensin system (RAS); such as angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors (ACEis), or beta blockers.

[0017] In some embodiments, the ACEi is selected from the group consisting of

Captopril, Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril, Fosinopril, Casokinins, lactokinins, the lactotripeptides Val-Pro-Pro and Ile-Pro-Pro, and a combination thereof.

[0018] In some embodiments, the compound comprises an angiotensin II type 1 (ATI) receptor blocker (ARB). In some embodiments, the composition comprises the antihypertensive medication named Telmisartan (Tel; Micardis™). Using ARBs such as Tel to promote the prevention of myelin deterioration and/or loss as well as promote its restoration/remyelination and thus reduce the age-related breakdown of myelin that leads to AD is a novel conceptualization of both the process that leads to AD and the possible use of ARBs and Tel in particular to slow down brain aging and thus prevent and treat AD as well as other neuropsychiatric disorders. In some embodiments of the invention composition, the composition further comprises a pharmaceutically acceptable carrier.

[0019] In some embodiments, the ARB is selected from the group consisting of Candesartan, Losartan, EXP 3174, Valsartan, Irbesartan, Eprosartan, Olmesartan, Azilsartan, and a combination thereof.

[0020] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the compound is Telmisartan (Tel; Micardis™). [0021] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the compound is Bexarotene

(Targretin™).

[0022] In one aspect, provided herein is a composition comprising a compound effective for preventing or slowing myelin deterioration or myelin loss and/or promoting myelination and myelin repair/remyelination.

[0023] In some embodiments, the composition comprises an retinoid X receptor (RXR) agonist. In some embodiments, the composition comprises a beta-blocker.

[0024] In some embodiments, the beta-blocker is selected from the group consisting of Alprenolol, Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol, Eucommia bark, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol, Butaxamine, ICI- 118,551 , SR 59230 A and a combination thereof.

[0025] In some embodiments, the compound is effective to treat, ameliorate or prevent a disorder associated with one selected from the group consisting myelin

deterioration, myelin loss, inadequate myelination, myelin repair, remyelination and a combination thereof.

[0026] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the disorder is a neuropsychiatric disease.

[0027] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the disorder is multiple sclerosis (MS), disorders of brain development such as schizophrenia, disorders due to damage to myelin due to toxins (whether willingly abused such as amphetamines, secondary to metabolic toxicities caused by pharmacologic treatments, or environmental such as pesticides), aging-related deterioration of myelin, amnestic mild cognitive impairment (MCI), or Alzheimer's disease (AD). In some embodiments, AD is familial (genetically

predetermined) Alzheimer's disease and/or the more common late onset Alzheimer's disease (LOAD). In some embodiments, the AD is late onset Alzheimer's disease (LOAD) or familial Alzheimer's disease (FAD).

[0028] In some embodiments of the composition, optionally in combination with any or all of the various embodiments disclosed herein, the disorder is multiple sclerosis (MS), schizophrenia, diseases caused by myelotoxins whether used willingly such as amphetamines, as part of pharmacologic treatment, or environmental toxins, metabolic toxicity such as caused by oxygen deprivation that causes strokes, Alzheimer's disease (AD), or other degenerative brain diseases such as forntotemporal dementia (FTD) and

Huntington's disease (HD).

[0029] In some embodiments, the disorder is a neuropsychiatric disease. In some embodiments, the disorder is multiple sclerosis (MS), schizophrenia, direct or indirect myelin toxicity-related damage from substances of abuse, pharmaceuticals, stress, or other toxins or insults such as trauma and strokes, the process of aging, mild cognitive impairment (MCI),

Alzheimer's disease (AD), or other degenerative brain diseases.

[0030] In another aspect, provided herein is a method of fabricating a

composition. The method comprises a step of forming a composition according to any embodiments or combination of embodiments disclosed herein.

[0031] In another aspect, provided herein is a method of treating, ameliorating, or preventing a disorder associated with myelin deterioration or loss as well as promoting myelination in cases of deficits in the myelination process. The method comprises a step of applying to a subject a composition according to any embodiments or combination of embodiments disclosed herein.

[0032] Embodiments described herein are applicable to any aspect described herein. In addition, embodiments disclosed herein can be used in any combination. For example, an ARB can be used in combination with an RXR agonist, an ACEi, a beta-blocker, or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0034] Figure 1 illustrates how gene and environment interact to optimize brain function. This schematic depicts the continual and dynamic interrelated processes supporting myelination. As a schematic focused on the key yet underappreciated role of

oligodendrocytes and myelin this figure does not depict a myriad of additional relationships such as the ones between genes, environment, epigenetic changes, and metabolism and all five interdependent CNS cell types (NG2 progenitor cells are subsumed under

oligodendrocytes) and their specialized structures such as synapses. In the continually dividing and differentiating oligodendrocyte cell line, epigenetic modifications on gene expression can be introduced in each subsequent generation of differentiating cells and thus reflect environmental conditions at different stages of the lifespan. These epigenetic modifications can help explain how at different periods in life, various environmental perturbations such as infections, physical and psychological trauma, metabolic disorders such as hypertension, education/mental/physical activity, diet, etc., can significantly influence temporally distant future risk of developing degenerative brain diseases. Note: Blue arrows, boxes, and italics summarize some of the available modes of interventions at the

pharmacotherapeutic and nutritional levels and their potential therapeutic consequences.

[0035] Figure 2 illustrates that intracortical myelin (ICM) that is elaborated during adulthood has a key role in optimizing network synchrony and compensating for subcortical insults and resulting action potential transmission deficits. Cortical myelination underlies a key mechanism of brain plasticity and its disturbance could have important consequences for disease pathophysiology. The importance of intracortical myelin optimizing brain function and compensating for subcortical transmission delays is supported by observations from multiple sclerosis (MS), a canonical myelin disease, and Alzheimer's disease (AD), a canonical "cortical" disease. Until recently myelin-destroying intracortical MS lesions, which post-mortem data show represent as much as 60% of MS lesions, were under-appreciated due in part to difficulty in detecting them on MRI. Prospective studies show that absence of such cortical lesions is associated with a favorable clinical and cognitive outcome independent of deep white matter lesion accumulation. Conversely, the presence and progression of intracortical MS lesions are most strongly associated with cognitive decline (including processing speed and memory). These phenomena can be parsimoniously explained by the plasticity of ICM and its ability to compensate for subcortical delays in transmission and re-establishing network synchrony by augmenting ICM. Thus, only when the optimizing/compensatory role of ICM is lost to intracortical demyelination would subcortical delays fully manifest as degraded network synchrony and function and thus become observable as clinical symptoms.

[0036] Figure 3 illustrates that myelin breakdown can drive age-related cognitive decline into Alzheimer's Disease with early loss of memory encoding. Risks of myelin breakdown and loss is multifactorial and similar to AD risks. The risks include age, suboptimal genes such as apolipoprotein E4 (ApoE4), amyloid precursor protein (APP), and presenilin 1 or 2 (PS1 or PS2), as well as iron accumulation and common age-related metabolic derangements such as hypertension, diabetes, and dyslipidemias. Myelin breakdown initially degrades network synchrony and cognitive functions through reductions in action potential refractory time which reduce higher frequencies action potentials on which certain functions such as long-term potentiation (LTP) and speed of movement are dependent. Loss of myelin segments can also reduce transmission speed and thus alter the synchronous function of networks and thus further degrade function. If myelin repair is slow, the support of distant synapses which is dependent on fast axonal transport (FAT) is lost resulting in synapse loss and further cognitive decline. If repair/remyelination fails, neurotrophic support from synapses back to the neuronal body is reduced which may result in loss of that particular axon. Eventually, toxic accumulations of tau, amyloid beta (Αβ) and loss of neurotrophic support could eventually result in neuronal loss. Note: not all interactions are depicted including a possible direct toxic effect of Αβ on intracortical myelin.

[0037] Figure 4 illustrates a heuristic systems biology model of renin angiotensin system (RAS) and dysmetabolism used to denote metabolic derangements (hypertension, insulin resistance, hyperlipidemia, and obesity) which when discussed in the context of peripheral consequences to the body are also often referred to as metabolic syndrome. These components of dysmetabolism have complex interactions involving the both the central and peripheral renin-angiotensin system (RAS). Angiotensin 2 (AT2) promotes systemic hypertension as well as increased local tissue iron, oxidation, and inflammation. AT2 also interferes with insulin/phosphoinositide 3 -kinase (Pi3K)/ serine/threonine kinase, also known as protein kinase B (Akt)/ glycogen synthase kinase-3 (GSK3) signaling and promotes insulin resistance, increasing tau phosphorylation and impairing cognitive function.

Antihypertensives such as angiotensin converting enzyme (ACE) inhibitors, AT2 receptor blockers (ARBs), and beta-blockers (which reduce renin) opposes these effects directly. By blocking angiotensin 1 receptors (AT1R) and shifting angiotensin (AT) metabolism to ACE2, ARBs promote formation of angiotensin 1-7 (AT1-7). ATI -7 generally opposes AT2 effects and is antihypertensive and antioxidant anxiolitic, restores insulin sensitivity through Mas R/Pi3K/Akt/GSK3 signaling and AT2R activity on PPARy, restores baroreceptor sensitivity, and enhances LTP. Furthermore, ARBs block only ATlRs and avoid interfering with largely beneficial effects of AT2Rs. DETAILED DESCRIPTION

[0038] Myelin is a dielectric (electrically insulating) material that forms a layer, the myelin sheath, usually around only the axons of neurons. It is essential for the proper functioning of the nervous system. It is an outgrowth of a type of glial cell called

oligodendrocyte. The production of the myelin sheath is called myelination. In humans, the production of myelin begins in the 14th week of fetal development, although little myelin exists in the brain at the time of birth. During infancy, myelination occurs quickly and continues through the adolescent and adult stages of life. Schwann cells supply the myelin for peripheral neurons, whereas oligodendrocytes myelinate the axons of the central nervous system.

[0039] Myelin is made by different oligodendrocyte cell types, and varies in chemical composition and configuration, but performs the same insulating function.

Myelinated axons are white in appearance, hence the "white matter" of the brain. The high lipid content of myelin insulates the axons facilitating efficient transmission of electrical impulses. Charged particles (ions) are found in the fluid of the entire nervous system. Under a microscope, myelinated axons look like strings of sausages. Myelin is also a part of the maturation process leading to a child' s fast development, including crawling and walking in the first year and the development of virtually all subsequent functions.

[0040] Myelin is about 40% water; the dry mass is about 70-85% lipids and about 15-30% proteins. Some of the proteins are myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein. The key lipids of myelin are a glycolipid called galactocerebroside and cholesterol while the intertwining hydrocarbon chains of

sphingomyelin serve to strengthen the myelin sheath.

[0041] The higher prevalence of myelin and myelination in the human nervous system suggests its importance in developing and maintaining normal neuropsychiatric functions. [0042] Demyelination: Demyelination is the loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative autoimmune diseases, including multiple sclerosis, acute disseminated encephalomyelitis, Neuromyelitis Optica, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, central pontine myelinosis, inherited demyelinating diseases such as leukodystrophy, and Charcot-Marie-Tooth disease. Sufferers of pernicious anemia can also suffer nerve damage if the condition is not diagnosed quickly. Subacute combined degeneration of spinal cord secondary to pernicious anemia can lead to slight peripheral nerve damage to severe damage to the central nervous system, affecting speech, balance and cognitive awareness. When myelin degrades, conduction of signals along the nerve can be impaired or lost and the nerve eventually withers. A more serious case of when myelin is deteriorated is also called Canavan Disease.

[0043] The immune system may play a role in demyelination associated with such diseases, including inflammation causing demyelination by overproduction of cytokines via up-regulation of tumor necrosis factor or interferon.

[0044] Demyelination results in diverse symptoms determined by the functions of the affected neurons. It disrupts signals between the brain and other parts of the body;

symptoms differ from patient to patient, and have different presentations upon clinical observation and in laboratory studies.

[0045] Exemplary symptoms include but are not limited to blurriness in the central visual field that affects only one eye, may be accompanied by pain upon eye movement; double vision; loss of vision/hearing; odd sensation in legs, arms, chest, or face, such as tingling or numbness (neuropathy); weakness of arms or legs; cognitive disruption, including speech and behavioral impairments and memory loss; loss of dexterity; difficulty coordinating movement or balance disorder; difficulty controlling bowel movements or urination; fatigue, etc.

[0046] Myelin repair. Research to repair damaged myelin sheaths is ongoing. Techniques include surgically implanting oligodendrocyte precursor cells in the central nervous system and inducing myelin repair with certain antibodies. While results in mice have been encouraging (via stem cell transplantation), whether this technique can be effective in replacing myelin loss in humans is still unknown. Cholinergic treatments, such as acetylcholinesterase inhibitors (AChEIs), may have beneficial effects on myelination, myelin repair, and myelin integrity. Increasing cholinergic stimulation also may act through subtle trophic effects on brain developmental processes and particularly on oligodendrocytes and the lifelong myelination process they support. By increasing oligodendrocyte cholinergic stimulation, AChEIs, and other cholinergic treatments, such as nicotine, possibly could promote myelination during development and myelin repair in older age. Glycogen synthase kinase 3β (GSK3 β) inhibitors such as lithium chloride have been found to promote myelination in mice.

[0047] Dysmyelination: Dysmyelination is characterized by a defective structure and function of myelin sheaths; unlike demyelination, it does not necessarily produce lesions and loss of myelin. Such defective sheaths often arise from genetic mutations affecting the biosynthesis and formation of myelin. The shiverer mouse represents one animal model of dysmyelination. Human diseases where dysmyelination has been implicated include leukodystrophies (Pelizaeus-Merzbacher disease, Canavan disease, phenylketonuria) and schizophrenia.

[0048] The human brain has historically been dichotomized into white and gray matter based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. Unfortunately this nomenclature propagated an artificial "split" in clinical and scientific thinking by promoting the segregation of neurons, whose bodies reside in gray matter, from glia. This dichotomy was particularly unfortunate for the study of the human brain whose gray matter structures including the cortex continues adding oligodendrocytes and myelin well into adulthood and even old age.

[0049] The artificial dichotomy between neurons and glia obscures the continuous dynamic communication between all brain cell types that culminates in the achievement and continued maintenance of optimal function of neural networks. This dichotomy has unfortunately also pervaded diagnostic and research efforts by categorizing diseases into many canonical gray matter diseases such as Alzheimer's and Parkinson's disease (AD and PD) and a few canonical white matter diseases such as multiple sclerosis (MS) thus markedly skewing the research focus toward neurons.

[0050] These historic biases undermine a more comprehensive systems biology examination of the dynamic and complex interdependence of the brain's cellular elements as well as their interplay with peripheral and environmental factors. The focus of the patent will be shifted onto glia and especially oligodendrocytes and the myelin they produce. This shift is not meant to diminish in any way the key role of neurons that form the basis of the brain's neural networks. Rather, the refocus is necessitated by the ultimate clinical imperative to improve/optimize brain function.

[0051] Optimal brain function is based on the timing and synchronous arrival of multiple action potentials at their myriads of destinations. Given the vastly different lengths of the brain's neural networks, the speed of neural transmission determines the timing and synchronization of action potential arrivals. The speed of transmission is dependent on the axonal size and properties of its myelin sheath that are optimized through complex and poorly understood neuro-glial signaling mechanisms. These signaling mechanisms as well as the cellular and chemical environment of the brain undergo considerable age-related changes driven primarily by a uniquely prolonged myelination process that underlies the exceptional cognitive and behavioral abilities of the human species. Unfortunately these changes also predispose humans to several unique developmental as well as age-related degenerative brain disorders.

[0052] Brain aging is the dominant risk factor for the major degenerative brain diseases such as AD, PD, and dementia with Lewy bodies (DLB). The pathognomonic amyloid beta (Αβ) and tau protein deposits that are used to define AD and ot-synuclein (aSyn) that is used to define PD and DLB most commonly co-occur with each other together with additional abnormal protein deposits as well as considerable damage due to vascular disease. This multifaceted pathology continues to keep the actual causes of these diseases ambiguous. In addition to aging, many powerful predisposing genetic as well as

environmental/lifestyle risk factors have been identified. The genetic factors are currently not easily modifiable and include both genetic mutations involved in production of proteins such as Αβ that cause rare familial phenotypes of AD (FAD) as well as other common and rare allele variants that somehow increase risk for the highly prevalent sporadic late onset disease phenotypes of AD (LOAD).

[0053] AD is by far the most prevalent and best studied of these diseases. The identified gene variants that increase risk for the sporadic late onset form of AD (LOAD) often have multiple physiologic roles that fall roughly into several general functions: lipid metabolism (e.g., apolipoprotein E: ApoE, ATP-binding cassette subfamily A member 7: ABCA7, apolipoprotein J or clusterin: CLU); inflammation/immunity (e.g., complement receptor 1 : CR1), triggering receptor expressed on myeloid cells-2 (TREM2), and angiotensin converting enzyme (ACE); and cellular signaling (phosphatidylinositol-binding clathrin assembly lymphoid myeloid leukemia protein: PICALM) which was recently discovered to influence iron metabolism.

[0054] It is important to note that after aging itself, ApoE is not only the dominant risk factor for LOAD (increasing risk approximately 10-fold), it seems to also be a powerful risk factor for pathologically "pure" DLB (increasing risk 6-fold), as well as pathologically "pure" PD (increasing risk 3-fold). ApoE also seems to increase risk for multiple other brain disorders ranging from MS to traumatic brain injury as well as brain aging itself. These all share an increased need for brain and specifically myelin "repair" a process that most often requires remyelination of myelin segments by a newly differentiated oligodendrocyte. In this way, myelin repair and remyelination processes even in old age or destructive disease may involve developmental processes that predominate at very young ages. A better understanding of the processes leading to the exceptional predisposition of the human brain to develop these highly prevalent age-related degenerative brain disorders (AD, PD, DLB) can be achieved by considering the human brain's exceptional cellular composition and the evolutionary changes that made it possible.

Si2nificance of Myelin and Myelin Processin2

[0055] The importance of myelin, myelination, dysmyelination, myelin repair and remyelination are demonstrated in numerous aspects. For example, there is prevalent myelination of white matter and gray matter in human brain. Epigenetic modifications of oligodendrocytes occur throughout the lifespan of a human being. An exceptionally myelinated brain has high metabolic requirements thus increase its vulnerability. As such, treatments targeting defects in myelin and myelin processing provides viable options for treating many myelin-associated disorders, including but not limited to multiple sclerosis (MS), schizophrenia, disorders due to damage to myelin due to toxins (whether willingly abused such as amphetamines, secondary to metabolic toxicities caused by pharmacologic treatments, or environmental such as pesticides), aging-related deterioration of myelin, amnestic mild cognitive impairment (MCI), or Alzheimer's disease (AD), or other degenerative brain diseases such as forntotemporal dementia (FTD), and Huntington's disease (HD).

Exceptional White Matter and Myelination of the Human Brain

[0056] The brain is classically divided into gray matter (defined as the regions containing neuronal cell bodies and almost all synaptic connections) and white matter (composed primarily of the very long neuronal appendage (axon) that acts as a "wire" connecting widely dispersed neurons plus oligodendrocytes that produce the axon's

"insulating" myelin sheaths). The human brain's roughly 100 billion neurons are a small minority of brain cells (10%). Glia, which are present in both gray and white matter, account for the rest with the following approximate proportions: astrocytes (45%), oligodendrocytes (35%), microglia (5%), and progenitor (NG2) cells (5%) the vast majority of which differentiate into oligodendrocytes. During brain evolution from nematodes to humans, the number of glia have increased 50-fold more than the number of neurons suggesting that glia have an increasingly important role in the function of larger-brain species. [0057] Myelin may have initially evolved to promote speed of reactions such as those needed for escape or predatory reflexes. As increasingly sophisticated cognitive networks evolved, the role of myelin in optimizing timing and neural network synchrony may have become the paramount reason for its continued exuberant elaboration throughout evolution. Continual life-long oligogenesis is a distinctive oligodendrocyte feature that is central to brain development and plasticity throughout life. Unlike neurons, whose numbers are essentially established at birth, in healthy primates, large numbers of progenitor (NG2) cells are produced to support the decades-long processes of postnatal myelination as well as remyelination. In primates, the NG2 cells continue to divide, increasing the number of differentiated oligodendrocytes by as much as 50% during adulthood. By dividing and differentiating into oligodendrocytes, NG2 cells can support both continued myelination of additional axons or portions thereof (e.g., intracortical) as well as remyelinate axons when myelin sheaths are damaged and lost.

[0058] During evolution, hyperscaling of white matter relative to gray matter seems to be a feature of all mammals. Gray matter scales in direct proportion to with the rest of the brain while white matter volume hyperscales. It is thus not surprising that compared to other primates species, the human brain is not only the largest but it also has proportionately more white matter and especially more frontal lobe white matter. Thus, frontal white matter can be considered a principal component in explaining species differences in brain size and accounts for higher structural connectivity.

[0059] The development of frontal white matter seems to be protracted in both chimpanzee and humans. However, while myelin is commonly thought of as a component of white matter, gray matter is also extensively myelinated and this process is especially prominent and protracted in the human brain. The key role of this intracortical myelin (ICM) in optimizing brain function has been generally overlooked. Nevertheless humans differ from their closest primate relatives the chimpanzee whose intracortical myelination ceases in young adulthood while in human brain the process continues well into adulthood. In humans full maturity (as judged by peak frontal lobe white matter volume) is not reached until the fifth-sixth decades. This extensive and protracted myelination has imposed exceptionally high metabolic demands and is associated with vulnerabilities that make the human species highly susceptible to distinctive and highly prevalent brain disorders throughout its lifespan. These include disorders of inappropriate myelin development such as schizophrenia and bipolar disorder as well as age-related degenerative disorders such as AD, PD, DLB, Huntington's disease (HD), Frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).

Epigenetic Modi fications of Oligodendrocytes Throughout the Li fespan

[0060] The continued oligogenesis, myelination, and repair/remyelination processes produce important consequences that is particularly significant to the understanding of myelin. Repair processes remove the debris from broken down myelin prior to remyelination therefore, these repair plus remyelination processes may "mask" the key role of myelin maintenance in healthy as well as disease states. The principal evidence for these processes is indirect and consists of thinner myelin sheaths and shorter segments

characteristic of the remyelination process that can be precisely quantified only using electron microscopy. Since remyelinated segments are produced by newly differentiated

oligodendrocytes, the generalized age-related increase in oligodendrocytes numbers (by as much as 50% during adulthood) are also indirect evidence of the pervasive

repair/remyelination of the CNS. These lifelong repair/remyelination processes also enrich the prospect that new "generations" of oligodendrocytes are subject to different epigenetic modifications of gene expression. Therefore, as a cell class, oligodendrocytes may be exceptionally susceptible to environmental-genetic interactions throughout the lifespan

(Figure 1).

[0061] A model of brain development that includes oligodendrocytes and the myelin they produce reframes the human lifespan in terms of seamless quadratic-like (inverted U) myelination trajectories of the myriad of neural networks that underlie cognition and behavior. This perspective redefines human brain "development" as roughly the first five decades of life.

[0062] Within this framework dysregulations occurring during the increasingly complex stages of the myelination process contribute to several early-life neuropsychiatric disorders defined by overlapping (comorbid) cognitive and behavioral symptom clusters. This myelin-centered perspective "cuts" across current symptom-based classifications of neuropsychiatric diseases and helps explain why the dysfunction manifest in the entire cadre of symptoms that define classic psychiatric disorders (psychosis, depression, obsessions, compulsions, poor impulse control, etc.) can reappear in the dementias of old age. This perspective suggests that both developmental deficits/dysregulation of myelination of neural networks that contribute to the earlier-life psychiatric disorders, as well as degenerative breakdown and loss of myelin of the same networks occurring in the dementias of old age, can result in similar behavioral and cognitive symptoms despite entirely different etiologies.

[0063] The detection and study of myelination-associated disorders is made more complex by the lifelong dynamism of myelination, repair, and remyelination as well as epigenetic modifications (Figure 1). Epigenetic modifications of gene expression result from environmental effects that alter nuclear chromatin through methylation and demethylation reactions and histone modifications. These modifications alter gene expression of cells as they differentiate and thus affect subsequent cell function. Environmental insults (defined as deviations from optimal conditions and include brain and peripheral diseases as well as environmental stressors such as malnutrition and psychosocial trauma) that occur in earlier stages of development can thus have both immediate as well as long-term effects on developmental/repair/remyelination processes through epigenetic changes of gene expression.

[0064] Myelination itself can also contribute to age-related changes in the brain's own intrinsic environment. Because oligodendrocytes require large amounts of iron in order to differentiate later differentiating oligodendrocytes precursors (NG2 cells) differentiate in a brain environment with more oligodendrocytes and higher iron levels. Nevertheless, the precursors that differentiate in adulthood or even old age continue to have "developmental" requirements (e.g., nutrition, iron, etc.) similar to the ones of present in infancy although their environment (internal (CNS) and external (stress, diet, etc.) is markedly different. These requirements may persist or even increase in older ages as an increasingly iron-rich CNS environment may promote oxidative stress and thus accelerate the need for

repair/remyelination.

[0065] The changing environments could introduce epigenetic changes that may contribute to the commonly observed age-related decline in myelin repair/remyelination efficiency. Without adequate interventions this slowed repair/remyelination ability would make age-related cognitive decline and dementia inevitable for the vast proportion of the population as they progress into old age.

[0066] In summary, myelin may arguably represent the "weakest link" of both brain development as well as age-related degeneration and thus contribute to many of the normal as well disease-related changes in brain function over the entire human lifespan. Including glia and myelin in a conceptual "myelin model" of the human brain can help explain normal brain function, clinical and pathologic phenomenology of multiple diseases, as well as their shared responsiveness to pharmaceutical and other (e.g., nutritional) interventions.

Metabolic Requirements of An Exceptionally Myelinated Brain Increase Vulnerability

[0067] Compared to other brain cells oligodendrocytes have extreme metabolic requirements of energy, iron, omega-3 fatty acids (especially docosahexaenoic acid: DHA), and cholesterol which render them the most vulnerable cell type in the brain. The production and maintenance of the myelin sheath(s) that is up to 600x the surface area of

oligodendrocyte soma membrane and lOOx the weight of the soma makes the energy requirements of oligodendrocytes 2-3 fold higher than other brain cells. An evolutionary switch occurred among primates changing lactate dehydrogenase function from supporting primarily anaerobic to oxidative metabolism. Thus in brain, astrocytes produce lactate to supply metabolic needs of neurons and especially oligodendrocytes, which use of 80% of all lactate to synthesize lipids at a 6-fold greater rate than neurons and astrocytes while their use of glucose for this purpose is 2-fold.

[0068] Cells with high metabolism such as oligodendrocytes and neurons are intrinsically more vulnerable. This is due in part to their elevated levels of damaging oxidative reactions because approximately 2-3% of oxygen consumed in normal

mitochondrial respiration is obligatorily transformed into free radicals. Such metabolic stress makes oligodendrocyte highly vulnerable to a variety of insults ranging from hypoperfusion, toxic products of activated microglia and inflammation, other free radicals, to heavy metals and excitotoxicity. These metabolic demands are even higher for oligodendrocyte precursors that are actively myelinating axon segments. Precursors produce three times their own weight in membrane lipids each day and are even more exquisitely vulnerable than mature cells.

[0069] Oxidative stress can be exacerbated by the presence of iron that accelerates free radical damage. Oligodendrocytes have the highest iron content of all brain cell types and as much as 70% of brain iron may be associated with myelin. Developmental and repair/remyelination processes increase the number of oligodendrocytes with age and may underlie the age-related increase in brain iron. Iron levels are further increased in degenerative diseases of old age such as AD possibly because of increasing numbers of oligodendrocytes that are produced during remyelination attempts. In addition to promoting the production of toxic free radicals, elevated iron may also compromise a variety of essential functions such as phagocytosis and lysosomal activity contributing to accumulation of lipofuscin (an undegradable intracellular byproduct of oxidation reactions). These changes can help explain the age-related slowing of myelin repair and the exceptional vulnerability of later-myelinating oligodendrocytes such as the intracortical ones. Not surprisingly, oxidative stress has been consistently observed in psychiatric disorders of development such as schizophrenia and bipolar disorder as well as degenerative disorders of older age such as AD, PD, and DLB.

[0070] The human brain is particularly vulnerable to oxidative stress as it consumes a disproportionate amount of the body's total energy expenditure (20%) compared to other species (13% in monkeys and 2-8% in other vertebrates). This striking shift in resource use was needed to support exuberant myelination and was made possible by evolutionary adaptations in lipid and energy metabolism. Brain-driven evolutionary shifts in human metabolism were partly "subsidized" by substantial reductions in the length and energy consumed by the gastrointestinal system. This made foods with high-nutritional content as well as increased absorption of nutrients through cooking key human

requirements. The evolutionary shifts in proportions of metabolic resources dedicated to brain are even more striking in developing infants. At 18 months human infants reach a peak requirement of 60% of the body's energy dedicated to brain development and growth. To support these high brain requirements through periods of nutritional deprivation the human species has evolved increased body fat deposits compared to other primates: 10% in men, 20% in women, peaking at 25% in 18 month infants. Body fat serves as a source of lipids as well as storage for essential omega-3 fatty acids such as DHA, a crucial brain building block that is concentrated in myelin as part of plasmalogen phospholipids. In women, DHA stores in body fat are twice as large as in men. These DHA stores are released primarily during pregnancy and lactation to support newborn brain development, and this sequestration of DHA in women may make them more vulnerable than men to cognitive deficits when subjected to DHA deficient diets.

[0071] The brain also contains a disproportionate amount (25%) of the body's cholesterol. The bulk of brain cholesterol is incorporated into myelin at disproportionately high concentrations (2-fold higher than other plasma membranes) because it is required for myelin formation and stability. Since the brain produces all of its cholesterol de novo, it is not surprising that additional adaptations have evolved for more efficient cholesterol metabolism, transport, and recycling. Apolipoprotein E (ApoE) alleles are responsible for most of the brain's cholesterol transport. Humans evolved ApoE3 and E2 alleles which are carried by approximately 70% and 10% of the population respectively with less than 20% carrying the ancestral (primate) ApoE4 allele. ApoE4 is the sole allele present in non-human primates who nevertheless do not develop AD as ApoE4 is sufficiently efficient to support the metabolic needs of a brain with 20-25% less myelin than humans. On the other hand, despite its presence in less than 20% of the human population ApoE4 accounts for as much as 50% of the genetic risk of AD and the great majority of LOAD cases with an onset before age 80. The ApoE4 allele also confers greater risk for a wide variety of other brain insults that put a premium on efficient lipid recycling of membrane/lipid debris to speed repairs.

[0072] Compared to other species, these evolutionary adaptations permitted humans to devote a greater proportion of their brain to white matter (approximately 50%), half of which is composed of myelin. This investment made it possible to achieve the exceptional information processing capacity that underlines the intellectual and behavioral repertoires which defines the human species. In humans, the brain's myelinated white matter volume continues expanding until middle age despite the fact that in late childhood (age 12) the human skull becomes rigid, ending further brain expansion. Myelin volume expansion is coordinated with the "pruning" (elimination) of 30-40% of the synapses and axons that continues well into adulthood (age 38). This pruning process can be re-conceptualized as a key permissive step (imposed by the cessation of skull enlargement) for the myelination- driven cognitive and behavioral development of humans on their way to becoming healthy adults. Thus, in order for myelin expansion to continue into adulthood, synapses and axons are sacrificed. It is important to note that such massive losses of synapses and axons do not result in cognitive decline or dementia. On the contrary, the losses allow the brain to optimize neural network timing and synchrony by continuing to increase myelin content until it peaks in middle age at approximately 25% of brain volume.

[0073] In non-human primates the synapse and axon pruning processes occur simultaneously in all cortical regions. In humans however, these processes are

heterochronous and substantial elimination of synaptic spines, continues in late-myelinating prefrontal cortex into the fourth decade. The human brain differs from other primate species not only in the higher proportion dedicated to myelin but also the temporal extent and locations of this added myelination. Unlike the chimpanzee, humans continue developing their intracortical myelin (ICM) well past the late teens and into middle age. This specialized ICM may be especially pertinent to optimizing human neural network synchrony as well as providing the last opportunity to compensate for any damage-induced delay in subcortical signal transmission by increasing intracortical transmission speed and thus restoring optimal network synchrony. Myelin and Connections to Diseases

[0074] Given the importance of myelin, myelination, dysmyelination, myelin repair and remyelination, malfunctioning of any part of the system can lead to undesirable and sometimes pathological disease states. Exemplary myelin-associated disorders, including but not limited to multiple sclerosis (MS), schizophrenia, disorders due to damage to myelin due to toxins (whether willingly abused such as amphetamines, secondary to metabolic toxicities caused by pharmacologic treatments, or environmental such as pesticides), aging- related deterioration of myelin, amnestic mild cognitive impairment (MCI), or Alzheimer's disease (AD), or other degenerative brain diseases such as forntotemporal dementia (FTD), and Huntington's disease (HD).

Both White and Gray Matter Myelination Determines Function of the Brain "Internet" Throughout the Lifespan

[0075] Myelination of the white and gray matters ensures proper functioning of the brain throughout the lifespan of a human. Although the brain is routinely conceptualized as a singular entity, it is composed of a myriad of interacting neural networks that have different myelin development and degeneration/repair/remyelination trajectories. Imaging and post-mortem studies show that even at the gross lobar level, the different trajectories reach peak myelination at different ages with frontal and temporal lobes myelinating last. These different trajectories are supported by oligodendrocytes that become increasingly more complex the later in life they differentiate. They range from robust oligodendrocytes that myelinate a single axon segment with over 100 wraps of myelin membrane in the early- myelinating motor and sensory regions/networks to more vulnerable oligodendrocytes that myelinate upwards of 50 different axon segments with less than 10 wraps in late-myelinating intracortical regions (Figure 2). The structurally more complex and metabolically overextended later-myelinating oligodendrocytes and their myelin are especially vulnerable during both developmental as well as degenerative phases of the lifespan myelination trajectories. From the perspective of the exceptionally myelinated human species, the development and maintenance/repair of myelin's integrity may be the single-most important as well as most vulnerable element for acquiring and maintaining optimal cognitive and behavioral functions.

[0076] Human brain myelination has a quadratic -like (inverted "U") trajectory across the lifespan with increasing myelin content that peaks in middle-age. The

"connectivity" provided by myelination consists of increased action potential transmission speed (over 100-fold) as well as decreased refractory time (34-fold) which increases the number of action potentials that can be transmitted per unit time (in Internet terminology this would represent expanded "bandwidth"). Myelination thus potentially increases human brain's "Internet" information processing capacity by over 3,000 fold, making human myelination indispensable for developing human species' elaborate cognitive and behavioral functions. Human cognitive functions are also highly dependent on later-myelinating oligodendrocytes. These cells myelinate the circuitry of human neural networks all the way to the neuron bodies located in gray matter structures such as the cortex. The extensive intracortical myelination process occurs after childhood and basically "upgrades" neural networks with immediate response capacity such that they are essentially "on line" and process information much more quickly and precisely.

[0077] Most important, continued myelination and repair processes allow neural networks to remain "plastic" (e.g., adaptable) and thus control the timing of action potential arrival at their destination (Figure 2). Timing is a key metric of brain function and directly influences a wide range of cortical operations. The plasticity of myelin makes it possible to synchronize the arrival of action potentials at disparate sites across many brain regions and thus makes cognitive integration of divergent information streams (e.g., gestalts) possible. Complex neuro-glial signaling (between neurons and oligodendrocytes and their precursors) allows for continual optimization of timing and synchrony of network function and thus facilitates learning and behavioral improvements. In gray matter regions where the vast majority of neurotransmitters are released, neurotransmitters themselves can serve as a key avenue of neuro-glial signaling to direct the appropriate myelination that will optimize timing and synchrony of neural networks.

[0078] The first step towards network synchronization is achieved in childhood by myelinating the subcortical white matter portion of axons connecting widely distributed brain regions into functional networks (Figure 2). This initial subcortical myelination can be initiated/directed by neuronal signals themselves and results in the remarkably faster conduction (>100 times faster than unmyelinated axon) between widely separated gray matter regions. Once subcortical myelination is achieved, the total conduction time between these highly dispersed regions becomes primarily dependent on the much longer time (roughly 10 times) action potentials spend traversing the short but unmyelinated portion of axons within cortex. This intracortical distance to a specific neuronal layer is roughly constant. The constant intracortical distance to layer III (which receives most of the cortico-cortical input), together with the slow intracortical signal propagation, establishes the initial roughly synchronous arrival of action potentials to all cortical regions despite different distances. The rough network synchrony achieved by this process underlines the vast repertoire of cognitive and behavioral abilities that can be achieved in childhood albeit few of these functions or their integration are "perfected'Voptimized at that early stage of life.

[0079] The short intracortical portion of axonal propagation (that is largely unmyelinated in childhood) exerts a markedly disproportionate influence on network synchronicity. Beyond childhood, even faster transmission as well as exquisitely more precisely synchronized timing can be achieved by adding the appropriate amounts of myelin to the intracortical portion of fibers. As Figures 2 depicts, this later-developed acceleration and "fine grained" synchronization of cognitive and behavioral networks may continue to be refined over the entire first six decades of life by cortical oligodendrocytes. This later- differentiating subgroup of oligodendrocytes seem to differ in subtle ways from their subcortical counterparts as may the composition of the myelin they produce.

[0080] Differences between oligodendrocytes may be most acutely pertinent to the protracted ICM development in humans. Oligodendrocyte heterogeneity based on location of origin such as dorsal versus ventral origin in spinal chord or corpus callosum versus overlying cortex has been reported. These differences can have important physiologic consequences. For example, the oligodendrocytes residing in gray matter seem to differ from subcortical white matter oligodendrocytes in their iron efflux abilities resulting in higher iron accumulation in gray matter oligodendrocytes. This difference may help explain the age- related accumulation of iron in cortical and subcortical gray matter regions and the higher vulnerability of gray matter myelin to Αβ toxicity.

[0081] Myelin breakdown and loss is associated with the release of iron which is highly concentrated in oligodendrocytes and their myelin. When myelin and

oligodendrocytes are damaged, astrocytes and especially microglia are activated and internalize the iron debris. Microglia may also have the capacity to subsequently recycle this iron by transferring iron loaded ferritin to oligodendrocyte precursors and thus promote their proliferation and differentiation into mature oligodendrocytes that can remyelinate lost sheaths (Figure 1). Consistent with a role in clearing myelin and iron debris microglia activation increases with age in these most vulnerable late-myelinating regions which undergo the most extensive repair/remyelination.

Lifelong Myelination and Repair/Remyelination: Failure Leads to Dysfunction

[0082] Myelin-based network plasticity is dependent, at least in part, on continued oligogenesis. Life-long oligogenesis is a distinctive oligodendrocyte feature that is central to brain development and plasticity throughout life. Unlike neurons, whose numbers are essentially established at birth, in healthy primates, vast numbers of progenitor (NG2) cells are produced to support the decades-long processes of postnatal myelination and

repair/remyelination. The NG2 cells comprise approximately 5% of total adult brain cells and continue to divide with more than 80% differentiating into oligodendrocytes whose numbers increase by as much as 50% during adulthood. NG2 cells can thus support both continued myelination of additional axons or portions thereof (e.g., intracortical) as well as remyelinate damaged or lost myelin sheaths (Figures 1 and 2).

[0083] Primate data suggests that during adult aging, repair/remyelination and plasticity processes result in oligodendrocyte numbers increasing substantially more in the cortex (50%) than in subcortical white matter tracks (<25%). Furthermore, associations between myelin damage and cognitive function are also strongest in cortex which myelinate primarily after childhood (Figure 2). Repaired/remyelinated myelin segments are thinner and shorter and can thus be detected on electron microscopy by an increased number of paranodal myelin regions. There are substantial differences in age-related increase in paranodal myelin with a 90% increase in later-myelinating prefrontal cortex compared to 57% and 69% in earlier myelinating visual cortex and in the anterior commissure

respectively.

[0084] The remyelination process is complex and involves interactions between neurons (especially their axons and synapses) and oligodendrocytes (Figure 3). Inefficient or disturbed neuron-glial communication can slow repair/remyelination and many have deleterious consequences. The organelles that coordinate protein synthesis are only present in the neuron body rendering synapses and axons dependent on "supplies" delivered by fast axonal transport (FAT) from the neuron body. FAT is a bidirectional process powered by energy-requiring motors (e.g., kinesins for anterograde and dyneins for retrograde transport). Almost everything from mitochondria (for energy) to neurotransmitters vesicles must be anterogradely transported down axons to synapses. Conversely, damaged mitochondria destined for destruction, and products such as neurotrophin signaling molecules that are essential for neuronal survival, need to be retrogradely transported from synapses back to neuron body. The dependence of synapses on FAT also means that synaptic deficits, often observed with normal aging as well as very early in the process of several degenerative diseases including AD, could be secondary to FAT disruption.

[0085] Amyloid precursor protein (APP), whose cleavage by β-site APP cleavage enzyme (BACEl also known as (β-secretase) and presenilin (PSl, also known as γ-Secretase) produces Αβ, is a key adhesion molecule for the FAT process itself. Thus APP adheres the vesicles transported by FAT to the energy -requiring kinesin protein motors that propel them down axons on microtubule "tracks" towards the synapses. BACEl and PSl are also transported in these APP-anchored vesicles. Additional roles of APP in membrane adhesion may involve maintenance of axonal-myelin adherence at perinodal regions. Cellular signaling promoting myelination involves BACEl and PSl while adhering newly formed myelin onto axons depends partly on APP. In the context of the myelin model, the co- transport by FAT of three components of the myelination machinery (BACEl, PSl, and APP) is suggestive of a coordinated delivery to specific axonal myelin segment in need of repair/remyelination. The mechanism through which the myelin repair process is executed involves stopping/slowing axonal transport mechanisms and especially FAT which creates axonal swellings that contain the necessary signaling components to promote the

repair/debris clearance and subsequent remyelination. Stopping FAT will also result in "starving" the synapses of the supplies delivered by FAT (Figure 3). Thus, myelin receives the highest "repair priority" reinforcing the suggestion that myelin holds a preeminent role in information fidelity and functional connectivity of vertebrate CNS.

Mechanism Behind Myelin-Associated Diseases

[0086] As summarized above, the human species' exceptional myelination is supported by recent evolutionary changes that may have evolved in part to support the extremely expensive metabolic processes of creating and maintaining a highly myelinated CNS. Given the very recent evolution of myelinating oligodendrocytes (in vertebrates), myelination's exceptional metabolic requirements had to be integrated with the many metabolic and developmental processes that predated its evolution. Glycogen synthase kinase-3 (GSK3) as well as other kinases that have similar/overlapping functions is highly conserved from sponges, through insects and vertebrates and is a central control mechanism that coordinates metabolism, inflammation, as well as myelination.

[0087] By the time myelin evolved, many processes were already modulated by GSK3 through its >40 substrates that include metabolic and signaling proteins, structural proteins, and transcription factors in different cellular components within the cytoplasm but also in nucleus and mitochondria where GSK3 is highly activated. These multiple GSK3 metabolic and signaling functions could thus be integrated with the negative control GSK3 exerts on myelination. Given the complexity of GSK3 actions, the plethora of pharmacologic and non-pharmacologic interventions that can impact the myelination process are not entirely unexpected. In this context it should also not be surprising that metabolic abnormalities such as insulin resistance and dyslipidemias that interact with GSK3 would impact myelination. These metabolic abnormalities not only increase the risk of AD and other degenerative brain disorders but also predate the onset of psychiatric disease such as schizophrenia and bipolar disorder and are associated with worse outcomes.

Coordination of Myelination & Inflammation via Glycogen Synthase Kinase 3 (GSK3)

[0088] Cholesterol and its derivatives such as sulfatide (a myelin- specific lipid that in brain is almost exclusively produced by oligodendrocytes) are indispensable for myelin formation and stability. However, when myelin breaks down, repair is initiated by the efficient removal of myelin and especially its sulfatide debris which is highly inflammatory. Myelin debris is also distinctive in its myelination-inhibiting properties and exceptionally high iron content. The repair processes that clear myelin debris is an essential permissive step for the subsequent remyelination and functional restoration to occur. The importance of lipid debris removal in the highly myelinated human brain may have contributed to human species evolving novel, more efficient ApoE isoforms (the brain's principal lipid binding and transport protein) to speed up the clearance and recycling of those lipids.

[0089] Activation and proliferation of microglia and astrocytes also have essential repair functions in debris clearance (see below) as well as helping to meet the increased metabolic needs associated with such plastic reorganization and repair of the CNS by producing substrates such as lactate. The GSK3 signal transduction pathway is capable of altering DNA methylation of imprinted loci. It could thus help coordinate epigenetic DNA changes to transform dormant to activated (phagocyte) microglia and astrocytes as well as helping trigger proliferation of microglia and oligodendrocyte precursors (Figure 1). Activated microglia are especially avid in clearing interstitial iron (five-fold more than astrocytes) although astrocytes are larger and more numerous especially in humans and therefore they also contribute significantly to debris clearance. Evidence of this function comes from accumulation within astrocytes of an internal insoluble byproduct produced by the cumulative history of cellular oxidative peroxidation called lipofuscin which is strongly associated with iron accumulation and aging. On the other hand, inhibiting GSK3 can limit microglia activation and inflammation.

[0090] It is thus possible that GSK3 serves as a linchpin for coordinating the opposing processes of reparative inflammation/debris clearance as well as remyelination (Figure 4). First, upregulation GSK3 activity would promote inflammation and facilitate clearance of myelin debris while inhibiting myelin production during this process. Second, removal of pro-inflammatory debris such as sulfatide and iron should aid in the termination of inflammatory responses. Third, downregulation of GSK3 would serve to pivot the process towards promoting remyelination while inhibiting inflammation and microglial activation during this rebuilding process. Inefficient remyelination could increase oligomeric (soluble) Αβ levels that may activate GSK3 , further inhibit remyelination, promote inflammation, and thus propagate a vicious cycle that leads to formation of AD pathologic lesions and synaptic, axonal, and eventually neuronal cell loss (Figure 3 and Figure 4). Failing to turn inflammatory pathways off, for example, by delaying the clearance of inflammatory debris, could also contribute to triggering intrinsic GSK3-mediated apoptotic pathways and cell loss. Given the importance of these process, it is likely that some signaling redundancy is provided by additional parallel pathways such as mammalian target of rapamycin complex (mTOR), mitogen-activated protein kinase (MAPK), and cyclin-dependant kinase (Cdk) (not depicted in Figure 4).

Dysmetabolism and Modifiable Risk Factors for Age-Related Degenerative Brain Diseases

[0091] The following will focus on risk factors for degenerative brain diseases that are modifiable. One example is LOAD, the most prevalent and best studied of these diseases. Modifiable risks include medical conditions subsumed under the rubric metabolic syndrome (central obesity, diabetes mellitus type 2: DM2, hypertension: HTN) and renal disease which are all strongly age-related. Additional contributors are late-life depression, and environmental/lifestyle factors including dietary patterns, physical activity, education level, and head trauma that have all been shown to affect myelination. These risk factors have produced calls for "eumetabolic" therapies dealing with multiple contributing biologic systems as a way to prevent and treat AD.

[0092] In addition to increasing AD risk, some of these risk factors (HTN, DM2, as well as ApoE4) are associated with white matter damage through mechanisms that seems to be partially independent of each other. These observations support the suggestion that with increasing age, metabolic deviations, epigenetic modifications, and suboptimal genetic endowment may converge to promote myelin damage and/or reduce repair/remyelination efficiency in vulnerable late-myelinating regions where the pathognomonic AD lesions first appear. Herein, the metabolic deviations that occur in middle and old age and increase risk of LOAD as "dysmetabolism" are referred to for specifying their detrimental impact on

CNS/myelin and differentiate them from "metabolic syndrome," which will denote processes that damage peripheral organs and vasculature. The Renin-Angiotensin System: Much more than Hypertension

[0093] The potentially modifiable risk factors may account for as many as half of LOAD cases. They seem to accelerate as well as exacerbate imaging biomarkers of brain aging. Recently, regional white matter hyperintensity (WMH) volume, which increases with age and is widely believed to be due to hypertension and vascular disease, was found to predict incident LOAD in the community while hippocampal or medial temporal lobe atrophy did not and reaffirmed earlier cross-sectional and prospective observations. Furthermore, WMH have been prospectively associated with AD pathology at post-mortem confirming an earlier association study. Similarly, presence of WMH as well as reduced white matter integrity predicted (by as much as 10 years) subsequent decline into amnestic mild cognitive impairment (aMCI) while hippocampal volume did not. Finally, both postmortem and imaging studies show substantial white matter alterations with relatively preserved gray matter in individuals at increased genetic risk or preclinical AD. These observations are consistent with a hypothesized model of AD that suggests myelin breakdown and

repair/remyelination attempts are the initiator of the disease and that Αβ and tau lesions as well as synapse loss are byproducts of this process (Figure 3).

[0094] White matter lesions denoted as WMH on MRI are often presumed to be due to preexisting hypertension, dyslipidemias, and/or DM2 which all promote vascular dysfunction. Hypertension is estimated to affect 50 million Americans, accounts for approximately 50% of population attributable risk for cerebrovascular and cardiovascular disease in individuals older than 50 years, and is the greatest risk factor for mortality. Like AD, hypertension is a strongly age-related disease. Systolic blood pressure increases linearly between ages 30 and 84 driving the lifetime risk of hypertension to nearly 90% and making its primary prevention a key public health goal. Prospective data showed that even in very healthy normotensive (mean blood pressure 117/71) older individuals small increases in blood pressure that are considered "clinically insignificant" and do not cross the generally accepted 140/90 threshold for initiating treatment are associated with increases in WMH and brain atrophy confirming meta-analyses that showed a progressively increasing risk of cerebrovascular accidents as blood pressures increases above a threshold of 115/75. The low blood pressures at which these risks begin increasing is consistent with suggestions that factors underlying hypertension, but not necessarily blood pressure elevation itself, are associated with white matter damage and increased risk of LOAD (Figure 4).

[0095] The assumption that hypertension causes brain damage has been recently re-conceptualized as the reverse. Considerable data support the suggestion that brain changes may be involved in promoting the imbalance in CNS sympathetic/parasympathetic outflow that eventually degrades cardiovagal baroreceptor reflex function during aging and ultimately promotes hypertension as well as insulin resistance and weight gain (e.g., metabolic syndrome). The age-related increase in the brain's local renin-angiotensin system (RAS) has been proposed to be the nexus of hypertension and aging. Within this framework, a reassessment of the apparent coincidence of myelin breakdown and hypertension is worthwhile. In healthy humans age-related myelin breakdown of the frontal lobe begins in the early 30's which is also the beginning of age-related increase in blood pressure.

Combined autopsy-MRI studies confirm that WMH are in large part imaging manifestations of myelin damage and loss. The age-related decline in myelin integrity and increasing WMH that begin at the same time as the beginning of blood pressure increases support the hypothesis that these brain changes may be an important cause of rising blood pressure as opposed to vice versa.

[0096] The RAS becomes more sensitive with age however, peripheral angiotensin cannot pass the blood brain barrier. Nevertheless, many organs including the brain have their own local RAS. Production of angiotensin 2 (AT2) is higher in brain than peripheral levels and is upregulated in hypertension. In brain, angiotensin 2 receptor type 1 (ATIR) is present on both astrocytes and oligodendrocytes while astrocytes and microglia are the primary source of angiotensinogen, the precursor of angiotensin (Figure 4).

[0097] Myelin breakdown could therefore be the initiator of increased brain RAS activity. The breakdown triggers microglia and astrocyte activation necessary for removal of lipid and iron debris and could therefore increase angiotensinogen levels. Not surprisingly, in certain progressively debilitating forms of the canonical myelin-destructive disease (MS), elevated levels of CNS angiotensinogen are observed. During normal aging, the large amount of myelin of the frontal lobe begins breaking down at an accelerating rate in the fourth decade. It is thus possible that the resulting increased activation of microglia and astrocytes may drive increased angiotensinogen levels and RAS activation and help trigger the peripheral triad of increased adiposity, hypertension, and insulin resistance as well as a decline in mitochondrial function. Support for this possibility comes from transgenic rodent models with reduced endogenous glial RAS that have reduced blood pressure, improved baroreflex function, and longer lifespans as well as improved mitochondrial function.

Extreme human longevity has also been associated with variations in the ATIR gene. Age- related cognitive decline as well as AD pathology seems to be modified by the use of brain- penetrant angiotensin converting enzyme inhibitors (ACEis) and especially angiotensin receptor blockers (ARBs). This protective effect on brain may also be shared in part by beta blockers that, like ACEis and ARBs, can also mitigate RAS activation by lowering renin (Figure 4).

[0098] The observations of reduced AD pathology with the use of such antihypertensives suggest that reducing brain RAS activity could modify the trajectory of age- related decline into AD. This possibility is supported by data from studies of DM2. Like AD and hypertension, aging is a key risk factor shared with DM2. Approximately 23% of individuals over the age of 60 afflicted as of 2007. Anti-hypertensive use in DM2 patients is associated with decreased risk of developing AD. Amongst the classes of antihypertensive treatments, AD risk mitigation was most robust with ARB use (24% risk reduction versus 14%, 11 %, 7%, and 4% for diuretics, ACE inhibitors, calcium channel blockers, and beta- blockers respectively). For the RAS anti-hypertensives, risk reduction was also observed in DM2 patients that did not have hypertension (12.5% risk reduction with ARBs and 5.9% reduction with ACE inhibitors) reinforcing the idea that these particular medications could have a protective/reparative CNS effect that is independent of their antihypertensive effects. [0099] More subtle changes in WM microstructural integrity can be detected with diffusion weighted imaging (DTI) as well as transverse relaxation rate (R2), a related non- diffusion MRI biomarker that has the advantage of helping quantify WM myelin content. Studies using these biomarkers suggest hypertension or its underlying causes can promote white matter/myelin damage, especially in the later-myelinating anterior brain regions and this damage is associated with declines in cognitive performance.

[0100] These deleterious effects were confirmed in recent studies which showed that radial diffusivity, the DTI parameter most influenced by myelin breakdown, is associated with increased blood pressure as well as reduced cognitive function. The association between cognitive function and radial diffusivity was also present in normotensive subjects and was independent of age, once again supporting the suggestion that the underlying mechanisms may directly damage myelin in the absence of elevated blood pressure (Figure 4). Notably, this association was reduced in a group of hypertensive subjects receiving antihypertensive treatment. These data support the hypothesis that treatment of the underlying causes of hypertension such, as brain RAS activation, may modify age-related myelin breakdown and repair processes and thus mitigate cognitive decline and LOAD (Figure 4).

Glucose Regulation, Insulin Resistance, and Glycogen Synthase Kinase 3 ( GSK3 )

[0101] Insulin signaling negatively regulates GSK3 and promotes myelination (Figure 4). Conversely, insulin resistance with decreased brain insulin/Pi3K/Akt signaling result in GSK3 activation and have been reported in AD with or without diabetes mellitus. The reduced insulin signaling is expected to contribute to myelination/remyelination deficits since myelination is also under negative control by GSK3 (Figure 4). These signaling abnormalities could therefore help explain why metabolic disorders such as diabetes mellitus and metabolic syndrome, both of which are characterized by increase in prevalence with age and reduced insulin signaling (e.g., insulin resistance), have been noted to double the risk of developing AD (Figure 4).

[0102] Activation of GSK3 seems to directly increase Αβ production and tau phosphorylation resulting in the proteinopathies that define the pathology of AD and other age-related degenerative brain diseases. Myelin repair needs increase with age and ordinarily require oligogenesis and remyelination of axons however, GSK3 activation inhibits remyelination. Inhibited or inefficient remyelination is hypothesized to drive Αβ as well as tau production that secondarily lead to AD pathology (Figures 3 and 4). Cortical Microinfarcts (CMIs) and White Matter Hyperintensities (WMHs)

[0103] Several studies observed that hypertension was associated with WMH as well as gray matter volume reductions. These associations are evident even in younger middle-aged individuals whose higher systolic blood pressure is associated with DTI evidence of WM injury in late-myelinating subcortical regions as well as reductions in cortical gray matter. Subcortical WMH can be explained, at least in part, by myelin damage/loss in vulnerable later-myelinating subcortical fibers of the anterior brain. Gray matter losses could also be partially due to losses in intracortical myelin (ICM, see Figure 2) which is also laid down late in development and damaged in AD. Nevertheless, successful treatment of hypertension with an ACEi (lisinopril) or beta blocker (atenolol) (both with low lipophilicity suggesting poor brain penetrance) does not seem to reduce the decline in cortical volume. This result can be reinterpreted to suggest that the more vulnerable ICM continued to be lost despite lowering of blood pressure. Focal loss of ICM associated with Αβ plaque deposits, cortical microinfarcts (CMI, see below), as well as other factors (Figure 4) could all contribute to ICM losses and manifest as gray matter volume deficits in AD.

[0104] Both DM2 and hypertension can increase infarct risk. Until recently cortical microinfarcts (CMI) have been underappreciated since by definition CMIs can only be observed with a microscope as they are too small to be detected on gross anatomy and, unlike subcortical WMH, are also difficult to identify on MRI. Nevertheless, recent data shows that they have a disproportionate impact on brain function and especially cognitive function. Studies examining CMIs suggest that they explain most of the functional effects (on cognition especially) that are usually attributed to WMH. When quantified separately and entered into logistic regression analyses, the impact of WMH is reduced compared to CMIs. CMIs are present in approximately half of AD patients (43-57%) compared to less than one third (24-31 ) of ones without dementia at death. It thus appears that the recently developed appreciation of the paramount importance of cortical compared to visible subcortical lesions in MS (Figure 2) may also apply in the new context of vascular damage. Macroscopic lesions such as WMH that are readily detectable on MRI may be "markers" for more numerous and widespread microinfarcts (50% of individuals with WMH had CMIs and vice versa). Importantly, as many as 50% of individuals with microinfarcts may not have macroscopic infarcts and thus vascular contributions may not be fully accounted for by routine MRI. Nevertheless CMIs have important and possibly independent effects on cognition.

[0105] A rodent model has shown that even a single or very few CMIs can produce cognitive deficits however, the model also demonstrated that reducing excitotoxicity through pharmacologic intervention may reduce these deficits. It thus appears that consistent with the MS data (Figure 2), ICM losses can have a very disruptive effect on cognitive processing. The loss of the compensatory effects of ICM, the "last line of defense" against the loss of network timing and synchrony (Figure 2), could unmask subcortical transmission deficits and reveal cognitive and behavioral symptoms early in the process before neuronal death and irreversible loss of function (Figure 3). Similar focal ICM losses associated with Αβ plaques was also been recently documented in AD. Age-related global declines in ICM as well as focal loses from CMIs and Αβ plaques may also significantly contribute to the trajectory of cognitive and behavioral function decline observed in aging and the transition into AD.

Conclusions

[0106] Provided herein is the dynamic and complex interdependence of all the brain's cellular elements with a special focus on the role of glia and especially

oligodendrocytes in the generation of degenerative brain disease. The historic bias that has focused attention primarily on neurons and gray matter is rebalanced. In doing so the importance of a systems-level understanding of healthy brain functioning is clarified and the age-related interdependent shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent age-related degenerative disease states such as AD (Figures 1-4). The integration of cellular, molecular, network, and systems-based definition of "health" and "disease" that includes the interplay between CNS and peripheral components (Figures 1 and 4) is essential for identifying, validating, targeting, and optimally timing an array of possible novel therapeutic interventions.

[0107] The emerging evidence suggests that the common assumption that mid-life peripheral metabolic changes such as hypertension, DM2/insulin resistance, hyperlipidemia, and obesity (e.g., metabolic syndrome) are the drivers of brain damage may not be entirely correct. Recent evidence suggests that vulnerable aspects of the brain such as myelin (Figures 1 and 2) that have evolved most recently may substantially contribute to creating some of these peripheral metabolic derangements (Figure 4). Furthermore, the vulnerability of myelin and the homeostatic repair mechanisms triggered by its breakdown may also drive the slow and continually progressive processes that result in cognitive decline as well as the pathology that define the prevalent degenerative diseases of the brain (Figure 3). The looming medical and financial crisis that will result from the exponential increase in degenerative brain diseases of the aging baby boomer generation has become an immediate threat to the fabric of human society. Safe therapeutic interventions that could mitigate the catastrophic age-driven exponential increase in degenerative brain diseases are urgently needed. Pharmacologic interventions that could mitigate this trajectory may already be in wide use and the epidemiologic and post-mortem evidence suggests that such interventions could have disease-modifying effects.

[0108] Imaging, blood, and genetic biomarkers have emerged that make it possible to track the complex, dynamic, nonlinear, and progressive trajectories from optimal function to dysfunction and into degenerative brain disease states. These developments provide unprecedented opportunities to prospectively examine the interactions between changes in disease state and environmental (including medications), genetic, and epigenetic factors (Figures 1 and 4).

[0109] Disease classification based on integrated molecular, cell function, neural network, and systems levels should lead to improved management and prevention of degenerative brain disease. Such an integrated approach can potentially replicate advances made in preventing peripheral diseases (e.g., cardiovascular disease) and targeting treatments based on etiologic as opposed to symptomatic stratification (e.g., latest cancer therapeutics). Discovering, developing, validating, and standardizing the most specific and informative biomarkers and utilizing them to track the pathology of common degenerative brain diseases and the impact of treatment and preventive interventions is a fundamental and acute clinical challenge.

Preventin2 or Slowin2 Deterioration or Loss of Myelin

[0110] In one aspect, compositions and methods for treating neuropsychiatric disorders are provided by preventing deterioration or loss of myelin.

Method of Makin2

[0111] A compound disclosed can be readily prepared according to established methodology in the art of organic synthesis. General methods of synthesizing the compound can be found in, e.g., Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, second Edition, Wiley, 2010. Synthesis of the compound is exemplified in Examples where the preparation of more than 41 different compounds is described in detail.

Methods of Use

[0112] The invention comprises using ARBs and Tel in particular as a treatment to slow myelin deterioration and loss. This use could be demonstrated most efficiently by showing a slowing of age-related myelin deterioration and loss using MRI in healthy individuals and/or individuals at high risk for developing AD based on genetic predisposition, family history, or MCI diagnosis. Alternatively, demonstrating that the age-related decline in cognitive processing speed can be slowed in the same populations. It may be possible to also show that treatment slows progression in patients with a diagnosis of AD. Beyond aging and decline into AD the same approach can be applied to all populations that suffer from myelin deterioration or loss and loss such as populations with multiple sclerosis or populations with psychiatric diagnoses such as schizophrenia and populations with substance abuse or dependence of myelotoxic agents such as amphetamines and cocaine or other direct or indirect my elo toxins.

[0113] Optimal brain function is dependent on the synchronized timing of action potential arrival at their destination. This synchronization is dependent on speed of transmission of action potentials which in turn is dependent on appropriate myelination. Myelin development, maintenance and repair/remyelination are key to multiple

neuropsychiatric diseases ranging from multiple sclerosis (MS, a known myelin disease) to schizophrenia (a developmental disease) to Alzheimer's disease (AD, a degenerative disease) or to damaging insults to the brain such as trauma, strokes, or direct or indirect myelotoxins such as pesticides drugs of abuse as well as psychological and physical stress which can be indirectly deleterious to myelin through hormonal changes such Cortisol elevations.

[0114] The composition and method of invention are effective for disorders associated with myelin deterioration and/or loss in brain. They are also effective for disorders associated with myelin deterioration and/or loss the central nervous system (CNS) in general (includes brain and spinal cord) and peripheral nervous system (PNS) which includes nervous tissue outside of the CNS. [0115] Bexarotene (Targretin ) has FDA approval for use as a relatively well tolerated anticancer drug that has been recently shown in animal models to be effective in improving brain function believed to occur through the reduction of the pathological hallmarks of AD. I propose that the improvements observed are due to improved myelin repair/remyelination and should therefore be beneficial in neuropsychiatric diseases where such repair is needed such as MS, strokes, trauma, or exposure to direct or indirect myelotoxins. Beyond these disorders the same approach can be applied to all populations that suffer from myelin deterioration or loss such as populations with psychiatric diagnoses such as schizophrenia and affective disorders.

Pharmaceutical Compositions

[0116] In another aspect of the present invention, a pharmaceutical composition is provided for use in treatment, amelioration, or prevention of a disorder associated with myelin development, maintenance, or repair. The pharmaceutical composition preferably comprises a compound described above or a pharmacologically acceptable salt or prodrug thereof.

[0117] In the aforementioned aspect of the present invention, the pharmaceutical composition may contain a pharmacologically acceptable carrier or excipients. An amount of the compound used in the pharmaceutical composition is not limited as far as it is an effective amount for treatment.

[0118] The disorder is generally a neuropsychiatric disease. In some

embodiments, the disorder is multiple sclerosis (MS), schizophrenia, toxin-induced damage, aging, degenerative diseases such as Alzheimer's disease (AD), or damaging brain insults such as strokes, trauma, or toxins.

[0119] The pharmaceutical composition in the aspect of the present invention may contain, as active ingredients, the aforementioned compound and other compounds, or may contain a mixture of two or more aforementioned compounds.

[0120] The pharmacologically acceptable salt in the present specification is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compound of the present invention forms with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0121] Further, the compounds of the present invention include hydrates thereof, various pharmaceutically acceptable solvates thereof, and polymorphic crystals thereof.

[0122] In some embodiment, the composition is administered continuously, e.g., at a low dose, over an extended period time, using a patch, an implant, or a portable drug dispensing pump.

[0123] A preferred formulation of the composition is oral formulation.

[0124] The pharmaceutical compositions of the present invention can be formulated in various dosage forms, which are exemplified by the following: oral administration forms such as tablets, capsules, powders, granules, pills, liquids, emulsions, suspensions, solutions, spirits, syrups, extracts, and elixirs; parenteral administration forms such as injections, for example, subcutaneous injections, intravenous injections,

intramuscular injections, and intraperitoneal injections; transdermal administration forms, plasters and pressure sensitive adhesives, ointments or lotions; intramouth administration forms such as sublingual forms and oral patch preparations; and nasal administration forms such as aerosols, but are not limited thereto. These preparations can be manufactured by using a known method generally used in a drug manufacturing process. In one embodiment of the present invention, the pharmaceutical composition of the present invention may be administered for treating muscular disease as an injection such as an intramuscular injection for administering directly into muscle.

[0125] The pharmaceutical compositions may contain various kind of ingredients generally used, for example, one or more pharmaceutically acceptable fillers, disintegrators, diluents, lubricants, flavoring agents, colorants, sweetening agents, corrigents, suspending agents, humectants, emulsifying agents, dispersing agents, auxiliary agents, preservatives, buffers, binders, stabilizers, and coating agents. In addition, the pharmaceutical composition of the present invention may be sustained-release dosage forms or extended-release dosage forms. [0126] A dosage unit may comprise a single compound or mixtures of compounds thereof. A dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules.

[0127] Dosage ranges of the pharmaceutical compositions are not particularly limited, and can be determined in accordance with the following: effectiveness of the ingredients contained therein; the administration form; the route of administration; the type of disease; the characteristics of the subject (e.g., body weight, age, symptomatic conditions, and whether a subject is taking other pharmaceutical agents); and the judgment of a physician in charge. In general, a suitable dosage may fall, for example, within a range of about 0.01 μg to 100 mg, per 1 kg of the body weight of the subject, and preferably within a range of about 0.1 μg to 1 mg, per 1 kg of body weight. However, the dosage may be altered using conventional experiments for optimization of a dosage that are well known in the art. The aforementioned dosage can be divided for administration once to several times a day.

Alternatively, periodic administration once every few days or few weeks can be employed.

[0128] In one embodiment, the amount of pharmaceutical composition administered is about 0.1 μg to 1 mg per kg body weight, 3 to 5 times a week. In another embodiment, the total amount of pharmaceutical composition administered is 0.25-2000.0 mg per day. In another embodiment, the total amount of pharmaceutical composition administered is 0.25 mg/day. In another embodiment, the total amount of pharmaceutical composition administered is 0.3 mg per day. In another embodiment, the total amount of pharmaceutical composition administered is 1.5 mg per day. In another embodiment, the total amount of pharmaceutical composition administered is 0.5-1.2 mg per day. In another embodiment, the total amount of pharmaceutical composition administered is 0.01 mg or more, 0.1 mg or more, 0.3 mg or more, 0.6 mg or more, 1.0 mg or more, 1.2 mg or more, 1.5 mg or more, 2 mg or more, 2.5 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more, 55 mg or more, 60 mg or more, 65 mg or more, 70 mg or more, 75 mg or more, 80 mg or more, 85 mg or more, 90 mg or more, 95 mg or more, 100 mg or more, 110 mg or more, 120 mg or more, 130 mg or more, 140 mg or more, 150 mg or more, 160 mg or more, 170 mg or more, 180 mg or more, 190 mg or more, 200 mg or more, 250 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg or more, 1000 mg or more, or 2000 mg or more per day. [0129] In terms of a route of administration of the pharmaceutical composition, it may be either systemic administration or local administration. The route of administration that is appropriate for a particular disease, symptomatic condition, or other factors, should be selected. For example, parenteral administration including normal intravenous injection, intra- arterial administration, subcutaneous administration, intracutaneous administration, and intramuscular administration can be employed. Oral administration can be also employed. Further, intranasal, transmucosal administration or transdermal administration can be employed.

[0130] In some embodiments, the composition is adapted for oral administration, e.g. in the form of a tablet, coated tablet, dragee, hard or soft gelatin capsule, solution, emulsion or suspension. In general the oral composition will comprise from 1 mg to 400 mg of such agent. It is convenient for the subject to swallow one or two tablets, coated tablets, dragees, or gelatin capsules per day. However, the composition can also be adapted for administration by any other conventional means of systemic administration including rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or nasally.

[0131] The biologically active compounds can be processed with

pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch, or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatin capsules, other than the soft gelatin itself. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semil-liquid or liquid polyols and the like.

[0132] The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances, particularly antidiabetic or

hypolipidemic agents that act through mechanisms other than those underlying the effects of the compounds of the invention. Agents which can advantageously be combined with compounds of the invention in a single formulation include but are not limited to biguanides such as metformin, insulin releasing agents such as the sulfonylurea insulin releaser glyburide and other sulfonylurea insulin releasers, cholesterol-lowering drugs such as the "statin" HMG-CoA reductase inhibitors such as atrovastatin, lovastatin, pravastatin and simvastatin, PPAR-alpha agonists such as clofibrate and gemfibrozil, PPAR-gamma agonists such as thiazolidinediones (e.g. rosiglitazone and pioglitazone, alpha-glucosidase inhibitors such as acarbose (which inhibit starch digestion), and prandial insulin releasers such as repaglinide as well as psychotropic compounds such as antipsychotics, antidepressants, and anxiolitics. The amounts of complementary agents combined with compounds of the invention in single formulations are in accord with the doses used in standard clinical practice. Established safe and effective dose ranges for certain representative compounds are set forth above.

[0133] The invention is described in more detail in the following illustrative examples. Although the examples can represent only selected embodiments of the invention, it should be understood that the following examples are illustrative and not limiting.

[0134] While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.

Bexarotene and Telmisartan for Treatment of Myelin-Related Diseases

[0135] Dysfunction of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) signaling in forebrain impairs long-term (hippocampal) social recognition and episodic memory (without impacting immediate memory) and synaptic long term potentiation (LTP). To produce LTP a high frequency action potential burst is required and such high frequency bursts are supported by the lower refractory time made possible by axonal myelination. Retinoid hypofunctioning contributes to aging-related declines in hippocampal memory functions. Treatment with retinoic acid (RA) can help reverse age-related cognitive decline in otherwise healthy wild-type mice that do not develop brain deposits of amyloid beta (Αβ) and tau proteins which form the neuritic plaques (composed of insoluble Αβ) and neurofibrillary tangle (composed of tau proteins) brain lesions that define Alzheimer's disease (AD). [0136] Bexarotene (Targretin ) has FDA approval as the only RXR agonist for use as a relatively well tolerated anticancer drug whose toxicities include central

hypothyroidism, xeroderma, and elevation of cholesterol and triglycerides. RXR is an obligatory heterodimer partner for a large number of class II nuclear receptors, including RAR, peroxisome proliferator- activated receptors (PPAR), liver X receptor (LXR), and farnesoid X receptor. Bexarotene is a synthetic selective RXR agonist that forms obligate heterodimers with LXR and PPAR gamma (PPARy). PPARy agonists accelerate CNS remyelination and oligodendrocyte maturation, and influences mitochondria function and oscillatory calcium waves. The importance of the PPARy mechanism for myelin

repair/remyelination has been demonstrated in the cuprizone toxicity demyelination rodent model. During cuprizone demyelination PPAR beta is induced in astrocytes however, during remyelination, PPARy is induced 20 fold.

[0137] In a transgenic rodent model of AD, bexarotene improved neural network oscillations and cognitive and social functions. These improvements were noted both in earlier as well as later/more severe stages of pathologic AD lesions accumulation. The improvements were ascribed to increased degradation of soluble oligomeric Αβ (that is generally believed to be the toxic causative agent in AD) as well as clearance of up to 75% of insoluble Αβ plaque deposits in the hippocampus and cortex brain regions. Four studies aimed to replicate these initial results. Of these, none replicated Αβ plaque removal and some did not replicate soluble (oligomeric) Αβ reductions while others did. Importantly however, all studies replicated increased lipidation (increased lipidation transporter ABCA1 and apolipoprotein E - ApoE) while a fifth study directly demonstrated of ApoE increases in brain interstitial fluid upon treatment with bexarotene. Most importantly, both studies that assessed cognition confirmed that treatment resulted in cognitive improvements.

[0138] The proposed mechanism of action involved increased levels of ApoE, its lipidation transporters (ABCA1 and ABCG1), as well as high density lipoprotein (HDL) that then promoted proteolytic degradation of soluble forms of oligomeric Αβ. Augmentation of phagocytosis by microglia and macrophages were additional effects attributed to the actions of PPARy:RXR and LXR:RXR heterodimers. The requirement of ApoE increases for the mechanism of action was deduced from the observation that treatment changes were not observed when the drug was administered to mice lacking the ApoE gene. However, a recent study refutes the possibility that ApoE accelerates Αβ clearance by direct binding to Αβ. [0139] Human and animal studies confirm that higher ApoE levels reduce risk of developing AD. Presence of the higher AD risk ApoE4 allele is associated with the lowest ApoE levels while the lower risk ApoE2 allele results in the highest ApoE levels.

Furthermore, ApoE genotype influences risk of multiple other brain diseases as well as brain aging itself which is the single strongest risk factor for developing late onset AD (LOAD). After age, ApoE4 is not only the dominant genetic risk factor for LOAD (increasing risk approximately 10-fold), it is also be a powerful risk factor for other dementias such as dementia with Lewy bodies (increasing risk 6-fold), and Parkinson's dementia (increasing risk 3 -fold). In addition, ApoE4 seems to also increase the risk for age-related myelin breakdown in otherwise healthy individuals suggesting that the higher brain ApoE levels achieved by ApoE3 and especially ApoE2 allele carriers may protect by mitigating the aging risk factor for AD.

[0140] Dementing diseases such as AD occur with high prevalence exclusively in the human brain. A better understanding of the processes leading to the unique

predisposition of the human brain to develop these age-related degenerative brain disorders (AD, PD, DLB) can be achieved by considering the human brain's exceptional myelination and the evolutionary changes that made it possible. An alternative to the Αβ hypothesis for AD is proposed that places myelin breakdown and repair processes at the initiation (trigger) of AD, with Αβ and tau deposits as byproducts of these processes. This myelin hypothesis of AD predicts that Αβ reduction may be observed when myelin repair/remyelination is accelerated. Reducing myelin breakdown or accelerating myelin repair would benefit aging related decline in brain function as well as the risk of developing a variety of diseases including AD.

[0141] Normal cognition and behavior depend on the synchronized oscillations of neural networks made possible by the exquisite timing afforded by adequate brain myelination. The efficiency of remyelination and repair declines with age, contributing to the generalized process of age-related myelin breakdown and loss as well as declines in motor and cognitive functions. This myelin loss is more severe in AD, and Αβ plaque deposits are themselves associated with demyelination in AD as well as transgenic mouse models of the disease. The myelin losses begin to occur prior to appearance of amyloid and tau lesions in AD transgenic mice and years before clinical symptoms appear in humans destined to develop the disease. Thus myelin breakdown and loss is hypothesized to contribute to age- related cognitive decline that eventually progresses to the more severe deficits associated with AD, while the homeostatic myelin repair mechanisms secondarily cause the

accumulation of the proteinacious brain lesions containing Αβ and tau that have been used to define this disease.

[0142] The general acceptance of the causal hypothesis of AD based on Αβ toxicity (the Αβ hypothesis for AD) has guided the vast majority of treatment research for the past 15 years. Clearance of Αβ and removal of plaques has been a frequent success story in transgenic mouse models of AD whose smaller brain contains a much smaller proportion of myelin. This Αβ toxicity-based approach to treating AD has not translated into treatment efficacy in human AD trials even when Αβ plaques were successfully reduced. These failures have been largely attributed to the introduction of treatments at a stage that was "too late" to make a difference in clinical outcome. The alternative explanation proposed by the myelin hypothesis is that production of oligomeric Αβ as well as AD lesions is a byproduct of upstream processes and not the etiology of the disease. The promotion of myelin repair may therefore be essential for clinical improvements to occur.

[0143] The efficacy of Bexarotene in AD transgenic mice may provide the opportunity to test these competing perspectives as well as provide the first successful translation of an effective treatment for mice to human AD. This assessment is based on the good probability that, unlike the many other failed anti-amyloid approaches, the underlying mechanism of action of Bexarotene is not limited to reducing Αβ as the investigators proposed. They did not consider the possibility that in the exceptionally myelinated human brain, myelin-related upstream mechanisms are etiologically important for AD and may also underlie some of the treatment efficacy observed in their transgenic mice.

[0144] Vitamin A and its RXR agonist metabolites such as retinoic acid are important signaling molecules during development. Their deficiency interferes with myelination and can result in Αβ accumulation supporting the suggestion that Αβ is produced during homeostatic myelin repair/remyelination. Correcting such deficits increases myelin lipids in a dose-dependent manner and can help reverse age-related cognitive decline in otherwise healthy wild-type mice that do not develop AD brain lesions.

[0145] The multi-pronged promotion of myelin repair may represent a broader "upstream" explanation for the success of RXR agonists such as Bexarotene in AD transgenic as well as wild-type mice. Augmenting myelin repair in the aging brain should be particularly pertinent to the human brain whose much larger size and greater proportion of myelin markedly increase its need for protection and repair/remyelination. Multi-pronged treatments such as Bexarotene and similar RXR agonists, as well as other compounds that act through PPARy:RXR or LXR:RXR heterodimers and PPARy activation can potentially improve myelin repair/remyelination efficiency. Such treatments could thus ameliorate the cognitive and behavioral changes associated with aging and AD as well as aiding in the treatment of other neuropsychiatric disorders involving myelination such as multiple sclerosis (MS).

[0146] In contradistinction to the Αβ hypothesis of AD this myelin-centered perspective can help explain key "disconnects" apparent in the AD literature. These include the disconnect between 1) antiamyloid and other treatments routinely curing the "AD" of transgenic mouse models (with their much lower levels of myelin) and the repeated failure of the same treatments in human AD trials and 2) the weak association between the brain burden Αβ lesions and clinical manifestations of human dementia. The myelin repair perspective predicts that a drug "cocktail" approach that reduces myelin destruction, increases debris clearance, and promotes remyelination should prove most effective in the treatment of AD. This perspective also suggests that Bexarotene and similar multi-action compounds that combine such attributes hold enough promise of efficacy to make the considerable side effect risks worthwhile for patients with existing AD or other myelin diseases such as MS.

[0147] In some embodiments, Telmisartan is used for a variety of reasons including the fact that it has the best brain penetrance as well as its PPARy activity. In addition, ACE inhibitors which reduce angiotensin, Telmisartan blocks the angiotensin 1 receptor (AT1R) but allowing angiotensin 2 receptor (AT2R) activity (which is primarily beneficial). There is evidence that brain penetrant medications (e.g., specifically ARB's) are best at treating cognitive deficits. Nevertheless, other brain penetrant ARBs can also work (some of the studies were done with other ARBs), as can some combination of such interventions. Similarly, beta-blockers reduce rennin and may also be helpful through that mechanism (Figure 4).

[0148] Interference with the rennin angiotensin system, whether by blocking rennin with beta blockers, inhibiting ACE, or blocking the AT2 receptor, can be effective in reducing inflammatory responses and disruptions in appropriate management of iron. If such treatments are started early enough, they can delay or prevent brain aging and transition to AD. An important caveat in existing human subjects with AD and transgenic animal models of AD literature is that protective effects can be expected primarily with brain- penetrant/centrally active treatments and not with compounds that do not cross the blood brain barrier. Both types of studies are important. Unlike the human studies, hypertension was not a contributing risk factor in the transgenic rodent AD model studies. Nevertheless, reducing ACE activity in the brain (but not peripherally) protected against cognitive impairment in these models even though it did not alter Αβ deposition. This suggests an Αβ- independent mechanism of action that is consistent with treatment mechanisms based on upstream myelin repair (Figure 4).

[0149] To date, humans trials include subjects with cognitive symptoms and hypertension. Nevertheless, uncontrolled as well as controlled studies of hypertensive individuals with AD or mild cognitive impairment (MCI) detected a reduced rates of cognitive decline. Two studies that examined subjects in the first 6-12 months of treatment reported improved cognition in demented and MCI subjects. In the controlled, randomized, double blind study of an ARB the beneficial effects on processing speed were observed to increase between 6 and 12 months when compared to other antihypertensives (diuretic and ACEi) with effect sizes of the difference in processing speed changes of against these active antihypertensive treatment arms of .43 and 1.05 respectively. Cognitive decline was slowed despite the fact that treated subjects had hypertension which itself is a risk factor for cognitive decline. Epidemiologic studies confirm the cognitive benefit of treatment. Most importantly however, post mortem studies consistently show a reduction in AD pathology in treated subjects whether or not they were suffering from AD and in one study, only the ARBs class of interventions showed this AD lesion-reducing effect.

[0150] In some embodiments, Bexarotene or Telmisartan is used in combination with an Angiotensin receptor blocker (ARB), ACE inhibitor, or beta-blocker. In some embodiments, the ARB, ACE inhibitor, or beta-blocker is brain penetrant and can cross the blood brain barrier. Such a combined "cocktail" treatment approach increases the number of mechanisms brought to bear to improve myelination (Figure 4). In some embodiments, multiple "brain penetrant" ARBs, ACE inhibitors, or beta-blockers are used in combination. Exemplary ARBs include but are not limited to Candesartan, Losartan, EXP 3174, Valsartan, Irbesartan, Eprosartan, Olmesartan, Azilsartan, and etc. Exemplary ACE inhibitors include but are not limited to sulfhydryl-containing agents (such as Captopril and Zofenopril);

dicarboxylate-containing agents (such as Enalapril, Ramipril, Quinapril, Perindopril,

Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril); phosphonate-containing agents (such as Fosinopril); naturally occurring (such as Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk), and the lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein. Exemplary beta-blockers include but are not limited to Alprenolol, Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, Timolol, Eucommia bark, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol, Butaxamine, ICI- 118,551, SR 59230A and etc.

[0151] Having described the invention in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing the scope of the invention defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

[0152] The various methods and techniques described above provide a number of ways to carry out the invention. Of course, it is to be understood that not necessarily all objectives or advantages described may be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as may be taught or suggested herein. A variety of advantageous and disadvantageous alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several advantageous features, while others specifically exclude one, another, or several disadvantageous features, while still others specifically mitigate a present disadvantageous feature by inclusion of one, another, or several advantageous features.

[0153] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

[0154] Although the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the invention extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

[0155] Many variations and alternative elements have been disclosed in embodiments of the present invention. Still further variations and alternate elements will be apparent to one of skill in the art.

[0156] In some embodiments, the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some

embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0157] In some embodiments, the terms "a" and "an" and "the" and similar references used in the context of describing a particular embodiment of the invention

(especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0158] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0159] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the invention can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this invention include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0160] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.

[0161] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other

modifications that can be employed can be within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present invention are not limited to that precisely as shown and described.

[0162] Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, C.Y., Karlo, J.C., Zinn,

A.E., Casali, B.T., Restivo, J.L., Goebel, W.D., James, M.J., Brunden, K.R., Wilson, D.A., Landreth, G.E., 2012. ApoE-Directed Therapeutics Rapidly Clear beta- Amyloid and Reverse Deficits in AD Mouse Models. Science. 335, 1503-1506.

[0163] Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM (2011): Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. J Alzheimers Dis 26:699-708. [0164] Fitz, N.F., Cronican, A.A., Lefterov, I., Koldamova, R., 2013. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 340, 924-c.

[0165] Furiya Y, Ryo M, Kawahara M, Kiriyama T, Morikawa M, Ueno S (2012): Renin- angiotensin system blockers affect cognitive decline and serum adipocytokines in Alzheimer's disease. Alzheimers Dement.

[0166] Gao, Y., O'Caoimh, R., Healy, L., Kerins, D.M., Eustace, J., Guyatt, G., Sammon, D., Molloy, D.W., 2013. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. BMJ Open. 3.

[0167] Gelber RP, Launer LJ, Petrovitch H, Masaki KH, Ross GW, White LR

(2013): Beta-blocker treatment of hypertensive older persons decreases the risk of cognitive impairment: the Honolulu- Asia Aging Study, Presented at the American Academy of Neurology 65th Annual meeting. San Diego, March 16-23.

[0168] Hajjar I, Brown L, Mack WJ, Chui H (2012): Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol: 1-7.

[0169] Hajjar I, Hart M, Chen YL, Mack W, Novak V, H CC, et al (2013):

Antihypertensive therapy and cerebral hemodynamics in executive mild cognitive impairment: results of a pilot randomized clinical trial. J Am Geriatr Soc 61 : 194-201.

[0170] Hanon O, Berrou JP, Negre-Pages L, Goch JH, Nadhazi Z, Petrella R, et al

(2008): Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive function And Systolic Blood Pressure Reduction open-label study. J Hypertens 26: 1642-50.

[0171] Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Grossman HT, et al (2009): Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology 72: 1720-6.

[0172] Imabayashi E, Matsuda H, Yoshimaru K, Kuji I, Seto A, Shimano Y, et al

(2011) : Pilot data on telmisartan short-term effects on glucose metabolism in the olfactory tract in Alzheimer's disease. Brain Behav 1 :63-9.

[0173] Johnson ML, Parikh N, Kunik ME, Schulz PE, Patel JG, Chen H, et al

(2012) : Antihypertensive drug use and the risk of dementia in patients with diabetes mellitus. Alzheimers Dement 8:437-44. [0174] Kume K, Hanyu H, Sakurai H, Takada Y, Onuma T, Iwamoto T (2012): Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer's disease. Geriatr Gerontol Int 12:207-14.

[0175] Li N-C, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, et al (2010): Use of Angiotensin Receptor Blockers and the Risk of Dementia in a Predominantly Male Population: A Prospective Cohort Analysis. BMJ (British Medical Journal) 340:b5465.

[0176] Morton KD, Johnson MD, Van de Kar LD (1995): Serotonin and stress- induced increases in renin secretion are not blocked by sympathectomy/adrenal

medullectomy but are blocked by beta antagonists. Brain Res 698: 185-92.

[0177] Price, A.R., Xu, G., Siemienski, Z.B., Smithson, L.A., Borchelt, D.R.,

Golde, T.E., Felsenstein, K.M., 2013. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 340, 924-d.

[0178] Tesseur, I., Lo, A.C., Roberfroid, A., Dietvorst, S., Van Broeck, B., Borgers, M., Gijsen, H., Moechars, D., Mercken, M., Kemp, J., D'Hooge, R., De Strooper, B., 2013. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 340, 924-e.

[0179] Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, et al (2000): Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging 21 :57-62.

[0180] Ulrich, J.D., Burchett, J.M., Restivo, J.L., Schuler, D.R., Verghese, P.B.,

Mahan, T.E., Landreth, G.E., Castellano, J.M., Jiang, H., Cirrito, J.R., Holtzman, D.M., 2013. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener. 8, 13.

[0181] Veeraraghavalu, K., Zhang, C, Miller, S., Hefendehl, J.K., Rajapaksha, T.W., Ulrich, J., Jucker, M., Holtzman, D.M., Tanzi, R.E., Vassar, R., Sisodia, S.S., 2013. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 340, 924-f.

[0182] Verghese, P.B., Castellano, J.M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C, Holtzman, D.M., 2013. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/ Abeta association in physiological conditions. Proc Natl Acad Sci U S A. 110, E1807-1816.

[0183] White LR, Gelber RP, Launer LJ, Zarow C, Sonnen J, Uyehara-Lock J, et al (2013): Beta blocker treatment of hypertensive older persons ameliorates the brain lesions of dementia measured at autopsy: the Honolulu- Asia Aging Study, Presented at the American Academy of Neurology 65th Annual meeting. San Diego, March 16-23.