Although neurodegenerative diseases have different causes, the dysfunction and loss of specific groups of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). The efforts to treat the neurodegenerative diseases by existing methods of cellular therapy are insufficiently effective. The modern methods do not provide correct restoration of cytoarchitecture and pattern of connections (the rewiring of specifically organized long-distance connections), which are essential to achieve a significant functional recovery. This article discusses existing methods of neural stem cell therapy and provides example of new approach to the treatment of various neurodegenerative diseases.

Neurodegenerative diseases are an assortment of central nervous system disorders characterized by neuronal loss and intraneuronal accumulation of fibrillary materials. Abnormal protein-protein interactions may allow the precipitation of these proteins, forming extracellular and intracellular aggregates. These abnormal interactions could play a role in the dysfunction and neuronal death that characterizes several common neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).

AD is the most common cause of dementia, with aging a major contributor to its onset. Currently, it is estimated that 40% of people over age 80 are afflicted with AD.  Autopsy examination of a patient’s brain reveals gross cerebral atrophy, signifying loss of neurons and the presence of large numbers of extracellular neuritic plaques and intracellular neurofibrillary tangles. Plaques and tangles are found predominantly in the frontal and temporal lobes, including the hippocampus. In more advance cases, the pathology extends to other regions of the cortex.  Similar plaques and tangles do occur in normal ageing brains.

PD is more common in people 60 years old and older. In the US, PD affects 1.5 million people. The degeneration and loss of dopaminergic neurons in PD causes akinesia, rigidity and tremor. Cell transplantation for the treatment of PD is the promising approach that has received most attention.

Cell therapy for PD

The potential of cell therapy for neurodegenerative diseases was demonstrated on implantation of different types of stem cells in the animals with PD (Kim J-H et al 2002, Parati EA et al 2003). Transplantation of stem cells into rat brain resulted in reinnervation of the striatal neurons and partial recovery of motor deficit associated with dopamine deficiency (Kim J-H et al 2002). The same results were obtained after transplantation of fetal dopaminergic neurons in clinical trials (Piccini P et al 2000, Freed CR et al 2001). It is possible to use different types of stem cells to generate dopaminergic neurons. Today the process of dopaminergic neurons differentiation from embryonic stem cells (ESC) in vitro is most effective and understandable (Kim J-H et al 2002, Isacson O, Ann Neurol 2003,  Isacson O, Lancet Neurol 2003, Barberi T et al 2003). Recent progress in human therapeutic cloning (Woo Suk Hwang et al 2004) makes this way to generate neurons more and more attractive. Differentiation of ESC in vitro and transplantation of dopaminergic neurons in the animal models of PD resulted in functional integration of implanted cells into recipient’s brain and partial recovery of motor functions (Kim J-H et al 2002, Barberi T et al 2003).

Although transplantation of neurons into striatum in PD model has a higher effectiveness in comparison with transplantation of neurons in other neurodegenerative disorders, it is too early to speak about full restoration of motor deficit associated with parkinsonism. In case of PD significant functional recovery requires cell replacement with, at least partial repair of original connections with neurons in the striatum. If such connections do not exist the full regress of motor deficit is impossible because dopamine release is under feedback control. This fact emphasizes the importance to develop effective methods to

The method to enhance accuracy of regeneration (Potential therapeutic strategy)

After transplantation stem cells make decisions regarding fate and patterning in response to external signals from extracellular environment and neighboring cells. The effectiveness of neural stem cell therapy may be facilitated by the ability to manipulate these signals in a temporal and spatially appropriate fashion (Liu CY et al 2003). The future methods of therapy could include in vitro processing of stem cells before implantation, supporting and guiding the cells after implantation with the help of nanorobots, as well as the in vivo creation of molecular scaffold (The Samuel I. Stupp Laboratory – sistagirl.ms.northwestern.edu, Silva GA et al 2004) for stimulating their growth in the correct direction.

During experiments on neonatal rats (Englund U et al 2002) the potential ability of neural stem cells to establish appropriate long-distance axonal projection after region-specific differentiation were shown. Unfortunately, adult brain, as compared to neonatal, has unfavorable conditions for axon growth in the correct direction. It is for this reason the stimulation of new neurons growth, for example along the surface of neurons in the zone of progressive degeneration, is necessary. The reconstruction of dysfunctional neural circuits may be facilitated in the following way . The proposed strategies are designed to increase accuracy of dysfunctional neurons regeneration.

Men and women are different indeed. Besides the obvious external anatomical differences, the brains of men and women tend to operate differently. Through recent research, scientists have been able to examine the human brain more than ever. With the use of MRI, fMRI (functional Magnetic Resonance Imaging), and PET (Positron Emission Tomography) researchers are able to see the brain in 2 to 3 dimensions. This enables them to conduct brain research on a functioning human brain. They are able to see what parts of the brain are activated when a specific task is given. With this new technology, scientists conduct more strenuous tests on subjects in order to see what part, or parts, of the brain is responsible for various functions. This research is done in controlled studies where they rule out social and environmental factors. With this in mind, a great deal of differences may exist in the brains of males and female. Male and female differentiated brains are not necessarily in one anatomically correct body. A male can have a female differentiated brain, and a female a male differentiated brain. When we speak in terms of male and female, we are talking about the brain itself, and not the external or physical appearance of the body.

Anatomically, the brains of both male and female are quite different. At birth, a boy’s brain is between 12-20% larger than that of girls. On average, the male brain weighs 11-12% more than a woman. This is due to the larger physical stature of men. Male’s larger muscle mass, and larger body size require more neurons to control them. This does not suggest that due to the larger brain, males are smarter than females. There are several differences between the two hemispheres. The left hemisphere, which is important to communication, is thicker in female oriented brains. This may conclude why women become more proficient with language skills. The corpus callosum is thicker allowing the free flow of communication between both hemispheres of the brain. Allowing more synapses between the two hemispheres. The female differentiated brain is able to use both sides of the brain, during communication. This allows them to become multitasked while conversing. When female subjects were asked to recall vocabulary and definitions, the entire brain lit up like a Christmas tree. The male brain on the other hand, only had highly concentrated neuron activity in the left hemisphere. The ability for the female differentiated brain to operate in this manner is due in part to the larger corpus callosum that allows more transmissions between the two hemispheres. The male differentiated brain has a thicker right hemisphere. This may be the reason males tend to be more spacial, and mathematical. The corpus callosum is thinner than it’s female counter part. This is the reason why when men communicate; they tend to only use one side of their brain. Male oriented brains, hardly express feelings. This is due to the use of the right hemisphere only. While men hold their emotions in until bursting point, women express how they feel. The corpus callosum allows this. Being larger, women use both hemispheres creating more synapses between the two sides of the brain. Male brains separate language, in the left, and emotions in the right, while the female’s emotions are in both hemispheres. This helps explain why the male brain has a hard time expressing its feelings. The male brain has its vocabulary making power seated only in the left hemisphere enabling him to develop a large vocabulary. Hence all the technical terms and terminology he may use. Whereas the female brain becomes more proficient in the vocabulary she already has using her emotions and feelings for others to aid in the production of language.

The hypothalamus is another area of the brain with differences between males and females. The hypothalamus is located at the base of the brain and regulates many of the body’s basic functions. Eating, sleeping, temperature control, and reproduction are some of the basic functions it provides. Many of which are primal in state. The preoptic area is involved in mating behavior. In males this area is about 2 times larger than in females, but also contains 2 times more cells. This enlargement is dependent on the amount of male sex hormones or androgens.

Scientists have discovered a region in the cortex called the inferior-parietal lobule (IPL) in the parietal cortex. This area is significantly larger in men than in women. More specifically, the left side IPL is larger than the right in men. Whereas the right side is larger than the left in the female brain. This is the same area that was shown to be larger in the brain of Albert Einstein, as well as in other physicists and mathematicians (Sabbatini). It seems that the IPL correlates with the mathematical ability. The IPL lets the brain process input from the senses and aid in selective attention and perception. Studies have shown that the right IPL is linked to understanding spatial relationships and the ability to sense relationships between body parts (Sabbatini). The left on the other hand, is linked with perception of time and speed, and the ability to rotate 3-D figures in your brain.

Sex hormones play a significant role in developing a male or female differentiated brain. This lies in the mother’s hormone levels during pregnancy. Studies in lab animals have proved that altering hormone levels during pregnancy can produce brains with male or female traits depending on the type of hormone added to the pregnant female. For instance, if testes of newborn male rats are removed, they tend to develop thicker left hemispheres than rats whose testes are still intact. This is a female trait. If a pregnant female monkey is injected with testosterone, the offspring will show one or more male traits. These traits are known as the five characteristics of the male-differentiated brain: aggression, competition, self-assertion, self-confidence, and self-reliance. These characteristics are related to levels of testosterone whether in males or females. Men who act as if they have female differentiated brains, in fact have lover levels of testosterone, and women who behave with male differentiated brains possess higher levels of testosterone than normal. The male differentiated brain tends to be one that is aggressive, spatial, and math proficient. The female differentiated brain is one in which is nurturing, and verbose. There can be a relationship between body asymmetry and gender behavior. The amount of androgens and estrogens in the body can affect both gender behavior and body asymmetry. These hormones are passed from mother to newborn during the embryonic stage of life. For example: if a female embryo receives an excess of androgen during pregnancy, she is likely to have a male appearance, behavior and male differentiated brain. On the other hand, if a male embryo receives an excess of estrogen. Male appearance, and behavior is prevalent, but with a female differentiated brain. When a female embryo is subjected to a large amount of estrogen, she has an excessive female appearance and behavior. The same is true for males when they receive large amounts of androgen during pregnancy. They tend to be a super male with lots of hair and very aggressive. Various events can cause this to happen during pregnancy. The unborn child can be subjected to various hormones during crucial periods during pregnancy. Mutations in the chromosomal matter may cause one of the events to occur. Major or sustained stress levels will suppress testosterone levels; renal dysfunction will produce too much testosterone. Injections for diabetes will cause an increase in estrogen, barbiturates, and exercise. Spurt exercise will cause an increase in testosterone, while sustained exercise like a long run or jogging will lower the amount. While the brain is immersed in hormones during pregnancy, the true affect does not appear until puberty begins and the brain becomes activated due to the full immersion of the hormones in the body.

Understanding that the differences between the male and female differentiated brain is not limited to just the external anatomical sex of the person. Many factors determine whether or not the brain is male or female. The actual size of the brain corresponds to the size of the individual. Does a larger brain determine the amount of knowledge one can possess? No. Through the research, we know that male differentiated brains tend to be more mathematical, spatial, and aggressive. Where the female differentiated brain tends to be more nurturing and verbose. This is not to say that women are not capable of higher achievement in math, but on average males tend to achieve higher test scores on standardized tests in math. Depending on the amount of hormonal activity during the embryonic stage of development may indicate whether a person’s brain is male or female differentiated.

Studies that have looked at differences in the brains of males and females have focused on:

(1) Total brain size: In adults, the average brain weight in men is about 11-12% MORE than the average brain weight in women. Men’s heads are also about 2% bigger than women’s. . This is due to the larger physical stature of men. Male’s larger muscle mass, and larger body size require more neurons to control them. This does not suggest that due to the larger brain, males are smarter than females.

(2) Cell number: men have 4% more brain cells than women , and about 100 grams more of brain tissue. this may explain why women are more prone to dementia (such as Alzheimer’s disease) than  men, because although both may lose the same number of neurons due to the disease, “in males, the functional reserve may be greater as a larger number of nerve cells are present, which could prevent some of the functional losses.”

(3) Cellular connections: while men have more neurons in the cerebral cortex, women have a more developed neuropil, or the space between cell bodies, which contains synapses, dendrites and axons, and allows for communication among neurons .

(4) Corpus callosum: it is reported that a woman’s brain has a larger corpus collusum, which means women can transfer data between the right and left hemisphere faster than men. Men tend to be more left brained, while women have greater access to both sides.(however other studies have told a different story).

(5) Hypothalamus: LeVay discovered that the volume of a specific nucleus in the hypothalamus (third cell group of the interstitial nuclei of the anterior hypothalamus) is twice as large in heterosexual men than in women and homosexual men, thus prompting a heated debate whether there is a biological basis for homosexuality .

(6) Language: two areas in the frontal and temporal lobes related to language (the areas of Broca and Wernicke) were significantly larger in women, thus providing a biological reason for women’s notorious superiority in language-associated thoughts. For men, language is most often just in the dominant hemisphere (usually the left side), but a larger number of women seem to be able to use both sides for language. This gives them a distinct advantage. If a woman has a stroke in the left front side of the brain, she may still retain some language from the right front side. Men who have the same left sided damage are less likely to recover as fully. Curiously, oriental people which use pictographic (or ideographic) written languages tend also to use both sides of the brain, regardless of gender.

(7) Inferior parietal lobule (IPL): it is a brain region in the cortex, which is significantly larger in men than in women. This area is bilateral and is located just above the level of the ears (parietal cortex). Furthermore, the left side IPL is larger in men than the right side. In women, this asymmetry is reversed, although the difference between left and right sides is not so large as in men. This is the same area which was shown to be larger in the brain of Albert Einstein, as well as in other physicists and mathematicians. So, it seems that IPL’s size correlates highly with mental mathematical abilities. Studies have linked the right IPL with the memory involved in understanding and manipulating spatial relationships and the ability to sense relationships between body parts. It is also related to the perception of our own affects or feelings. The left IPL is involved with perception of time and speed, and the ability of mentally rotate 3-D figures .

(8) Orbitofrontal to amygdale ratio (OAR): In one project, they measured the size of the orbitofrontal cortex, a region involved in regulating emotions, and compared it with the size of the amygdala, implicated more in producing emotional reactions. The investigators found that women possess a significantly larger orbitofrontal-to-amygdala ratio (OAR) than men do. One can speculate from these findings that women might on average prove more capable of controlling their emotional reactions.

(9) Limbic size: females, on average, have a larger deep limbic system than males. This gives females several advantages and disadvantages. Due to the larger deep limbic brain women are more in touch with their feelings, they are generally better able to express their feelings than men. They have an increased ability to bond and be connected to others . Females have a more acute sense of smell, which is likely to have developed from an evolutionary need for the mother to recognize her young. Having a larger deep limbic system leaves a female somewhat more susceptible to depression, especially at times of significant hormonal changes such as the onset of puberty, before menses, after the birth of a child and at menopause. Women attempt suicide three times more than men. Yet, men kill themselves three times more than women, in part, because they use more violent means of killing themselves (women tend to use overdoses with pills while men tend to either shoot or hang themselves) and men are generally less connected to others than are women. Disconnection from others increases the risk of completed suicides.