Genesis of Brain

By: Pharma Tips | Views: 20767 | Date: 30-Apr-2011

From a single fertilised egg of about 0.14 millimetres in diameter, to an adult human being, the neurophysiology of development of the brain and nervous system is nothing short of remarkable.We are born with around 100 billion neurons, and the development of the brain continues long after birth, with dendrites of some neurons in the neocortex continuing to grow well into old age.


Genesis of Brain







From a single fertilised egg of about 0.14 millimetres in diameter, to an adult human being, the neurophysiology of development of the brain and nervous system is nothing short of remarkable.We are born with around 100 billion neurons, and the development of the brain continues long after birth, with dendrites of some neurons in the neocortex continuing to grow well into old age.



1. INTRODUCTION
From a single fertilised egg of about 0.14 millimetres in diameter, to an adult human being, the neurophysiology of development of the brain and nervous system is nothing short of remarkable. We are born with around 100 billion neurons, and the development of the brain continues long after birth, with dendrites of some neurons in the neocortex continuing to grow well into old age. The brain, together with the spinal cord, makes up the central nervous system. This is the 'control centre' which coordinates the body’s functions.Between the surfaces of the brain and the skull there are three layers of membrane called the meninges, which completely cover the brain and spinal cord. Between two of these layers is a space called the subarachnoid space. The subarachnoid space contains a fluid called cerebrospinal fluid (CSF). The human brain goes through several large-scale changes as the individual progresses from embryo through to old age. Developmental neurobiology concerns itself with the development of the brain. The process of neurogenesis populates the brain, and then programmed cell death cuts the growing brain down to size. During adolescence the brain goes through a process of synaptic pruning. Brain aging is the major risk factor for most common neurodegenerative diseases, including alzheimer's disease, cerebrovascular disease, Parkinson's disease and amyotrophic lateralising Sclerosis. Other risk factors, including genetic mutations, female sex, low educational attainments and head injury contribute much less to the risk of these disorders. The molecular biology of brain aging is poorly understood and this is of importance when seeking to understand the pathogenesis of alzheimer's disease. In humans, brain aging is characterized by macroscopic changes that include: enlargement of ventricles, widening of sulci, thinning of gyri and a progressive decrease of brain weight, which is around 10% at 80 years of age. 
These alter¬ations can be summarized by a significant shrinkage of the whole organ or a progressive reduction of the brain-to¬skull volume.(1) During the past decades this age-related atrophy of the brain was proposed to be due to the progressive decrease of the number of neurons with advancing age. More recently, it has been clearly documented that a significant loss of neurons affects selected areas of the brain only in neurode-generative diseases, i.e. Alzheimer’s and Parkinson’s disease, while in physiological aging neuronal death is not significant even in zones of the central nervous system (CNS) particularly vulnerable to aging (i.e. the hippocam¬pus).(2) Atrophy of neurons and of their connections have been claimed to be responsible of the macroscopic alterations occurring in physiological aging of the human brain, however a still unanswered question is what are the causative events and/or mechanisms able to trigger the initial changes leading to nerve cell dys¬function and atrophy. Research also shows that the morphofunctional involutive rearrangements occur-ring at synapses and mitochondria in aging and on the potential role played by zinc dishomeostasis in these alterations and some disease related with the ageing of brain.


2. GENESIS OF BRAIN
2.1 THE FIRST EIGHT WEEKS:(3)
Through the initial stages of cell development and division, when the zygote (The diploid cell resulting from union of a sperm and an ovum.), duplicates to around 32 cells, and becomes what is known as the blastocyst, implantation in the uterine wall occurs. This establishes the rudimentary placenta as the embryonic disk, which will give rise to the embryo. The first 8 weeks after implantation are termed the embryonic period. It is during this time that the organs, systems and tissues of the future being are induced, differentiated, and put into place. The remaining 30-40 weeks of gestation are devoted to growth, development and refinement of these organs, systems and tissues. The latter tends to be more amenable to subsequent intervention. At about 14 days, the embryo is about 2 millimetres long. By the 17th - 20th day of gestation, the primitive embryo develops what is known as the neural plate, which is a sheet of cells that will ultimately develop into the nervous system of the individual. 
 From: Prentice Hall -cwx.prenticehall.com
By the 23rd day, or the third week of development of the new entity, the neural groove (which is the embryonic brain structure) is visible. Two days later, the edges of this groove, which have continued to 'curl up' until now, start to join together to form the neural tube, which forms the basis of the entire nervous system. The closure of the neural tube is dependent upon protein bridges bound together by calcium.It is interesting to note that the neural tube, at this stage of development, contains around 125,000 cells. At birth, the human brain contains around 100 billion neurons - we can infer from this information that new neurons are being generated at the rate of about 250,000 per minute during the nine months of gestation. By the 27th day, the ends of the tube - the pores close. Once closure is affected, the neural crest also begins to form. The crest is the source of neurons for the peripheral nervous system as well as for chromoform cells in the inner part of the adrenal gland. Chromoform cells are responsible for synthesising and secreting two important hormones instrumental in emotional arousal - epinepherine and norepinepherine. 
The neural crest is derived from neuroectodermal cells that originate in the dorsal aspect of the neural folds or neural tube; these cells leave the neural tube or folds and differentiate into various cell types including dorsal-root ganglion cells, autonomic ganglion cells, the chromaffin cells of the adrenal medulla, Schwann cells, sensory ganglia cells of cranial nerves, 5, 9, and 10, part of the meninges, or integumentary pigment cellsThe neural tube is of course the precursor of the spinal canal. Failure or ineffective closure of the neural tube, is the cause of spina bifida (embryologic failure of fusion of one or more vertebral arches; subtypes of spina bifida are based on degree and pattern of malformation associated with neuroectoderm involvement); meningocele (Protrusion of the membranes of the brain or spinal cord through a defect in the skull or spinal column); myelocele anencephaly; and pilonidal cyst.
Also during this third busy week of embryonic development (or proliferation of cells), three vesicles develop at the 'head end' of the neural tube, which will develop into: The forebrain or proencephalon, the midbrain or mesencephalon, the hindbrain or rhombencephalon. These rudimentary 'parts' will further differentiate in due course through proliferation and migration.

From Prentice Hall -cwx.prenticehall.com
 
From:Prentice Hall - cwx.prenticehall.com
Table 1: Summary of the Developmental Sequence of Brain Regions
Three-vesicle stage Five-vesicle stage Brain region 
Prosencephalon Telencephalon Cerebral hemisphere 
Diencephalon Diencephalon 
Mesencephalon Mesencephalon Mesencephalon 
Rhombencephalon Metencephalon Pons 
MyelencephalonCerebellum
Medulla oblongata
Currently, it is not known what initiates migration, and many theories have been proposed. New molecular imaging techniques are being utilised in research establishments and may reveal the triggers and antecedants. Many neuroblasts migrate (travel) in a fashion we can consider as similar to an amoeba, that is, by extending a part of itself, grabbing something to hang onto and then pulling the rest of the cell along. In the neocortex and cerebellum, neuroblasts must travel to their final destinations, locating themselves in the correct cell layer, orient themselves, and initiate dendritic growth to make the appropriate synaptic connections.
 
From: Prenticice Hall - cwx.prenticehall.com
Deviations from the 'appropriate' locations can lead to abnormalities in brain structure and behaviour. An example of this was noted by Geshwind and Galaburda in 1985, in a few dyslexic individuals. Failure in the proper migration during foetal development was found in abnormal arrangement of neurons in a region of the left hemisphere important for language comprehension.
 
Abnormal cell aggregation in the brain of a person with dyslexia.
Brain malformations may result from exogenous and endogenous causes. Exogenous causes are nutritional, radiologic, viral, chemical, medications, or ischemic. Endogenous causes are genetic. This migration which results in cells being arranged in a particular alignment with other cells by layer and direction is called aggregation. Theoretically, each cell in the human body carries with it the entire DNA coding of the individual and can therefore differentiate into any cell type required at a particular location. Growth cones, at the end of 'buds' on the cell body are responsible for the growth of axons and dendrites which 'close' the synaptic connections. The growth cones appear to 'recognise' target cells. 
The third and fourth week sees the development of the spinal cord, and by the end of the fourth week of gestation, the marginal layer nerve fibres appear and begins to accept fibres of ganglion nerves that are sent in to them from the peripheral ganglia. Once onnected, they begin to function. The cerebral hemispheres differentiate around the fifth week. By the end of the sixth week the rudimentary development of the five brain vesicles is complete. The cerebral hemispheres have grown and now cover the diencephalon, the mesencephalon and the cerebellum, which has only just begun development. As these two hemishpheres grow toward each other, they meet in the middle and continue their growth downwards. The membrane that separates them is the falx cerebri - a part of the dural membrane system of the meninges, of which it is the outer layer - the dura mater. The fissure thus created is known as the longitudinal fissure. By the seventh week of life, the embryo will achieve a crown to rump length of around 20-25 millimetres. It is at this stage of development that differentiation of the genitals - male or female - takes place. In the seventh week also, the pineal gland forms, as does the choroid plexus, that place in the roof of the diencephalon whose specialised cells secrete cerebrospinal fluid. By the eighth week, which is the end of the embryonic period, all of the organ systems are established - the blue prints have been laid out - and from this time forward the organ system will continue to develop.   From:  Prentice Hall -cwx.prenticehall.com
The cerebral cortex has undergone remarkable growth and development during this first eight weeks. By its growth and folding, it now caps two thirds of the sub-cortical brain. First the frontal lobes form, then the parietal and concurrently, the temporal and occipital lobes. The limbic system is well developed by this time and all will continue to grow and develop during the next stages.

2.2 THE FOETAL STAGE OF DEVELOPMENT:
The third through ninth month is known as the foetal stage of human development. Brain functions are expressed through activity of neural circuits. These circuits are formed throughout the foetal period and throughout the life by the formation of synapses in a process which has been called synaptogenesis. Not all synapses formed in the foetal period will survive, and new synapses are formed shortly after birth. During the third month the foetus will have grown to around 75mm and a growth rate of about 12 mm each week. The face now looks much more human, with the eyes having moved from the sides to a more frontal position. The ears are visible and some of the inner structures of the ears, the tympani (ear drums), and vestibular apparatus are now recognisable. At 9 weeks the spinal galant reflex emerges. Ossification of cartilage continues throughout this stage of development, as does refinement of the organs and systems of the body. At 11 weeks, the palmar reflex emerges.The communication lines between the brain and the periphery of the body (cortico-spinal tracts) develop very rapidly and are largely complete by the seventh month of gestation. The cerebral cortex continues to grow and fold in an effort to develop more surface area.

2.3 THE SECOND TRIMESTER:
In the fourth month of gestation, the foetus is about 12-13 centimetres in length from crown to rump. This is the beginning of motor function for the new entity, as evidenced in the first bringing of its hands together and turning bodily within the uterus.By this stage the foetus is now inhaling and exhaling amniotic fluid. All the raw materials are in place and the brain and spinal cord are growing at a rapid rate. At around 18 weeks, the asymmetrical tonic neck reflex emerges. The fifth month sees the foetus growing to around 165 millimetres, and motor development rate increases, as felt by the interuterine movements of the foetus. The development of the vernix caseosa (the fatty substance, consisting of desquamated epithelial cells, lanugo hairs, and sebaceous matter, which covers the skin of the fetus) takes place. By the sixth month of pregnancy the foetus will have reached a length of about 255 millimetres (10 inches). Sebaceous glands are evident and lymph glands which will help to protect the foetus from noxious substances from this moment to the end of its days. Up until now the foetus has relied exclusively on mother's anti-bodies for protection from toxins including environmental ones. It is here that the rooting reflex emerges, this reflex will be required for early feeding after birth. The cerebral hemispheres now cover the whole top and sides of the brain including the cerebellum. Cerebellar development begins from this moment, but will not be complete until two years after birth. Six distinct layers are now differentiated within the cerebral cortex, and almost all of the neurons within the central nervous system are present by the end of this sixth month of life and neural 'circuitry' continues to develop.

2.4 THE THIRD TRIMESTER:
The seventh month of gestation witnesses the appearance of many new osseous (bone) formations. The developing foetus is now 305 millimetres long. Sulci and gyri (the convolutions) of the brain are much more in evidence, membranes over the pupils disappears and the eyes open. The insula and the tubercula quadrigemina develop.The seventh month is essentially characterised by rapid growth, development and organisational refinement. By the eighth month, the foetus will be 405+ millimetres (16+ inches), from crown to heel. During this month of development the foetus will strengthen its body and the nervous system will increase its connections and receive more sensory input, and gain more motor control. During the ninth month the foetus will reach 510 millimetres (20 inches) or more. All ossification points are in place, and further refinement of motor and other neuronal connections takes place for the ninth month foetus is usually very active.
           Picture from Prentice Hall -cwx.prenticehall.com
Table 2: Summary Table of the Stages of Brain Development
Developmental StageMain Feature of Developmental Stage
  Induction
Production of cells that will become nervous tissue
  Proliferation
Cell reproduction (mitosis)
  Migration
Location of cells in appropriate brain areas
  Differentiation
Development of neurons into particular type
  Synaptogenesis
Formation of appropriate synaptic connections
  Selective cell death
Elimination of mislocated cells and cells that failed to form the proper synaptic connections
  Functional validation
Strengthening of synapses in use, weakening of unused synapses
 The Labour Process and Delivery: The labour and birthing process are part of the foetus' continuing education in sensory motor perception and integration. During uterine contractions the pressure of the amniotic fluid is increased, and as the process continues, it forces part of the fluid filled membraneous sac containing the foetus into the birth canal. At this point the foetus' head enters the canal (engages) with a volume of fluid preceding it. Soon the membranes will rupture under the continued pressure of the contractions, and still further contractions will force the foetus down the birth canal. The head is subjected to pressure from all sides and the still forming skull accommodates this by allowing the head to shape somewhat to the opening. Once free of the birth canal, the body still has a twisting wringing sort of exit to make, comparable to a whole friction body massage during which the spinal galant reflex is instrumental in the foetus making it's way down the birth canals. At birth, all reflexes are of brain stem origin with minimal cortical control. Many children who are caesarian births, and/or have missed out on some part of the natural development or birth process, viz. trauma, toxicity exposure, anesthetics etc., are more at risk of having retained reflexes that will require specialist intervention for either transformation or inhibition. These retained reflexes are of themselves evidence of delayed motor development that if left unattended, can further inhibit normal sensory-motor development, impacting upon subsequent learning capability.

2.5 POSTNATAL BRAIN DEVELOPMENT:(4)
The weight of the brain of the newborn is approximately 300 grams (or around 10% of body weight) in contrast to the adult brain - which weighs approximately 1400 grams (only 2% of body weight). Brain weight increases with age and acheives 'adult' weight between six and fourteen years of life. We are born with our full compliment of neurons. Postnatal growth of the brain is due to an increase in the size of neurons, and subsequent increase in number of supporting cells (glia), development of neural processes and synapses (The contacts with other neurons which provide for the 'circuitry' of the brain), and the laying down of the insulation of nerve processes (myelin sheaths). Synapses are formed at a very rapid rate during the early months of life, usually achieving maximum density between six and twelve months after birth. There is a decrease after this due to disuse or natural attrition. In the neonate, metabolic activity is most noticeable in the sensory-motor cortex and brain stem, areas necessary for reflex functions. At two to three months, metabolic activity is prominent in the visual and the adjacent parietal cortex which corresponds with the development of visual-spatial integrative function. Between six months and a year, metabolic activity is notably in the frontal cortex which corresponds to the development of higher cortical functions such as interactions with the immediate environment, stranger anxiety, etc. 
Functional imaging studies have demonstrated that early stimulation will enhance brain function, whereas a lack of early stimulation correspondingly leads to loss of brain function. Developmental research has determined that there are "developmental windows of opportunity" for different brain functions. As a guide, the windows of opportunity for emotional development is 0-2 years, mathematics and logic is around 0-4 years, language is 0-10 years, and music from about 3-10 years. If these "windows of opportunity" are not appropriately capitalised upon by parents, care-givers and educators, then impedance of the potential of the child, and/or a loss of the appropriate function will result. 

2.6 PRE-NATAL DEVELOPMENT:(5)
Developmental neurobiology concerns itself with the development of the brain. The process of neurogenesis populates the brain, and then programmed cell death cuts the growing brain down to size Adolescence. During adolescence the brain goes through a process of synaptic pruning. The purpose of synaptic pruning is a simple means of removing un-necessary neuronal structures from the brain, as the human develops, the need to understand more complex structures becomes much more pertinent and more simple associations formed at childhood are thought to be removed for more complex structures. Despite the fact it has several connotations with regulation of cognitive childhood development, pruning is thought to be a process of removing neurons which may have become damaged or degraded in order to further improve the "networking" capacity of a particular area of the brain. Furthermore, it has been stipulated that the mechanism not only works in regards to development and reparation, but also as a means of continually maintaining more efficient brain function by removing neurons by their synaptic efficiency. During maturation phases in humans In terms of humans, synaptic pruning has been observed through the inference of differences in the estimated numbers of glial cells and neurons between children and adults, which differs greatly in the area of the mediodorsal thalamus. In a study conducted in 2007 by Oxford University, it was found that by comparing 8 newborn human brains with those of 8 adult brains using estimates based upon size and gathering from stereological fractionation, showed that on average, adult neuron estimates were 41% lower than those of the newborn. 
However, in terms of glial cells, adults had far larger estimates than those in newborns, 36.3 million on average in adult brains, compared to 10.6 million in the newborn samples. In terms of the development of the brain, the structure is thought to change due to the structural changes, in which degeneration and deafferentation occur in postnatal situations, although in terms of some studies, these phenomenon have not been observed.(6) In the case of development, neurons which are in the process of loss via programmed cell death are unlikely to be re-used, but rather replaced by new neuronal structures or synaptic structures, and have been found to occur alongside the structural change in the sub-cortical gray matter.

2.7 AGING:
Over the years, the human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter  region in the genome.                                                                
Genes that are down-regulated over the age of 40 include:                                                                                                                                                                                                     
GAMPA receptor subunit (GluR1 alpha-amino-3-hydroxy-5-Methyl-4-isoxazolePropionic Acid receptor)
NMDA R2A(N-methyl D-aspartate) receptor subunit (involved in learning) 
Subunits of the GABA-A receptor 
Genes involved in long-term potentiation e.g. calmodulin 1 and CAM kinase II alpha. 
Calcium signalling genes 
Synaptic plasticity genes 
Synaptic vesicle release & recycling genes 
Genes that are upregulated include:
Genes associated with stress response and DNA repair 
Antioxidant defence 
Normal aging is distinct from Neurodegenerative disease. DNA damage due to oxidation increase as the brain ages, possibly due to impaired mitochondrial function.
Neuroinflamation is a common feature of aging in the mammalian brain. Astrogliosis [measured by immunohistochemistry of GFAP, (Glial fibrillary acidic protein)] increases with age in mouse, rat as well as human brain.
 
3. CHEMICAL AND BIOLOGICAL CONCEPTS OF AGEING

3.1 CYTOKINES AND THE AGEING BRAIN:

By the age of 80, the brain of a non-demented human exhibits 10–15% neuronal loss and typical pathological features of Alzheimer’s disease (AD), such as amyloid plaques and neurofibrillary tangles (Charles Duyckaerts, Hospitalier Pitie-Salpetriere, Paris, France). Therefore, additional features must be present for onset of AD. In particularAD is associated with inflammation in the CNS and increased expression of complement and acute-phase proteins.(7) Mounting evidence that non-steroidal anti-inflammatory drugs (NSAIDs) delay the onset of AD suggests that thisinflammation contributes to the disease process.(8)
The expression of the prostaglandin-synthesizing enzyme, cyclo-oxygenase-2 (COX-2), – one of the main targets of NSAIDs – is upregulated in AD brain. The resultant rise in prostaglandin E2 (PGE2) is responsible for the induction of the inflammatory cytokine, interleukin (IL)-6. Potential sources of IL-6, such as microglial cells become activated during ageing. (9)                                                  
 Underlying mechanisms: Ageing has long been associated with impaired peripheral immune responses.With age, naïve T cells levels decrease, natural killer (NK) cell activity decreases and in addition, levels of advantageous gut bacteria decrease. This impaired specific immunity might result in an increase in active innate-immunity.

3.2 DIET AND HORMONES IN AGEING:

It was reported that Vitamin E inhibits age-associated increases in peripheral macrophage COX-2 expression, and subsequent serum PGE2 in humans (Dayong Wu, Tufts University, Boston, MA, USA) and brain IL-6 in rodents (Johnson). These results indicate that free radical formation, possibly owing to inflammation, contributes to tissue damage with ageing.In an eight-year follow-up study of a French cohort of aged individuals, Jean-Marc Orgogozo (Hopital Pellegrin, Bordeaux, France) revealed that moderate red wine consumption (providing anti-oxidative polyphenols) and fish-rich diets (providing anti-inflammatory poly-unsaturated -3 fatty acids) reduce the risk of dementia. Thus, dietary factors with anti-inflammatory properties might be important in the evasion or delay of dementia (i.e. ‘successful ageing’).Hormonal changes occur during ageing, such as reduced oestrogen (menopause), testosterone (andropause) and growth hormone and/or insulin-like growth factor-1 (IGF-1) (somatopause), and evidence is emerging to suggest that these changes might play a role in brain ageing. Hans Koppeschaar (Universitair Medisch Centrum Utrecht, The Netherlands) reported declining cognitive performance in elderly men that correlated with decreased IGF-1.In addition, IGF-1 prevents kainate-induced cognitive impairments in vivo, possibly through inhibition of TNF. Despite such encouraging findings, the positive association between IGF-1 and certain cancers raises caution about the Dehydroepiandrosterone (DHEA) also correlates with increased serum IL-6 and TNFand chronic use of IGF-1 and other hormones to counter brain ageing.(10) Decreased a shift from T helper type 1 responses towards type 2 responses, decreased NK activity, increased antibody production and decreased cytotoxic T cell responses. This shift in immune mediators might lead to increases in tumour growth and an acceleration of atherosclerosis because of increased monocyte activation. Interestingly, DHEA inhibits IL-6 synthesis in human monocytes, suggesting that some of its claimed effects on ‘successful ageing’ are mediated through inhibition of this cytokine. The myriad of factors involved are reviewed in more detail elsewhere.(11)

3.3 SYNAPTIC PLASTICITY AND AGING:

With advancing age, a progressive impairment in cell-to ¬cell communication is documented to occur and it is sup-posed to constitute the underlying alteration responsible of the age-related decline of important brain performances (e.g. learning and memory). In the fully differentiated adult CNS, structural adaptive changes occur throughout the individual lifespan, i.e. the synaptic terminal regions are in a very dynamic condition responsible for continuous remodelling interventions to optimize their architecture to the changing experiential framework.(12) In this context, an important research issue is represented by synaptic plastic¬ity.(13) Function-related ultrastructural parameters of the synapses include their numeric density, i.e. the number of contacts in a unit vol¬ume of tissue (Nv), the average area (size) of the junctional zones (S) and the overall contact area of the synapses per unit volume of tissue referred to as synaptic surface density (Sv). Synaptic junctions are well differentiated zones of the neuronal membrane and this has enabled to carry out reli-able measurements of the above parameters in different animal species both by applying conventional staining pro¬cedures and preferential cytochemical techniques.(14)(15) 
The marked increase of the syn¬aptic size in normal aging and AD is referred to represent a compensating phenomenon to the decreased synaptic numeric density, but this event appears to be a too weak reaction clearly unable to fully recover an overall synaptic surface density needed to perform adequately the many complex tasks in charge to the neuronal network. A tenable interpretation of these data is that synaptic plasticity pro¬gressively declines with aging and AD. In turn,(16) this is supposed to be due to the many and different unfavourable factors that consti¬tute basic biological determinants pacing physiologically the process of aging.An uncontrolled acceleration (or an increased and prolonged action) of these unfavourable events may result in a clear manifestation of age-related pathological conditions. A growing body of experimental and clinical data is documenting that the decay of mito¬chondrial functions may play an early and critical role in the above processes.
The significant reduction of the overall synaptic contact area found both in physiological aging and at a higher extent in AD may constitute the reliable structural correlate of the marked impairment in cognitive functions commonly associated with physiological aging and AD pathology.

3.4AGE-RELATED DECLINE OF THE MITOCHONDRIAL
   METABOLIC COMPETENCE IN THE AGING BRAIN:
Synaptic transmission, the key event of the function of the nervous system, is accomplished by the release of neu¬rotransmitters from pre-synaptic terminals of one neuron that activates post-synaptic receptors on dendrites of another neuron. In this process, repeated events of oxida¬tive and metabolic stress occur at synaptic terminals as a consequence of changing ion concentrations and energy needs. Mitochondria play a pivotal role both in matching ATP provision with synaptic energy demands and in regu¬lating ion.(17)(18) In addition, since ion pumps use ATP, the adequate production of this molecule is of critical importance also in ion buffering processes. Because of their central functions, mitochondria are strategically located within different neu¬ronal compartments (e.g. cell body, axons, dendrites, syn¬aptic terminals) in order to provide the actually needed ATP amounts. Synaptic mitochondria can be reliably supposed to play an important role in the functional and structural remodelling of the synaptic junctional areas.(19) Several quantitative esti¬mations of the mitochondrial structural dynamics have been carried out in aging and a clear trend has been envis¬aged: in the old organisms mitochondria decrease in num¬ber, but increase in size and the final outcome of these balanced changes is that the mitochondrial volume density (or fraction) is maintained constant during the individual’s lifespan.(20)(21)(22) The functional meaning of these age-related ultrastructural changes has been tested by quantitative cytochemistry of cytochrome oxidase (COX), a key enzyme of the mitochondrial respiratory chain, as evidenced by using diaminobenzidine (DAB) as electron donor. 
Namely, by matching the ultrastructural features of the COX-positive organelles with the amount of the cytochemical precipitate due to enzyme activity it has been found that COX activity significantly decreases in aging. Moreover, it appears that the fraction of over-sized mitochondria is responsible of these age-related decays since the small and medium sized organelles show the same value of the ratio between the area of the cyto¬chemical precipitate and the area of the mitochondrion both in adult and old animals.(23)(24) COX, an integral transmembrane protein of the inner mitochondrial membrane, is the terminal enzyme of the electron transport chain (complex IV), thus the esti¬mation of its activity has been considered a reliable endog¬enous marker of neuronal metabolism.(25) Conceivably, the overall area of the DAB-COX cytochem¬ical precipitate represents the surface fraction of the inner membrane of the single mitochondrion directly involved in cellular respiration and when referred to the overall area of the organelle it may be considered a reliable index of the mitochondrial metabolic competence (MMC).(26)

3.5 AGE-RELATED SYNAPTIC AND MITOCHONDRIAL DYSFUNCTION: THE ZINC CONNECTION:
Three distinct pools of cellular zinc can be found in the central nervous system: the most abundant fraction, accounting for about 80% or more, is tightly bound to intracellular proteins and is immobile; a second pool (about 5–15% of cellular totals) is sequestered within the vesicles present at glutamatergic synapses.(27) This vesicu¬lar zinc is found colocalized with glutamate and can be released into the synaptic cleft where it has neuromodula¬tory effects. The third pool of zinc (about 5%) is repre-sented by the free, unbound ions in the cytoplasm. Although still under investigation, it has been reported that a transient ([Zn++]i) increase may cause excitotoxic injury(28)(29)and, in turn, the adequate control of this parameter is to be considered a key event in neuronal dam-age.(30) Namely, a hypothe¬sized sequence of steps leading to neuronal injury and involving a defective control of zinc ion intracellular con-centration may be the following:
(1) The zinc present in the synaptic vesicles is released from pre-synaptic terminals upon stimulation.
(2) A substantial increase of the synaptic zinc concentration occurs during neural transmis¬sion.
(3) Following glutamate receptor activation, zinc ions can enter neurons through the same routes of calcium ions.
(4) This may result in the rapid micromolar increase of intracellular zinc levels that may directly affect mitochon¬drial functions. In the cell, zinc ion homeostasis is in charge to the coordinated action of three systems involved in: (a) the extrusion by zinc transporters; (b) buffering by metallo¬thioneins; (c) sequestration by mitochondria. If these three systems, or their coordinated action is impaired, the rise in ([Zn++]i) may persist longer than needed for physiological function and this may result in a toxic effect of this ion. 
With specific reference to cellular bioenergetics, elevated ([Zn++]i) are reported to exert inhibiting actions on differ¬ent targets. Intracellular overload of zinc ions inhibits gly-colysis by impairing the activity of glyceraldehyde-3-phosphate dehydrogenase.(31) In mito¬chondria, zinc inhibits the alpha-ketoglutarate complex of the tricarboxylic cycle and also complex III of the electron transport chain at cytochrome bc1. Reduction of oxygen consumption, decreased ATP levels, impaired mitochon¬drial membrane potential increased free radical generation leading to neuronal death are the reported cellular conse¬quences of increased ([Zn++]i).(32)
In conclusion, although many factors involved in brain aging have been clearly identified, given the multifactorial and progressive aspects of this process, the early triggering causative events should deserve specific investigation. Among these, recent evidence suggests that zinc ion disho¬meostasis may play a pivotal role being consistent with the reported primary deterioration of synapses and synaptic mitochondria.
  

4. DISEASE RELATED WITH AGE
4.1 ALZHEIMER’S DISEASE:
Alzheimer's disease (AD), also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist Alois Alzheimer in 1906. Generally it is diagnosed in people over 65 years of age,(33) although the less-prevalent early-onset Alzheimer's can occur much earlier. An estimated 26.6 million people worldwide had Alzheimer's in 2006; this number may quadruple by 2050.
EPIDEMIOLOGY:
In 1996, approximately 4 million people in the United States were clinically diagnosed with AD; this figure is expected to triple in the next 50 years. Women are more affected than men at a ratio of almost 2:1, partly because of the larger population of women who are over 70 years of age; however, the prevalence is still higher in women even after statistical correction for longevity.(34)Age is another important risk factor. At the age of 60, the risk of developing AD is estimated to be 1%, doubling every 5 years to reach 30% to 50% by the age of 85.(35)Other reported risk factors include lower levels of intelligence and education (defined as primary education only), small head size, and a family history of the disease. A recent meta-analysis of head injury as a risk factor for Alzheimer's disease seems to establish that in males there is a definite association.
PATHOPHYSIOLOGY:
The classic neuropathologic findings in AD include amyloid plaques, neurofibrillary tangles, and synaptic and neuronal cell death. Granulovacuolar degeneration in the hippocampus and amyloid deposition in blood vessels may also be seen on tissue examination, but are not required for the diagnosis.
Amyloid Plaques:
Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is a 39- to 42-amino acid peptide that is formed by the proteolytic cleavage of β-amyloid precursor protein (APP) and is found in extracellular deposits throughout the central nervous system (CNS).(42) Aβ is believed to interfere with neuronal activity because of its stimulatory effect on free radical production resulting in oxidative stress and neuronal cell death.
Neurofibrillary Tangles:
Neurofibrillary tangles are paired helical filaments composed of tau protein, which in normal cells is essential for axonal growth and development. However, when hyper-phosphorylated, the tau protein forms tangles that are deposited within neurons located in the hippocampus and medial temporal lobe, the parieto-temporal region, and the frontal association cortices leading to cell death.
Neuron and Synapse Loss:
Areas of neuronal cell death and synapse loss are found throughout a similar distribution pattern as the neurofibrillary tangles, but greatly affect neurotransmitter pathways. The death of cholinergic neurons in the basalis nucleus of Meynert leads to a deficit in acetylcholine (Ach), a major transmitter believed to be involved with memory. In addition, serotonergic neurons in the median raphe and adrenergic neurons in the locus coeruleus lead to deficits in serotonin and norepinephrine, respectively.
Chromosomal Mutations:
Genetic mutations in chromosomes 21, 14, and 1 have been shown to cause familial early-onset AD. Inherited in an autosomal-dominant pattern, the chromosomal mutations account for fewer than 5% of all cases and result in the overproduction and deposition of Ab.(43) Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down syndrome patients with the trisomy 21 aberration were observed to develop dementia in the fourth decade. Mutations in presenilin 1 (PS-1) on chromosome 14 and presenilin 2 (PS-2) on chromosome 1 also cause AD and are responsible for the majority of familial early-onset cases.
Inflammation:
The exact role of inflammation in the pathogenesis of AD is still controversial. Although some studies have been able to demonstrate the presence of activated microglia (a marker of the brain's immune response) in patients with probable AD, a number of prospective clinical trials evaluating the use of drugs targeting various aspects of the immune system such as prednisone, hydroxychloroquine, and selective COX-2 inhibitors have been able to demonstrate only marginal benefits at best.
While some studies have suggested a neuroprotective role for nonsteroidal anti-inflammatory drugs,(36) a recent large study of 351 patients revealed that these medications did not slow progression and cognitive decline in established mild-to-moderate Alzheimer's disease.   

SIGNS AND SYMPTOMS:
 AD is a progressive dementia with memory loss as the major clinical manifestation. Although short-term memory impairment is often the manifesting symptom, remote memory loss also appears to be affected over time. Another important feature of AD is the disturbance of language. Initially, AD patients may search for words when naming objects or while engaged in a simple conversation. But with progression of the disease, the language difficulties evolve into a communication breakdown as the patient struggles with a markedly limited vocabulary, nominal aphasia, and defects in verbal comprehension.
Other cortical signs and symptoms such as apraxia, acalculia, and visuospatial dysfunction may become apparent over the course of the disease. With the development of apraxia, patients lose the ability to carry out such simple tasks as combing their hair or turning on a water faucet. Acalculia may become evident when the patient is no longer able to maintain a checkbook or household accounts. Visuospatial abnormalities can also be seen as patients become disoriented with their body position in space.

TREATMENT:
The major issues in treating AD are the improvement of memory and cognition and the delay of disease progression. At present there are no proven medications that cure or slow progression in Alzheimer's disease. Temporary improvements in cognition and behavior can be seen with the two existing drug classes of cholinesterase inhibitors and NMDA receptor antagonists.
The three cholinesterase inhibitors as well as the NMDA receptor antagonist memantine are listed in Table:3. The new patch formulation of rivastigmine (Exelon) allows the convenience of once-daily administration, with a marked decrease in the common GI side effects seen with the cholinesterase inhibitors. Efficacy appears to be similar among the cholinesterase inhibitors. The only reported differences are the dosing schedule and side-effect profile of each individual drug. The second drug class widely used in the treatment of Alzheimer's disease recognizes the increasing role of glutamate overstimulation of NMDA receptors on the surface of neurons. It is believed that this results in long-term excessive calcium influx into the neuron through the NMDA surface channel. By inhibiting this excessive influx, some improvements in cognition as well as behavior have been demonstrated in severe Alzheimer's disease.
Management of Noncognitive Symptoms
Depression is common in patients with AD and may require pharmacologic treatment. Serotonin reuptake inhibitors are relatively well tolerated by patients and are preferred over tricyclic antidepressants, which can often exacerbate the cognitive impairment as a result of its anticholinergic properties. The occurrence of behavioral disturbances such as psychosis and agitation requires an investigation for a correctable underlying cause—such as a urinary tract infection—before a neuroleptic agent should be considered. If there is no external etiology, then the establishment of a quiet, controlled, and familiar environment for the patient can help to decrease confusion and disorientation.Behavioral disturbances in AD may also be treated pharmacologically with both traditional and atypical neuroleptics. Although haloperidol can be effective, the atypical antipsychotics, which include risperidone, quetiapine, and olanzapine, may be better tolerated than traditional agents. There is not enough evidence to support the use of benzodiazepines, lithium, and anticonvulsants for the treatment of psychosis in patients with AD.(37)Special care units within long-term care facilities may be considered because some studies have shown a reduced need for anti-psychotics and physical restraints as well as a decrease in behavioral disturbances in AD patients who reside there. Finally, psychosocial intervention for the caregiver is an integral part of managing patients with AD. Education, support groups, and respite care services are invaluable to family members and friends who provide the primary care for AD patients.
 
Table:3
CLASS OF DRUGDRUGDOSE
ACETYLCHOLINESTERASE INHIBITOR DOSINGDonepezil5 mg once daily, can increase to 10 mg daily after 4-6 wk
Rivastigmine tartratePill: 1.5 mg BID initially, can  increased 12 mg daily
Patch: 4.6 and 9.5 mg patch size daily
Galantamine4 mg BID initially, can  increased up to 24 mg daily
Galantamine ER8 mg daily, can  increased up to 24 mg daily
NMDA RECEPTOR ANTAGONISTSMemantine (Namenda)10 mg BID
 
4.2 PARKINSON’S DISEASE                                                                                       
Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the brain (central nervous system) that often impairs motor skills, speech, and other functions. Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

EPIDEMIOLOGY:        
 According to some sources. Parkinson’s disease is slightly less prevalent in the African-American community. The average crude prevalence is estimated at being from 120-180 out of 100,000 among the Caucasian (white) community. The Parsi community in Mumbai, India suffers from particularly high rates of Parkinson's disease. 
SIGN AND SYMPTOMS:  
 Parkinson disease affects movement (motor symptoms). Other typical symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms).    Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individul: Tremor, Rigidity, Akinesia/bradykinesia, Festination, Gait freezing, Dystonia, Hypophonia, Monotonic speech, Festinating speech, Dysphagia, Fatigue (up to 50% of cases), Blinking.(38)
PATHOPHYSIOLOGY:
 

Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure. The symptoms of Parkinson's disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway. The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles—the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.(39) 
Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to neuromelanin in the affected neurons of the substantia nigra. Neuromelanin may be acting as a protective agent. The most likely mechanism is generation of reactive oxygen species.(40) Iron also induces aggregation of synuclein by oxidative mechanisms.(41) Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson's has been generated by introduction of human wild-type alpha-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.(42) 

TREATMENT:
Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, physiotherapy, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.                                    LevodopaThe most widely used form of treatment is L-dopa in various forms. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa) and benserazide/levodopa (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed. There is also Stalevo (Carbidopa, Levodopa and Entacapone).
COMT-Inhibitors                                                                                                                    Tolcapone inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa. However, due to its possible side effects such as liver failure, it is limited in its availability. A similar drug, entacapone has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time.(43) 
Dopamine-agonists                                                                                                                    The dopamine agonists bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and/or insomnia. Several forms of dopamine agonism have been linked with a markedly increased risk of problem gambling. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms. Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and primary caregiver (often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules. Apomorphine is also available in a more acute dose as an autoinjector pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone (an antiemetic). 
MAO-Binhibitors                                                                                                             Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), thereby inhibiting the breakdown of dopamine secreted by the dopaminergic neurons. Metabolites of selegiline include levoamphetamine and levomethamphetamine. This might result in side effects such as insomnia. A side effect of selegiline in conjunction with L-dopa can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa.(44) however subsequent studies have not confirmed this finding.(45) In contrast to non-selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.                                                                                     
Surgery and deep brain stimulation
 Illustration showing an electrode placed deep seated in the brain.                                     Treating Parkinson's disease with surgery was once a common practice, but after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. Deep brain stimulation is presently the most used surgical means of treatment, but other surgical therapies that have shown promise include surgical lesion of the subthalamic nucleus(46) and of the internal segment of the globus pallidus, a procedure known as pallidotomy.(47) 
Neurorehabilitation                                                                                                             There is partial evidence that speech or mobility problems can improve with rehabilitation although studies are still scarce and of low quality.(48)(49)(50)(51) Regular physical exercise and/or therapy can be beneficial to the patient for maintaining and improving mobility, flexibility, strength, gait speed, and quality of life,(50) and speech therapy may improve voice and speech function.(51) One of the most widely practiced treatment for the speech disorders associated with Parkinson's disease is the Lee Silverman Voice Treatment (LSVT). LSVT focuses on increasing vocal loudness.(52) 

5.3 HUNTINGTON'S DISEASE:

Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder(53)characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities. These characteristics vary per individual, physical ones less so, but the differing decline in mental abilities can lead to a number of potential behavioral problems. The disorder itself isn't fatal, but as symptoms progress, complications reducing life expectancy increase.(54) Research of HD has increased greatly in the last few decades, but its exact mechanism is unknown, so symptoms are managed individually.(55) Globally, up to 7 people in 100,000 have the disorder, although there are localized regions with a higher incidence. Onset of physical symptoms occurs gradually and can begin at any age, although it is statistically most common in a person's mid-forties (with a 30 year spread). If onset is before age twenty, the condition is classified as juvenile HD.(56) 
The disorder is named after George Huntington, an American physician who published a remarkably accurate description in 1872.(57) In 1983 a marker for the altered DNA causing the disease was found,(58) followed a decade later by discovery of a single, causal, gene.(59) As it is caused by a single gene, an accurate genetic test for HD was developed; this was one of the first inherited genetic disorders for which such a test was possible. Due to the availability of this test, and similar characteristics with other neurological disorders, the amount of HD research has increased greatly in recent years.(60)

EPIDEMIOLOGY:
As HD is autosomal dominant, and does not usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using genetic haplotypes.(61) Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. Without the test, only individuals displaying physical symptoms or neurologically examined cases were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available and estimates have shown the incidence of HD could be two to three times higher when these results are included.(62) 
The prevalence varies greatly according to geographical location, both by ethnicity and local migration; The highest occurrence is in peoples of Western Europe descent, averaging between 3 to 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 of Asian and African descent. Some localised areas have a much higher prevalence than their geographical average, for example the isolated populations of the Lake Maracaibo region of Venezuela (where the marker for the gene was discovered), have an extremely high prevalence of up to 700 per 100,000,(63) leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local founder effect. 

SIGNS AND SYMPTOMS:
Physical symptoms are usually the first to cause problems and to be noticed, but at this point they are usually accompanied by unrecognized cognitive and psychiatric ones. Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but cognitive and psychiatric symptoms can vary significantly between individuals. 
The most characteristic physical symptoms are jerky, random, and uncontrollable movements called chorea. In a few cases, very slow movement and stiffness (called bradykinesia and dystonia) occur instead, and often become more prominent than the chorea as the disorder progresses. Abnormal movements are initially exhibited as general lack of coordination, an unsteady gait and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal facial expression, and difficulties chewing and swallowing. Eating difficulties commonly cause weight loss and may lead to malnutrition.(64)Associated symptoms involve sleep cycle disturbances, including insomnia and Rapid eye movement sleep alterations.(65)(66) Juvenile HD generally progresses faster, is more likely to exhibit rigidity and bradykinesia, instead of chorea, and commonly includes seizures. 
Select cognitive abilities are impaired progressively. Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.(67) Psychomotor function, controlling muscles, perception and spatial skills, is also affected. As the disease progresses, memory deficits tend to appear. Memory impairments reported range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (Memory of one's life), procedural (Memory of the body of how to perform an activity) and working memory. 
Psychiatric symptoms vary far more than cognitive and physical ones, and may include anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, which can cause, or worsen addictions, including alcoholism and gambling, or hypersexuality.(68)(69) Difficulties in recognizing other people's negative expressions has also been observed. 

PATHOPHYSIOLOGY:
HD is associated with progressive degeneration of neurons in certain regions of the brain and the presence of astrocytes that accumulate due to destruction of nearby neurons (gliosis). These neurodegenerative changes primarily occur within the caudate nuclei and the putamen, substructures of the basal ganglia that are collectively known as the striatum. (The basal ganglia consist of specialized nerve cell clusters deep within the brain that organize motor behavior. Major substructures of the basal ganglia include the caudate nuclei, the putamen, and the globus pallidus as well as other cell groups.) HD is also characterized by associated neuronal degeneration within the temporal and frontal lobes of the cerebral cortex. This part of the brain is responsible for integrating higher mental functioning, movements, and sensations.
The degenerative changes in HD primarily affect certain nerve cells of the striatum known as medium-sized "spiny" neurons, which are named for their size and appearance and project into the globus pallidus and substantia nigra. These highly specialized "spiny" neurons secrete gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits the release of neurotransmitters from other nerve cells. One theory suggests that selective loss of these specialized cells results in decreased inhibition (i.e., increased activity) of the thalamus. Therefore the thalamus increases its output to certain regions of the brain's cerebral cortex. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea.
Some studies demonstrate reduced uptake of the neurotransmitter dopamine within the striatum, potentially playing a role in causing the choreic movements associated with HD. 
Several investigations indicate that impaired energy metabolism (mitochondrial dysfunction) may result in excessive or prolonged activation (excitotoxicity) by neurotransmitters, such as glutamate or N-methyl-D-aspartate (NMDA). This may cause damage to and loss of nerve cells (apoptosis). 
Evidence suggests that the formation of toxic compounds known as oxygen-free radicals may contribute to striatal cell injury. An imbalance between free radical production and elimination results in an increasing accumulation of these toxins in certain tissues. Eventually, this causes damage and impaired functioning of affected cells. Many researchers theorize that free radicals may play some role in the loss of neurons associated with many neurodegenerative diseases. 
In patients with HD, positron emission tomography (PET) scanning has shown decreased glucose and oxygen metabolism within the caudate nuclei early in the course of the disease. These findings occur in patients with other neurodegenerative diseases associated with chorea. This lends support to the theory that disturbances in the metabolism of certain neurotransmitters and heightened sensitivity of particular neuroreceptors may contribute to the symptoms associated with HD.                                 


TREATMENT:
Treatments for cognitive and psychological symptoms include antidepressants and sedatives, and low doses of antipsychotics. There is limited evidence for specific treatments aimed at controlling the chorea and other movement abnormalities, although tetrabenazine has been shown to reduce the severity of the chorea; it was approved in 2008 specifically for this indication. 
Nutrition management is an important part of treatment; most people in the later stages of the disease need more calories than average to maintain body weight.(70) Thickening agent can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a percutaneous endoscopic gastrostomy (i.e., a feeding tube into the stomach) is available when eating becomes too hazardous or uncomfortable. A "stomach PEG" greatly reduces the chances of aspiration of food, which can lead to aspiration pneumonia, and also increases the amount of nutrients and calories that can be ingested, aiding the body's natural defenses.(71)
Although there are relatively few studies of rehabilitation for HD, its general effectiveness when conducted by a team of specialists has been clearly demonstrated in other pathologies such as stroke, or head trauma.(72) As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability.(73) There is some evidence for the usefulness of physical therapy and speech therapy but more rigorous studies are needed for health authorities to endorse them.(74)
Physicians often prescribe various medications to help control emotional and movement problems. 
Antipsychotics (hallucinations, delusions, violent outbursts): haloperidol, chlorpromazine, olanzapine (contraindicated if patient has dystonia) 
Antidepressants (depression, obsessive-compulsive behavior): fluoxetine, sertraline hydrochloride, nortriptyline
Tranquilizers (anxiety, chorea): benzodiazepines, paroxetine, venlafaxin, beta-blockers
Mood-stabilizers (mania, bipolar disorder): lithium, valproate, carbamazepine 
Botulinum toxin (dystonia, jaw clenching)

6. REFERENCES
1.Bertoni FC, Mocchegiani E, Malavolta M., Casoli T,Stefano G, Fattoretti                                              
P. Synaptic and mitochondria phys¬iopathologic changes in the aging nervous system and the role of zinc ion homeostasis. Mech. Ageing Dev. 2006b; 127:590–596.
2.West MJ, Coleman PD, Food DG, Troncoso J Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer’s disease. Lancet 2004; 344: 769–772.
3.Kimble DP,Biological Psychology. Harcourt Brace Publishers, Fort Worth, TX.1992;314-328.
4.Makrides M. Effect of maternal docosahexanoic acid (DHA) supplementation on breast milk composition. European. Jouirnal of Clinical Nutrition 1996;50:352-357.
5.Crawford M. N-6 and n-3 fatty acids during early human development.Journal of Internal Medicine 1989; 225(Suppl 1): 159-169.
6.Stedman's Medical Dictionary,Maryland: Lipponcott, Willimas & Wilkins, Baltimore USA.2000.
7.Perry VH. Altered antigen expression of microglia in the aged rodent CNS. Glia1993;7(1), 60–67.
8.Kari FW. Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J Nutr. Health Aging 1999;3: 92–101.
9.Straub RH. The process of aging changes the interplay of the immune, endocrine and nervous systems. Mech. Age Dev 2001; 122: 1591–1611.
10.Buonomano DV, Merzenich MM. Cortical plasticity: from synapses to maps. Ann. Rev. Neurosci 1998;21:149–186.
11.Geinisman Y, Toledo-Morrell DL, Morrell F, Heller RE. Hippocampal markers of age-related memory dysfunction: behav¬ioural, electrophysiological and morphological perspectives. Prog. Neurobiol.1995; 45:223–252.
12.Dekosky ST, Scheff SW. Synapses loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Ann. Neurol1990; 27:457–464.
13.Bertoni FC, Fattoretti P, Giorgetti B, Grossi Y, Balietti M, Casoli T, Perretta  G. Alterations of the synaptic turnover rate in aging may trigger senile plaque formation and neurodegeneration. Ann. NY Acad Sci 2007;1096: 128–137.
14.Bertoni FC, Fattoretti P, Paoloni R, Caselli U, Galeazzi L, Meier-Ruge W. Synaptic structural dynamics and aging. Gerontology1996; 42: 170–180.
15.Williams JM, Thompson SE, Mason-Parker WC, Abraham WP. Synaptic activity-dependent modulation of mitochondrial gene expression in the rat hippocampus. Mol. Brain Res.1998; 60: 50–56.
16.Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J  Neurotrauma 2000; 17: 843–855.
17.Bertoni FC, Fattoretti P, Casoli T, Neurobiology of the aging brain. In: Conn, M. (Ed.), Handbook of Models for the Study of Human Aging. Elsevier, San Diego, CA,2006a; 485–506.
18.Bertoni FC, Fattoretti P, Casoli T, Spagna C, Meier RW, Ulrich J Morphological plasticity of synaptic mitochon¬dria during aging. Brain Res 1993; 628:193–200.
19.Solmi R, Pallotti F, Rugolo M. Lack of major mitochondrial bioenergetic changes in cultured skin fibroblasts from aged individuals. Biochem. Mol. Biol. Int 1994; 33:477–484.
20.Walter PB, Beckman KB, Ames BN.The role of iron and mitochondria in aging. In: Cadenas, M. Packer, L. (Eds.), Understanding the Process of Aging: The Role of Mitochondria, Free Radicals and Antioxidants. Marcel Dekker, New York.1999; 203–227.
21.Bertoni FC, Fattoretti P, Paoloni R, Caselli U, Giorgetti B, Solazzi M. Inverse correlation between mitochondrial size and metabolic competence: a quantitative cytochemical study of cyto¬chrome oxidase activity. Naturwissenschaften 2003; 90: 68–71.
22.Bertoni FC, Fattoretti P, Giorgetti B, Spazzafumo L, Solazzi M, Balietti M. Age-related decline in metabolic competence of small and medium-sized synaptic mitochondria. Naturwissenschaften 2005; 92, 82–85.
23.Wong RM. Cytochrome oxidase:an endogeneous metabolic marker for neuronal activity. Trends Neurosci 1989; 12: 94–101.
24.Bertoni FC, Fattoretti P, Casoli T, Stefano G, Solazzi M, Meier RW. Quantitative cytochemical mapping of mitochondrial enzymes in rat cerebella. Micron 2001; 32: 405–410.
25.Frederickson CJ, Suh SW, Silva D, Thompson RB. Impor¬tance of zinc in the central nervous system: the zinc containing neuron. J Nutrition 2000; 130:1471S–1481S.
26.Adlard PA, Bush AI. Metals and Alzheimer’s disease. J Alzheimers. Dis 2006;10: 145–163.
27.Frazzini V, Rockabrand E, Mocchegiani E, Sensi SL. Oxidative stress and brain aging: is zinc the link? Biogerontology 2006;7: 307–314.
28.Bertoni FC, Mocchegiani E, Malavolta M, Casoli T, Fattoretti P.Synaptic and mitochondria phys¬iopathologic changes in the aging nervous system and the role of zinc ion homeostasis. Mech. Ageing Dev2006b; 127: 590–596.
29.Sheline CT, Beherens MM, Choi DV. Zinc-induced corti¬cal neuronal death: contribution of energy failure attributable to loss of NAD+ and inhibition of glycolysis. J Neurosci 2006; 20: 3139– 3146.
30.Dineley KE, Votyakova TV, Reynolds IJ. Zinc inhibition of cellular energy production: implications for mitochondria and neuro¬degeneration. J Neurochem 2003; 85: 563–570.
31.Brookmeyer R, Gray S, Kawas C.Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88 (9): 1337–42.
32.Brookmeyer R, Johnson E, Ziegler GK, Arrighi MH. Forecasting the global burden of Alzheimer’s disease. Alzheimer's and Dementia 2007;3(3): 186–91. 
33.Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88 (9): 1337–42.
34.Canadian Study of Health and Aging Working Group. Canadian study of health and aging: Study methods and prevalence of dementia. Can Med Assoc J 1994; 150:899-913. 
35.Morris JC. The epidemiology of dementia. Handbook of Dementing Illneses. New York: 1994;23-69.
36.Terry RD, Katzman R, Bick KL. Alzheimer Disease. Clinical genetics of familial Alzheimer's disease. Am J Public Health New York: 1994;65-74. 
37.Ziegler GK. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med  2001; 345:1515-1521. 
38.Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol. Neurosurg Psychiatry 2008;79 (4): 368–76. 
39.Jenner P.Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov. Disord 1998;13 Suppl 1: 24–34.
40.Deuschl G. Goddemeier C. Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects. J Neurol. Neurosurg. Psychiatr. 1998; 64 (3): 320–4. 
41.Andersen DJ. Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?. Aging Cell 2002; 1 (1): 17–21. 
42.Masliah E, Rockenstein E, Veinbergs I. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287 (5456): 2000;1265–9. 
43.Cilia R. Long-term Efficacy of Entacapone in Patients with Parkinson's Disease and Motor Fluctuations - A Six-Year Clinical Follow-Up study. J Neurol. Neurosurg. Psychiatr 2006;314-326.
44.Thorogood M, Armstrong B, Nichols T, Hollowell J. Mortality in people taking selegiline: observational study. BMJ 1998; 317 (7153): 252–4. 
45.Marras C, McDermott M, Rochon P, Tanner C, Naglie G, Rudolph A, Lang A Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology 2005;64 (1): 87–93.
46.Guridi J, Obeso JA .The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma. Brain 2001; 124 (Pt 1): 5–19.
47.Fukuda M, Kameyama S, Yoshino M, Tanaka R, Narabayashi H .Neuropsychological outcome following pallidotomy and thalamotomy for Parkinson's disease. Stereotactic and functional neurosurgery 2000; 74 (1): 11–20. 
48.Deane KH, Jones D, Playford ED, Ben SY, Clarke CE. Physiotherapy for patients with Parkinson's Disease: a comparison of techniques. Cochrane Database Syst Rev 2001; (3): CD002817. 
49.Deane KH, Whurr R, Playford ED, Ben SY, Clarke CE.A comparison of speech and language therapy techniques for dysarthria in Parkinson's disease. Cochrane Database Syst Rev 2001; (2):CD002814.
50.Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL. The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis. Mov. Disord.2008; 23 (5): 631–40.
51. Schulz GM. The effects of speech therapy and pharmacological treatments on voice and speech in Parkinson s disease: a review of the literature. Curr. Med. Chem 2002; 9 (14): 1359–66.
52.Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG. The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders. Semin Speech Lang 2006;27 (4): 283–99. 
53.Imarisio S, Carmichael J, Korolchuk V, et al .Huntington's disease: from pathology and genetics to potential therapies. Biochem. J 2008;412 (2): 191–209. 
54.Gillian B, Peter H,Lesley J. Huntington's Disease - Third Edition. Oxford: Oxford University Press. ISBN 0-19-851060-8.2002.
55. Bonelli RM, Wenning GK. Pharmacological management of Huntington's disease: An evidence-based review. Curr. Pharm. Des.2006; 12 (21): 2701–20.
56.Nance MA, Myers RH. Juvenile onset Huntington's disease--clinical and research perspectives. Ment Retard Dev Disabil Res Rev 2001; 7 (3): 153–7.
57. Huntington G. On Chorea. Medical and Surgical Reporter of Philadelphia 1872; 26 (15): 317–321.
58. Gusella JF, Wexler NS, Conneally PM. A polymorphic DNA marker genetically linked to Huntington's disease.1983; 306 (5940): 234–8.
59.Macdonald MA. Novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 72 (6)1993: 971–83.
60. Walker FO. Huntington's disease. Lancet 2007;369 (9557): 218–28. 
61.Squitieri F, Andrew SE, Goldberg YP.DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum. Mol. Genet.1994; 3(12): 2103–14.
62.Almqvist EW, Elterman DS, MacLeod PM, Hayden MR. High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin. Genet 2001; 60 (3): 198–205. 
63.Avila GR. Medical and Social Aspects of Huntington's chorea in the state of Zulia, Venezuela. Advances in Neurology.1973; 1: 261–6.  
64.Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN. Energy balance in early-stage Huntington disease. Am. J. Clin. Nutr.2005; 81 (6): 1335–41. 
65.Morton AJ, Wood NI, Hastings MH. Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease. J  Neurosci 2005; 25 (1): 157–63.
66.Arnulf I, Nielsen J, Lohmann E. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol 2008; 65 (4): 482–488. 
67.Montoya A, Price BH, Menear M, Lepage M.  Brain imaging and cognitive dysfunctions in Huntington's disease. J Psychiatry Neurosci 2006; 31 (1): 21–9. 
68.Sandyk RL. Tryptophan in neuropsychiatric disorders: A review. Int. J. Neurosci 1992; 67 (1-4): 127–44. 
69.Van DE, Kingma EM, Mast RC. Psychopathology in verified Huntington's disease gene carriers. J Neuropsychiatry Clin Neurosci 2007; 19 (4): 441–8.
70.Kuliev A, Verlinsky Y. Preimplantation diagnosis: A realistic option for assisted reproduction and genetic practice. Curr Opin Obstet Gynecol 2005; 17 (2): 179–83. 
71.Panagiotakis PH, DiSario JA, Hilden K, Ogara M, Fang JC. DPEJ tube placement prevents aspiration pneumonia in high-risk patients. Nutr Clin Pract 2008;23 (2): 172–5. 
72.Turner SL, Disler PB, Nair A, Wade DT. Multi-disciplinary rehabilitation for acquired brain injury in adults of working age. Cochrane Database Syst Rev 2005; (3): CD004170. 
73.Zinzi P, Salmaso D, Grandis DR.Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study. Clin Rehabil 2007; 21 (7): 603–13.
74.Bilney B, Morris ME, Perry A. Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington's disease: a systematic review. Neurorehabil Neural Repair 2003; 17 (1): 12–24.


Previous Page Next Page

People Searching On This Page:
  • addictions rehabilitation medicine medical hospital loc:IN
  • understanding the endocrine sytem illneses
  • Baby zygote Mather rs 1400 Hopstal
  • parts of the brain and their functions worksheet
  • hippocampus
  • the illustration of a brain nervous system
  • nervous system brain diagram
  • vernix cerebral
  • central nervous system brain diagram
  • limbic system
  • brain anatomy inc striatum
  • nervous system brain
  • Brain with no division genisus
  • brain structures and functions
  • brain structures and functions primitive

Related Pages


Mechanism of Ischemic brain injury

Mechanism of Ischemic brain injury

Articles | Pharmacology | Central Nervous System
Date:
30-Apr-2011  Views: 3092

Brain requires a continuous and steady flow of glucose and oxygen to undergo oxidative phosphorylation for energy production because brain has no stor ...
Risk Factors  of Ischemic Brain Injury

Risk Factors of Ischemic Brain Injury

Articles | Pharmacology | Central Nervous System
Date:
30-Apr-2011  Views: 2461

Risk Factors That Can Be TreatedRisk Factors That Cannot Be ChangedContributing Risk Factors ...
Introduction of Ischemic Brain Injury

Introduction of Ischemic Brain Injury

Articles | Pharmacology | Central Nervous System
Date:
30-Apr-2011  Views: 2527

Stroke is caused by an interruption of the blood supply to a part of brain by thrombus or embolus occlusion or hemorrhage due to bursting of blood ves ...
A Review On Mechanism Of Ischemic Brain Injury

A Review On Mechanism Of Ischemic Brain Injury

Articles
Date:
22-Jun-2010  Views: 12168

Stroke is caused by an interruption of the blood supply to a part of brain by thrombus or embolus occlusion or hemorrhage due to bursting of blood ves ...
Potential  Targets in the Treatment of Brain Stroke

Potential Targets in the Treatment of Brain Stroke

Articles
Date:
15-Jun-2010  Views: 3087

The blood supply to the forebrain is derived from the two internal carotid arteries & the basilar artery. Their branches form anastomosis at the base ...
Post Your Comments (No Login Require)
Name : (required)
Email : (required)
Website :

Comment : (required)

35  + 6 =     
Comments
Nancy Falhoven  |  21-Apr-2019 13:11:14 IST
Hi

My name is Nancy Falhoven, you remember me, it may have been a while since we met,
we met in a cafe, I enjoyed talking whit you about motors, and I would like to see you again.
I didn't dare ask for your telephone number. but I can remember that you had talked about your website.
so I thought why not just send you an email through your website, if you can not remember who I am
i have photo of myself http://bit.ly/FotoNancyFalhoven i hope you can remember me now, hihihihi

i hope to see you again
xxx
Nancy Falhoven
People Searched About:
Addictions Rehabilitation Medicine Medical Hospital Loc:IN   |   Understanding The Endocrine Sytem Illneses   |   Baby Zygote Mather Rs 1400 Hopstal   |   Parts Of The Brain And Their Functions Worksheet   |   Hippocampus   |   The Illustration Of A Brain Nervous System   |   Nervous System Brain Diagram   |   Vernix Cerebral   |   Brain With No Division Genisus   |   Brain Structures And Functions   |   Brain Structures And Functions Primitive   |   Image   |   Brain Structure And Function   |   Structure Of Hand Brain In Central Nevious Sytem   |   Brain Damage And Central Nervous System In Regards To Dyslexia   |   Email Insula.It Loc:IN   |   Brain Structures And Functions Diagram   |   Email Integrativa.Com.Br Loc:IN   |   Brain Structure Diagram   |   Organ Development By Stages   |   Embryonic Closure   |  
Google : 2334 times | Yahoo : 34 times | Bing : 429 times |